Fisher, M. What We Should All Know About HIV
& AIDS.
Fisher, M. What We Should All Know About HIV & AIDS. 1995 1995, 2000.
Gay Men's Health Crisis. Treatment issues: second survey of physicians' treatment practice. Gay Men's Health Crisis. Treatment issues: second survey of physicians' treatment practice. GMHC Treatment Issues. 1997; 12(1)
Effects of glutamine-supplemented diets on immunology of the gut. Alverdy JC. JPEN J Parenter Enteral Nutr. 1990 Jul; 14(4 Suppl):109S-13S. Recent research developments have identified the gastrointestinal tract as the most metabolically active organ after surgical stress. In addition to fulfilling its role as an organ of digestion and absorption, the gut must maintain immunologic function in order to protect the host from invading pathogens. Central to the function of the intestinal immune system is the expression of secretory IgA, the most abundant immunoglobulin in external secretions. The synthesis and expression of IgA in secretions appear to be sensitive to dietary alteration and may be impaired after surgical stress. Data are presented suggesting that maintenance of gut mass and barrier function to bacteria via dietary manipulation may be essential to ensure host survival during critical illness
The AIDS incubation period in the U.K. estimated from a national register of HIV seroconverters. Anon, U.K.Register of HIV Seroconverters Steering Committee. AIDS. 1998 Apr 16; 12(6):659-67.
The AIDS incubation period in the U.K. estimated from a national register of HIV seroconverters. Anon. U K Register of HIV Seroconverters Steering Committee AIDS. 1998 Apr 16; 12(6):659-67.
The Durban Declaration. Nov 16; 408(6810): 286. Anon. Nature. 2000 Jul 6; 406(6791):15-6.
Markedly disturbed glutathione redox status in CD45RA+CD4+ lymphocytes in human immunodeficiency virus type 1 infection is associated with selective depletion of this lymphocyte subset. Aukrust P, Svardal AM, Muller F, et al. Blood. 1996 Oct 1; 88(7):2626-33. We investigated the percentage of CD45RA+ and CD45RO+ T cells in peripheral blood and the intracellular glutathione redox balance in these lymphocyte subsets in patients with human immunodeficiency virus type 1 (HIV-1) infection and healthy controls. In HIV-1-infected patients there was a preferential depletion of CD45RA+CD4+ cells, which was most pronounced in symptomatic patients. In CD4+ lymphocytes from HIV-1-infected patients the glutathione abnormalities were clearly most pronounced in the CD45RA+ subset with a marked increase in level of oxidized glutathione and decreased ratio of reduced to total glutathione as the major characteristics. These abnormalities were shown in CD45RA+ CD4+ lymphocytes from both symptomatic and asymptomatic patients, whereas similar abnormalities in CD45RO+CD4+ cells were found only in symptomatic patients. The glutathione abnormalities in CD45RA+CD4+ lymphocytes were significantly correlated with low numbers of total CD4+ lymphocytes, decreased proportion of CD45RA+CD4+ lymphocytes, and raised serum levels of tumor necrosis factor-alpha. In the CD8+ lymphocytes a decrease in both proportion and absolute numbers of CD45RA+ cells was found, with markedly increased level of oxidized glutathione and decreased ratio of reduced to total glutathione in this subset. These findings suggest that glutathione redox disturbances in CD45RA+ T cells may be of pathogenic importance for the preferential depletion of this subset considered to represent naive T cells, during HIV-1 infection
Interim Dietary Recommendations to Maintain Adequate Blood Nutrient Levels in Early HIV-1 Infection. Baum MK. 2004; Abstract POB-3675
Preventive actions of a synthetic antioxidant in a novel animal model of AIDS dementia. Bjugstad KB, Flitter WD, Garland WA, et al. Brain Res. 1998 Jun 8; 795(1-2):349-57. Accumulating evidence indicates that the mechanism for causing AIDS dementia complex (ADC) involves the release of damaging inflammatory-related agents by HIV-infected microglia in the brain resulting in CNS oxidative damage. One such agent, tumor necrosis factor alpha (TNF-alpha) is consistently elevated in the brains of ADC patients compared to non-demented HIV patients. To model this aspect of ADC in rats, chronic ventricular infusions of TNF-alpha were given and found to induce several aspects of ADC, including weight loss, learning/memory impairment, enlarged lateral ventricles, and increased apoptosis. Concurrent oral treatment with the antioxidant CPI-1189 prevented all of these TNF-alpha induced effects. The results support TNF-alpha as a key toxic agent in ADC and provide the first in vivo evidence that chronic treatment with a synthetic antioxidant may protect HIV-infected patients against ADC. Our findings may also have implications in other neurological diseases where brain TNF-alpha levels are elevated and inflammation/oxidative stress is suspected to be a contributing cause, such as Alzheimer's disease and Parkinson's disease
[Clinical immunopharmacology of RU 41740]. Boissier MC. Presse Med. 1988 Jul 27; 17(28):1438-40. The clinical immunopharmacology of RU 41740 was studied in man by means of double-blind, drug versus placebo trials. When the compound was administered concomitantly with an anti-influenza vaccine, the anti-influenza antibody titers were higher than in the group which received a placebo. RU 41740 increased delayed hypersensitivity as demonstrated in vitro by lymphocyte proliferation tests in treated subjects and in vivo by cutaneous reactions in patients with malignant diseases. The drug was also found to stimulate phogocytosis in patients with chronic bronchitis. These studies show that RU 41740 has a non-specific enhancing effect on humoral and cellular immune responses and on phagocytic functions
Plant sterols and sterolins: a review of their immune-modulating properties. Bouic PJ, Lamprecht JH. Altern Med Rev. 1999 Jun; 4(3):170-7. Beta-sitosterol (BSS) and its glycoside (BSSG) are sterol molecules which are synthesized by plants. When humans eat plant foods phytosterols are ingested, and are found in the serum and tissues of healthy individuals, but at concentrations orders of magnitude lower than endogenous cholesterol. Epidemiological studies have correlated a reduced risk of numerous diseases with a diet high in fruits and vegetables, and have concluded that specific molecules, including b-carotene, tocopherols, vitamin C, and flavonoids, confer some of this protective benefit. However, these epidemiologic studies have not examined the potential effect that phytosterols ingested with fruits and vegetables might have on disease risk reduction. In animals, BSS and BSSG have been shown to exhibit anti-inflammatory, anti-neoplastic, anti-pyretic, and immune-modulating activity. A proprietary BSS:BSSG mixture has demonstrated promising results in a number of studies, including in vitro studies, animal models, and human clinical trials. This phytosterol complex seems to target specific T-helper lymphocytes, the Th1 and Th2 cells, helping normalize their functioning and resulting in improved T-lymphocyte and natural killer cell activity. A dampening effect on overactive antibody responses has also been seen, as well as normalization of the DHEA:cortisol ratio. The re-establishment of these immune parameters may be of help in numerous disease processes relating to chronic immune-mediated abnormalities, including chronic viral infections, tuberculosis, rheumatoid arthritis, allergies, cancer, and auto-immune diseases
Improvement of immune functions in HIV infection by sulfur supplementation: two randomized trials. Breitkreutz R, Pittack N, Nebe CT, et al. J Mol Med. 2000; 78(1):55-62. To determine the therapeutic effect of sulfur amino acid supplementation in HIV infection we randomized 40 patients with antiretroviral therapy (ART; study 1) and 29 patients without ART (study 2) to treatment for 7 months with N-acetyl-cysteine or placebo at an individually adjusted dose according to a defined scheme. The main outcome measures were the change in immunological parameters including natural killer (NK) cell and T cell functions and the viral load. Both studies showed consistently that N-acetyl-cysteine causes a marked increase in immunological functions and plasma albumin concentrations. The effect of N-acetyl-cysteine on the viral load, in contrast, was not consistent and may warrant further studies. Our findings suggest that the impairment of immunological functions in HIV+ patients results at least partly from cysteine deficiency. Because immune reconstitution is a widely accepted aim of HIV treatment, N-acetyl-cysteine treatment may be recommended for patients with and without ART. Our previous report on the massive loss of sulfur in HIV-infected subjects and the present demonstration of the immunoreconstituting effect of cysteine supplementation indicate that the HIV-induced cysteine depletion is a novel mechanism by which a virus destroys the immune defense of the host and escapes immune elimination
A pilot study of diethyldithiocarbamate in patients with acquired immune deficiency syndrome (AIDS) and the AIDS-related complex. Brewton GW, Hersh EM, Rios A, et al. Life Sci. 1989; 45(26):2509-20. We investigated the use of diethyldithiocarbamate (DTC, or Imuthiolr, Merieux Institute) as a therapeutic agent in patients with Acquired Immune Deficiency Syndrome (AIDS) and AIDS-Related Complex (ARC). Patients were prospectively stratified and randomized to receive DTC 200 mg/m2 intravenously weekly for 16 weeks or no therapy, followed by crossover to the opposite arm for an equal period. Forty-four patients were entered and forty were evaluable. There was a statistically significant decrease in symptoms in the DTC treated patients compared to the controls (p = .002). There was a significant improvement in lymphadenopathy in the treated patients compared to the controls (p = .005). One patient showed disappearance of splenomegaly, one clearing of antifungal agent-resistant perianal moniliasis, and one clearing of hairy leukoplakia. No significant differences in progression were noted. No changes were seen in any of the immunological parameters measured. There was no significant toxicity. Because of the changes in symptoms and in lymphadenopathy, we suggest that further study of DTC, both alone and in combination with other agents, may be indicated
Guidelines for the treatment of HIV-infected adults with antiretroviral therapy. British HIV Association. 2000; 1:76-101.
Complementary therapies in HIV disease. Complimentary therapies with reported antiretroviral activity. Bryson YJ. 1996.Sep;(4):3.
Antiretroviral therapy for HIV infection in 1998: updated recommendations of the International AIDS Society-USA Panel. Carpenter CC, Fischl MA, Hammer SM, et al. JAMA. 1998 Jul 1; 280(1):78-86. OBJECTIVE: To provide recommendations for antiretroviral therapy based on information available in mid-1998. PARTICIPANTS: An international panel of physicians with expertise in antiretroviral research and care of patients with human immunodeficiency virus (HIV) infection, first convened by the International AIDS Society-USA in December 1995. EVIDENCE: The panel reviewed available clinical and basic science study results (including phase 3 controlled trials; clinical, virologic, and immunologic end point data; data presented at research conferences; and studies of HIV pathophysiology); opinions of panel members were also considered. Recommendations were limited to drugs available in mid-1998. CONSENSUS PROCESS: Panel members monitor new clinical research reports and interim results. The full panel meets regularly to discuss how the new information may change treatment recommendations. Updated recommendations are developed through consensus of the entire panel at each stage of development. CONCLUSIONS: Accumulating data from clinical and pathogenesis studies continue to support early institution of potent antiretroviral therapy in patients with HIV infection. A variety of combination regimens show potency, expanding choices for initial regimens for individual patients. Plasma HIV RNA assays with increased sensitivity are important in monitoring therapeutic response; however, more data are needed to determine precisely the HIV RNA levels that define treatment failure. Long-term adverse drug effects are beginning to emerge, requiring ongoing attention. Some issues regarding optimal long-term approaches to antiretroviral management are unresolved. The increased complexity in HIV management requires ongoing monitoring of new data for optimal treatment of HIV infection
Antiretroviral therapy in adults: updated recommendations of the International AIDS Society-USA Panel. Carpenter CC, Cooper DA, Fischl MA, et al. JAMA. 2000 Jan 19; 283(3):381-90. OBJECTIVE: To update recommendations for antiretroviral therapy for adult human immunodeficiency virus type 1 (HIV-1) infection, based on new information and drugs that are available. PARTICIPANTS: A 17-member international physician panel with antiretroviral research and HIV patient care experience initially convened by the International AIDS Society-USA in December 1995. EVIDENCE: Available clinical and basic science data including phase 3 controlled trials; data on clinical, virologic, and immunologic end points; research conference reports; HIV pathogenesis data; and panel expert opinion. Recommendations were limited to therapies available (US Food and Drug Administration approved) in 1999. CONSENSUS PROCESS: The panel assesses new research reports and interim results and regularly meets to consider how the new data affect therapy recommendations. Recommendations are updated via full-panel consensus. Guidelines are presented as recommendations if the supporting evidence warrants routine use in the particular situation and as considerations if data are preliminary or incomplete but suggestive. CONCLUSIONS: The availability of new antiretroviral drugs has expanded treatment choices. The importance of adherence, emerging long-term complications of therapy, recognition and management of antiretroviral failure, and new monitoring tools are addressed. Optimal care requires individualized management and ongoing attention to relevant scientific and clinical information in the field
Pneumocystis pneumonia-Los Angeles. CDC. 1981 30:250-2.
Notice to Readers: CDC statement on study results of products containing nonoxynol-9. CDC. 2000.Aug.11 49 (31):717-8.
Biochemistry and pharmacology of S-adenosyl-L-methionine and rationale for its use in liver disease. Chawla RK, Bonkovsky HL, Galambos JT. Drugs. 1990; 40 Suppl 3:98-110. The major biological functions of S-adenosyl-L-methionine (SAMe) include methylation of various molecules (transmethylation) and synthesis of cysteine (trans-sulphuration). A stable double salt of SAMe has been found to be effective in intrahepatic cholestasis. The mechanism of its therapeutic effect is not fully understood but presumably involves methylation of phospholipids. Methylation of plasma membrane lipids may affect membrane fluidity and viscosity, which modulate the activities of a number of membrane-associated enzymes, for example, the activity of enzymes involved in Na+/Ca++ exchange (e.g. sarcolemmal vesicles), Na+/K+ adenosine triphosphatase (ATPase) [e.g. hepatocyte plasma membranes], and Na+/H+ exchange (e.g. plasma membranes of colonic cells). Recently, patients with cirrhosis were shown to have an acquired metabolic block in the hepatic conversion of methionine to SAMe. These patients, when administered conventional elemental diets, develop abnormally low plasma concentrations of cysteine and choline, 2 nonessential nutrients present in low concentrations in most elemental diets. These low concentrations probably reflect systemic deficiencies attributable to reduced endogenous syntheses of cysteine and choline caused by limited availability of hepatic SAMe. Such cirrhotic patients are often in negative nitrogen balance and have abnormal hepatic functions, which are corrected by cysteine and choline supplements. Noncirrhotic patients on parenteral elemental diets also become deficient in cysteine and choline. Consequently, these patients may require SAMe as an essential nutrient to normalise their overall hepatic transmethylation and trans-sulphuration activities
Changes in cortisol/DHEA ratio in HIV-infected men are related to immunological and metabolic perturbations leading to malnutrition and lipodystrophy. Christeff N, Nunez EA, Gougeon ML. Ann N Y Acad Sci. 2000; 917:962-70. HIV-1 infection is associated with immune deficiency and metabolic perturbations leading to malnutrition and lipodystrophy. Because immune response and metabolic perturbations (protein and lipid metabolism) are partly regulated by glucocorticoids and DHEA, we determined serum cortisol and DHEA concentrations, and the cortisol/DHEA ratio in HIV-positive men, either untreated or receiving various antiretroviral treatments (ART), including highly active antiretroviral therapy (HAART). Cortisol levels were found increased in all patients, whatever the stage of the disease and independently of the ART treatment. In contrast, serum DHEA was elevated in the asymptomatic stage, and it was below normal values in AIDS patients, either untreated or mono-ART-treated. The DHEA level was low in HAART-treated patients with lipodystrophy (LD+) and highly increased in HAART-treated patients without lipodystrophy (LD-). Consequently, the cortisol/DHEA ratio was similar to controls in asymptomatic untreated or mono-ART-treated patients, but increased in AIDS patients. Interestingly, this ratio was increased in LD+ HAART-treated men, but normalized in LD- HAART-treated patients. Changes in the cortisol/DHEA ratio were negatively correlated with the in vivo CD4 T-cell counts, with the malnutrition markers, such as body-cell mass and fat mass, and with the increased circulating lipids (cholesterol, triglycerides, and apolipoprotein B) associated to the lipodystrophy syndrome. Our observations show that the cortisol/DHEA ratio is dramatically altered in HIV-infected men, particularly during the syndromes of malnutrition and lipodystrophy, and this ratio remains elevated whatever the antiretroviral treatment, including HAART. These findings have practical clinical implications, since manipulation of this ratio could prevent metabolic (protein and lipid) perturbations
Effect of L-carnitine treatment in vivo on apoptosis and ceramide generation in peripheral blood lymphocytes from AIDS patients. Cifone MG, Alesse E, Di Marzio L, et al. Proc Assoc Am Physicians. 1997 Mar; 109(2):146-53. Lymphocyte apoptosis in HIV-infected individuals may play a role in T-cell depletion and therefore favor progression to AIDS. In this study, we examined the effects of a short-term (5-day) intravenous treatment with L-carnitine (6 g/day) on apoptosis of CD4 and CD8 cells from 10 AIDS patients. L-carnitine administration has been shown to induce a strong reduction in the percentage of both CD4 and CD8 cells undergoing apoptosis. Interestingly, the L-carnitine treatment, which did not show relevant side effects in four patients, led to a strong and significant reduction of peripheral blood mononuclear cell-associated ceramide, an intracellular messenger of apoptosis, that positively correlated with the decrease of apoptotic CD4- and CD8-positive cells. These results suggest that L-carnitine could be an effective antiapoptotic drug in the treatment of AIDS patients
Immunoendocrinologic abnormalities in human immunodeficiency virus infection. Clerici M, Galli M, Bosis S, et al. Ann N Y Acad Sci. 2000; 917:956-61. Alterations in the production of adrenal steroids and a complex pattern of dysregulation in cytokine profiles accompany the progression of HIV infection. Cortisol levels increase in HIV infection, while those of dehydroepiandrosterone (DHEA), a physiologic antagonist of the immunoregulatory activities of cortisol, decrease. A shift from type-1 to type-2 cytokine production is also detected in most patients during disease progression. This shift is summarized as a defective production of interferon gamma (IFN gamma), interleukin-2 (IL), and IL-12 accompained by increased production of IL-4, IL-5, IL-6, and IL-10. IFN gamma and IL-2 are suppressed, while the generation of IL-4 is stimulated by cortisol and pharmacological doses of glucocorticoids (GC). GC and IL-4 stimulate the differentiation of B lymphocytes into IgE-producing plasma cells, the concentration of which augments in HIV infection. Finally, GC induces programmed cell death (PCD) in a variety of different cells, including mature T lymphocytes. Because (1) TH1 but not TH2 undergo rapid Fas-mediated PCD upon antigen-stimulation, and (2) TH2 clones preferentially survive in vitro cell cultures, the progressive shift from type-1 to type-2 cytokine production observed in HIV infection could be at least partially provoked by the increase in the production of cortisol and the reduction of DHEA. Progression of HIV infection to AIDS can be controlled by highly active antiretroviral therapy (HAART); HAART drastically reduces HIV plasma viremia, but is less effective in immune reconstitution. Additionally HAART is associated in a sizable portion of patients by complex lypodistropyc phenomena that often involve the endocrine system
Shots in the Dark: The Wayward Search for an AIDS Vaccine. Cohen J. 2001;
Beta-carotene in HIV infection. Coodley GO, Nelson HD, Loveless MO, et al. J Acquir Immune Defic Syndr. 1993 Mar; 6(3):272-6. beta-Carotene has been reported to have an immunostimulatory effect. Recent studies suggest that beta-carotene supplementation can increase CD4 counts in HIV-infected patients. Our double-blind, placebo-controlled clinical trial was designed to test the efficacy of beta-carotene in raising CD4 counts in HIV-infected patients. Twenty-one HIV-seropositive patients were randomized to receive either beta-carotene, 180 mg/day or placebo for 4 weeks, and then crossed over to receive the alternative treatment for the following 4 weeks. beta-Carotene resulted in a statistically significant increase in total WBC count (p = 0.01), % change in CD4 count (p = 0.02), and % change in CD4/CD8 ratios (p = 0.02) compared to placebo. The absolute CD4 count, absolute CD4/CD8 ratio, and total and B-lymphocytes all increased on carotene and fell during placebo, but these differences did not reach statistical significance. No toxicity was observed on either treatment. beta-Carotene appears to have an immunostimulatory effect in HIV-infected patients. Further studies are needed to demonstrate whether beta-carotene has a role as adjunct therapy in treatment of HIV-infected patients
Some aspects of the natural history of HIV infection. Coutinho RA. Trop Med Int Health. 2000 Jul; 5(7):A22-A25. Studying factors influencing the length of the incubation period of HIV/AIDS is important to our understanding of the natural history of the disease and for the decision when to start with anti-retroviral therapy. In a multicentre study among HIV-positive homosexual men with a known date of seroconversion, we found that the median survival time after HIV infection was 12.1 years. Age is an important determinant of the survival: the older the shorter the incubation period and survival. Gender does not seem to play a role, but women appear to have higher CD4 counts than men at seroconversion, AIDS and death. HIV-positive drug users often die before they 'reach' AIDS often from HIV-related causes e.g. bacterial infections. In a multicentre study we found that such pre-AIDS mortality is now also found among homosexual men and haemophiliacs but at a much lower level. Most studies show that HIV subtype does not influence the incubation period. On the other hand genetic factors do play an important role
Therapeutic interventions in HIV infection - a critical view. Darbyshire J. Trop Med Int Health. 2000 Jul; 5(7):A26-A31. The introduction of highly effective combination regimens of antiretroviral drugs has led in recent years to substantial improvements in morbidity and mortality. As yet immune-based therapies have had little if any impact. However it is clear that eradication of HIV is not achievable with existing anti-HIV drugs and in spite of the major advances there remain many challenges in the clinical management of HIV-infected individuals. These benefits are unlikely to be extended to resource poor countries in the foreseeable future. The barriers are primarily but not only the costs. In resource-rich countries there are concerns about long term toxicities and many people have already exhausted all of the current therapeutic options. There is an urgent need for new drugs, ideally attacking new targets or with no cross resistance to existing drugs, and which are well tolerated and safe, easy to take and cheap. Many important questions still remain unanswered, in particular when to start antiretroviral therapy
High dose L-carnitine improves immunologic and metabolic parameters in AIDS patients. De Simone C, Tzantzoglou S, Famularo G, et al. Immunopharmacol Immunotoxicol. 1993 Jan; 15(1):1-12. Several reports indicate that systemic carnitine deficiency could occur in acquired immunodeficiency disease syndrome (AIDS), and that primary and secondary carnitine deficiency leads to critical metabolic dysfunctions. L-carnitine supplementation to peripheral blood mononuclear cells (PBMCs) of AIDS patients resulted in significant enhancement of the phytohemagglutinin (PHA)-driven proliferative response. High dose L-carnitine administration (6 gr per day for two weeks) to AIDS patients treated with zidovudine also led to increased PBMCs proliferation and reduced blood levels of triglycerides. In addition, a reduction of beta 2-microglobulin serum levels as well as circulating tumor necrosis factor (TNF)-alpha, mostly in patients exhibiting highly elevated levels, were found at the end of the treatment period. Our data suggest that in vivo L-carnitine could prove useful in ameliorating both the immune response and lipid metabolism in patients with AIDS, irrespective of initial serum carnitines levels. The mechanism(s) accounting for the observed results are currently not clear. Further studies are needed to confirm the hypothesis that L-carnitine affects the expression of HIV-induced cytokine
Carnitine depletion in peripheral blood mononuclear cells from patients with AIDS: effect of oral L-carnitine. De Simone C, Famularo G, Tzantzoglou S, et al. AIDS. 1994 May; 8(5):655-60. OBJECTIVE: Reduced levels of serum carnitines (3-hydroxy-4-N-trimethyl-ammonio-butanoate) are found in most patients treated with zidovudine. However, since serum carnitines do not strictly reflect cellular concentrations we examined whether a carnitine depletion could be found in peripheral blood mononuclear cells (PBMC) from AIDS patients with normal serum carnitine levels. In addition, we explored whether it was possible to relate the host's immunoreactivity to the content of carnitine in PBMC and whether carnitine levels can be corrected by oral supplementation of L-carnitine. DESIGN: Immunopharmacologic study. METHODS: Twenty male patients with advanced AIDS (Centers for Disease Control and Prevention stage IVCI) and normal serum levels of carnitines were enrolled. Patients were randomly assigned to receive either L-carnitine (6 g/day) or placebo for 2 weeks. At baseline and at the end of the trial, we measured carnitines in both sera and PBMC, serum triglycerides, CD4 cell counts, and the frequency of cells entering the S and G2-M phases of cell cycle following mitogen stimulation. RESULTS: Concentrations of total carnitine in PBMC from AIDS patients was lower than in healthy controls. A significant trend towards the restoration of appropriate intracellular carnitine levels was found in patients treated with high-dose L-carnitine and was associated with an increased frequency of S and G2-M cells following mitogen stimulation. Furthermore, at the end of the trial we found a strong reduction in serum triglycerides in the L-carnitine group compared with baseline levels. CONCLUSIONS: Our data indicate that carnitine deficiency occurs in PBMC from patients with advanced AIDS, despite normal serum concentrations. The increase in cellular carnitine content strongly improved lymphocyte proliferative responsiveness to mitogens. Because carnitine status is an important contributing factor to immune function in patients with advanced AIDS, we therefore believe that L-carnitine supplementation could have a role as a complementary therapy for HIV-infected individuals
Impairment of circulating lactoferrin in HIV-1 infection. Defer MC, Dugas B, Picard O, et al. Cell Mol Biol (Noisy -Le-Grand). 1995 May; 41(3):417-21. Levels of plasma lactoferrin are decreased in HIV-1-infected patients in relation to the progression of the disease. Plasma lactoferrin concentrations were determined using a specific and sensitive enzyme immunoassay. 97 plasma were studied (22 asymptomatic, 45 symptomatic patients compared to 30 healthy controls) and the results showed a highly significant decrease (p < 0.001) of the level of lactoferrin in HIV-1-infected patients (respectively 2.79 +/- 1.2 and 0.68 +/- 0.22 micrograms/ml) compared to controls (4.37 +/- 0.83 micrograms/ml). Since it is well established that plasma lactoferrin level could be influenced by the number of neutrophils, the experiments were reproduced in neutropenic patients who represent 10% of recruitment (6 among 45 symptomatic patients). The plasma from neutropenic symptomatic patients (neutrophils < or = "1,300/mm3)" showed their mean lactoferrin level at 0.36 micrograms/ml still far above the normal values. In view of the different reported biological effects of lactoferrin that are of great importance in the non-specific defences, the real biological place of the lack of such a molecule could be one important component of the multifactorial nature of HIV-1 infection
In vivo recovery of natural killer cell activity by the association of thymosin alpha-1 and cytokines during cocaine administration. Di Francesco PPFGRFCGE. Med Sci Res. 1994; 22:41-2. Not Available
Influence of L-carnitine on CD95 cross-lining-induced apoptosis and ceramide generation in human cell lines: correlation with its effects on purified acidic and neutral sphingomyelinases in vitro. Di Marzio L, Alesse E, Roncaioli P, et al. Proc Assoc Am Physicians. 1997 Mar; 109(2):154-63. Recently, we examined the effects of a short-term (5-days) intravenous L-carnitine (6 g/die) treatment on apoptosis of CD4 and CD8 cells from 10 AIDS patients. Without inducing side effects, L-carnitine administration has been shown to induce a potent reduction in the percentage of cells undergoing apoptosis, paralleled by a significant increase of CD4 an CD8 cells. Interestingly, L-carnitine treatment led to a significant reduction of peripheral blood mononuclear cell-associated ceramide (an intracellular messenger for apoptosis) that correlated with the decrease of apoptotic CD4- and CD8-positive cells. These results suggest that L-carnitine could be an effective antiapoptotic drug use with AIDS patients. In this article we report the results of in vitro studies performed to better characterize the effects of L-carnitine on cell apoptosis. Previously, a high expression of the Fas (CD95/APO-1)/Fas ligand system in peripheral blood mononuclear cells from HIV-positive individuals has been reported and could be responsible for the observed relevant apoptosis of both infected and uninfected cells. Thus, we investigated the in vitro effects of L-carnitine on CD95 cross-linking-induced apoptosis through an anti-CD95 mAb in Fas-sensitive cell lines (HuT78 and U937). The results strongly support the in vivo observations. Our data indicate that L-carnitine is able to inhibit CD95-induced apoptosis of these cells, most likely by preventing sphingomyelin breakdown and consequent ceramide synthesis. The effect of L-carnitine seems to be specific for acidic sphingomyelinase as shown by experiments performed in vitro and using purified neutral or acidic sphingomyelinases
Fatal methemoglobinemia resulting from ingestion of isobutyl nitrite, a "room odorizer" widely used for recreational purposes. Dixon DS, Reisch RF, Santinga PH. J Forensic Sci. 1981 Jul; 26(3):587-93. The alkyl nitrites, specifically isobutyl nitrite, have taken a prominent place among those substances enjoying widespread recreational use, primarily in discotheques and in any toxicologically verified deaths, the chemical may cause fatal toxic methemoglobinemia if ingested. A case with a fatal outcome is presented, and the chemistry and toxicology of the substance are discussed
The use of a transscrotal testosterone delivery system in the treatment of patients with weight loss related to human immunodeficiency virus infection. Dobs AS, Cofrancesco J, Nolten WE, et al. Am J Med. 1999 Aug; 107(2):126-32. PURPOSE: Weight loss is a strong predictor of morbidity and mortality in human immunodeficiency virus (HIV)-infected patients. Men with acquired immunodeficiency syndrome (AIDS) lose body cell mass. Hypogonadism is also common. This study tested the efficacy of a testosterone transscrotal patch (6 mg/day) in improving body cell mass and treating hypogonadism in these patients. SUBJECTS AND METHODS: This multicenter, randomized, double-blinded, placebo-controlled trial was conducted from August 1995 to October 1996 in 133 men, 18 years of age and older, who had AIDS, 5% to 20% weight loss, and either a low morning serum total testosterone level (<400 ng/dL) or a low free testosterone level (<16 pg/mL). Outcomes included weight, body cell mass as measured using bioelectrical impedance analysis, quality of life, and morning measurements of serum testosterone and dihydrotestosterone levels, lymphocyte subsets, and HIV quantification. RESULTS: There were no significant differences in baseline weight, CD4 cell counts, or HIV serum viral quantification between treatment arms. Morning total and free testosterone levels increased in those treated with testosterone, but not with placebo. Following 12 weeks of treatment there were no differences (testosterone-placebo) in mean weight change (-0.3 kg [95% confidence interval (CI): -1.4 to 0.8]) or body cell mass (-0.2 kg [95% CI: -1.0 to 0.6]) in the two groups. There were also no changes in quality of life in either group. CONCLUSION: Hypogonadal men with AIDS and weight loss can achieve adequate morning serum sex hormone levels using a transscrotal testosterone patch. However, this system of replacement does not improve weight, body cell mass, or quality of life
Alternative medicine: an attractive nuisance. Durant JR. J Clin Oncol. 1998 Jan; 16(1):1-2.
Low concentrations of acid-soluble thiol (cysteine) in the blood plasma of HIV-1-infected patients. Eck HP, Gmunder H, Hartmann M, et al. Biol Chem Hoppe Seyler. 1989 Feb; 370(2):101-8. Blood plasma samples from HIV-1-infected persons contain elevated glutamate concentrations up to 6-fold the normal level and relatively low concentrations of acid-soluble thiol (i.e. decreased cysteine concentrations). The intracellular glutathione concentration in peripheral blood-mononuclear cells (PBMC) and monocytes from HIV antibody-positive persons are also significantly decreased. Therapy with azidothymidine (AZT) causes a substantial recovery of the plasma thiol levels; but glutamate levels remain significantly elevated and intracellular glutathione levels remain low. Cell culture experiments with approximately physiological amino-acid concentrations revealed that variations of the extracellular cysteine concentration have a strong influence on the intracellular glutathione level and the rate of DNA synthesis [( 3H]thymidine incorporation) in T cell clones and human and murine lymphocyte preparations even in the presence of several-fold higher cystine and methionine concentrations. Cysteine cannot be replaced by a corresponding increase of the extracellular cystine or methionine concentration. These experiments suggest strongly that the low cysteine concentration in the plasma of HIV-infected persons may play a role in the pathogenetic mechanism of the acquired immunodeficiency syndrome
Malabsorption and deficiency of vitamin B12 in HIV-infected patients with chronic diarrhea. Ehrenpreis ED, Carlson SJ, Boorstein HL, et al. Dig Dis Sci. 1994 Oct; 39(10):2159-62. Deficiency of vitamin B12 is commonly reported in HIV-infected patients. We measured vitamin B12 levels in 36 HIV-infected patients with chronic diarrhea (> 3 stools/day for six weeks or more). Eight patients had an identifiable cause of diarrhea. Vitamin B12 levels were low in 39%. Sixteen of these patients were selected to undergo further testing, eight patients with low levels of vitamin B12 and eight with normal B12 levels. These 16 patients had both a stage II Schilling test and measurement of multiple serum D-xylose concentrations performed after both oral and intravenous doses of D-xylose. Integrated areas under the curves (AUC) for D-xylose concentration versus time were calculated for intravenous and oral doses, and D-xylose bioavailability was determined. Stage II Schilling tests were abnormal in 11 patients, (69%). D-Xylose bioavailability correlated closely with vitamin B12 absorption (r = 0.648, P < 0.01). Comparisons of mean values for CD4 count, serum albumin, Karnovsky score, six-month weight loss, 1-hr serum D-xylose levels and MCV failed to reveal a significant difference between those with and without abnormal serum vitamin B12 levels. These data indicate that below-normal levels of vitamin B12 are highly prevalent in HIV-infected patients with chronic diarrhea. Malabsorption of vitamin B12 occurs in the setting of an enteropathic process effecting both the proximal and distal small bowel. Since no risk factors for vitamin B12 deficiency could be identified, screening for vitamin B12 deficiency in HIV-infected patients with chronic diarrhea is strongly recommended
In vitro and in vivo effects produced by the immunomodulating agent RU 41740 on human polymorphonuclear leukocytes in the elderly. el Abbouyi A, Roch-Arveiller M, Marchiani C, et al. Mech Ageing Dev. 1988 Sep; 44(3):215-29. The activity of RU 41740, a glycoprotein extract from Klebsiella pneumoniae has been investigated on some polymorphonuclear (PMN) functions. Chemotaxis, random migration and oxidative metabolism (assessed by chemiluminescence, O2 consumption and O2- generation) were studied in parallel. PMN were collected from adult and aged human volunteers. Experiments were performed either in vitro or in vivo in a double blind placebo assay. In both PMN populations RU 41740 enhanced oxidative metabolism either in in vivo or in vitro experiments. However, a higher and dose-related activity was observed on PMN collected from the younger subjects whereas maximal effective concentration was reached earlier with PMN collected from aged subjects. RU 41740 did not modify random migration but inhibited chemotaxis of PMN collected from the younger population in a dose-related manner. These data corroborated previous results observed on PMN collected from various animal species and suggested an interaction of RU 41740 on PMN membrane. Moreover drug-induced macrophage and lymphocyte stimulation might also explain, at least in part, the in vivo effects described in this study. Thus RU 41740 could partly account for the protective effects exerted against bacterial and fungal infections through its activity on PMN functions
Synergistic effect of thymosin alpha 1 and alpha beta-interferon on NK activity in tumor-bearing mice. Favalli C, Mastino A, Jezzi T, et al. Int J Immunopharmacol. 1989; 11(5):443-50. We have investigated the possibility of thymosin alpha 1 (TH) cooperating with alpha beta-interferon (IFN) in boosting natural killer (NK) activity in tumor-bearing, immunosuppressed mice in vivo. Treatment with a single injection of 30,000 IU of IFN 24 h before testing enhanced NK activity in tumor-bearing mice if the IFN was administered 9 days after tumor inoculation, when the animals have normal NK responsiveness. On the other hand, the same treatment led to lower or no improvement of NK responses if the treatment was given 13 or 17 days after tumor inoculation, at a time when tumor growth causes immunosuppression. However, combination treatment with TH (200 micrograms/kg) for 4 days, followed by IFN was found to restore normal NK cell activity. Selective depletion of antigen-positive cells showed that killer cells stimulated by combination treatment with TH and IFN seem to bear phenotypic characteristics of NK cells. These studies provide the first documentation of a novel combination approach to reconstitution of immunosuppressed tumor-bearing mice using TH and IFN. We hypothesize that TH restores NK boosting activity by IFN by effecting the differentiation/induction of precursor populations of IFN-responsive cells
Dehydroepiandrosterone sulfate (DHEAS) and testosterone: relation to HIV illness stage and progression over one year. Ferrando SJ, Rabkin JG, Poretsky L. J Acquir Immune Defic Syndr. 1999 Oct 1; 22(2):146-54. This study explored associations between serum dehydroepiandrosterone sulfate (DHEAS), free and total testosterone levels, and HIV illness markers, including viral load, and the behavioral problems of fatigue and depressed mood. Subjects were 169 HIV-positive men evaluated at baseline, 6, and 12 months for levels of DHEAS, total and free testosterone, HIV RNA, CD4, HIV symptoms, opportunistic illnesses, fatigue, and depression. Men with AIDS (N = 105), compared with men with less advanced illness, had lower mean levels of DHEAS. Baseline DHEAS was positively correlated with CD4 count, HIV symptom severity, and was inversely correlated with HIV RNA. Baseline DHEAS below the laboratory reference range (96 microg/dl) was associated with history of opportunistic infections and malignancies (adjusted odds ratio [OR], 4.4; 95% confidence interval [CI], 1.9-10.4) and with incidence of these complications or death over 1 year (adjusted OR, 2.6; 95% CI, 1-7.2). Initiating protease inhibitor combination therapy was associated with an increase in DHEAS over 6 months. Free testosterone was inversely correlated with HIV RNA, but there were no other significant associations between testosterone and HIV illness markers. No hormone was related to fatigue or depression. This study confirms that low serum DHEAS is associated with HIV illness markers, including viral load, and carries negative prognostic value. Further, protease inhibitor therapy may result in increased circulating DHEAS
Double-blind trial RU 41740 vs. placebo: immunological and clinical effects in a group of patients with chronic bronchitis. Fietta A, Bersani C, De R, V, et al. Respiration. 1988; 54(3):145-52. A double-blind trail was performed to investigate the effects of RU 41740, a glycoprotein extract from Klebsiella pneumoniae, on host defenses and its efficacy in reducing the number of exacerbation in 29 evaluable patients with chronic bronchitis, out of 36 patients who entered the study. The drug enhanced the phagocytosis indexes of both polymorphonuclear and mononuclear phagocytes. Increased candidacidal activity of monocytes was also observed. These effects, already detectable after one course of therapy and during the entire period of treatment, were no longer detectable when tested 6 months after the end of treatment. A significantly (p less than 0.05) larger number of patients in the treated group than in the placebo group had no exacerbations during drug administration (0-3 months). Moreover, patients treated with RU 41740 had significantly fewer and shorter episodes of acute exacerbation. The positive decreases in these two parameters persisted throughout the follow-up
Milk thistle (Silybum marianum) for the therapy of liver disease. Flora K, Hahn M, Rosen H, et al. Am J Gastroenterol. 1998 Feb; 93(2):139-43. Silymarin, derived from the milk thistle plant, Silybum marianum, has been used for centuries as a natural remedy for diseases of the liver and biliary tract. As interest in alternative therapy has emerged in the United States, gastroenterologists have encountered increasing numbers of patients taking silymarin with little understanding of its purported properties. Silymarin and its active constituent, silybin, have been reported to work as antioxidants scavenging free radicals and inhibiting lipid peroxidation. Studies also suggest that they protect against genomic injury, increase hepatocyte protein synthesis, decrease the activity of tumor promoters, stabilize mast cells, chelate iron, and slow calcium metabolism. In this article we review silymarin's history, pharmacology, and properties, and the clinical trials pertaining to patients with acute and chronic liver disease
Biochemical deficiencies of coenzyme Q10 in HIV-infection and exploratory treatment. Folkers K, Langsjoen P, Nara Y, et al. Biochem Biophys Res Commun. 1988 Jun 16; 153(2):888-96. AIDS patients (2 groups) had a blood deficiency (p less than 0.001) of coenzyme Q10 vs. 2 control groups. AIDS patients had a greater deficiency (p less than 0.01) than ARC patients. ARC patients had a deficiency (p less than 0.05) vs. control. HIV-infected patients had a deficiency (p less than 0.05) vs. control. The deficiency of CoQ10 increased with the increased severity of the disease, i.e., from HIV positive (no symptoms) to ARC (constitutional symptoms, no opportunistic infection or tumor) to AIDS (HIV infection, opportunistic infection and/or tumor). This deficiency, a decade of data on CoQ10 on the immune system, on IgG levels, on hematological activity constituted the rationale for treatment with CoQ10 of 7 patients with AIDS or ARC. One was lost to follow-up; one expired after stopping CoQ10; 5 survived, were symptomatically improved with no opportunistic infection after 4-7 months. In spite of poor compliance of 5/7 patients, the treatment was very encouraging and at times even striking
Coenzyme Q10 increases T4/T8 ratios of lymphocytes in ordinary subjects and relevance to patients having the AIDS related complex. Folkers K, Hanioka T, Xia LJ, et al. Biochem Biophys Res Commun. 1991 Apr 30; 176(2):786-91. Coenzyme Q10 (CoQ10) is indispensable to biochemical mechanisms of bioenergetics, and it has a non-specific role as an antioxidant. CoQ10 has shown a hematological activity for the human and has shown an influence on the host defense system. The T4/T8 ratios of lymphocytes are known to be low in patients with AIDS, ARC and malignancies. Our two patients with ARC have survived four-five years without any symptoms of adenopathy or infection on continuous treatment with CoQ10. We have newly found that 14 ordinary subjects responded to CoQ10 by increases in the T4/T8 ratios and an increase in blood levels of CoQ10; both by p less than 0.001. This knowledge and survival of two ARC patients for four-five years on CoQ10 without symptoms, and new data on increasing ratios of T4/T8 lymphocytes in the human by treatment with CoQ10 constitute a rationale for new double blind clinical trials on treating patients with AIDS, ARC and diverse malignancies with CoQ10
The activities of coenzyme Q10 and vitamin B6 for immune responses. Folkers K, Morita M, McRee J, Jr. Biochem Biophys Res Commun. 1993 May 28; 193(1):88-92. Coenzyme Q10 (CoQ10) and vitamin B6 (pyridoxine) have been administered together and separately to three groups of human subjects. The blood levels of CoQ10 increased (p < 0.001) when CoQ10 and pyridoxine were administered together and when CoQ10 was given alone. The blood levels of IgG increased when CoQ10 and pyridoxine were administered together (p < 0.01) and when CoQ10 was administered alone (p < 0.05). The blood levels of T4-lymphocytes increased when CoQ10 and pyridoxine were administered together (p < 0.01) and separately (p < 0.001). The ratio of T4/T8 lymphocytes increased when CoQ10 and pyridoxine were administered together (p < 0.001) and separately (p < 0.05). These increases in IgG and T4-lymphocytes with CoQ10 and vitamin B6 are clinically important for trials on AIDS, other infectious diseases, and on cancer
A Study of the Olive Leaf Preparation Tincture Ole Foliorum in the Treatment of Infection Caused by HIV. Fredrickson WR. 1994.Sep.9 (unpublished study) see The Townsend Letter for Doctors and Patients; 1997 May; 166: 110-11.
S-Adenosyl-L-methionine. A review of its pharmacological properties and therapeutic potential in liver dysfunction and affective disorders in relation to its physiological role in cell metabolism. Friedel HAeal. Drugs. 1998 Sep; 38(3):389-416.
The effect of supplemental beta-carotene on immunologic indices in patients with AIDS: a pilot study. Fryburg DA, Mark RJ, Griffith BP, et al. Yale J Biol Med. 1995 Jan; 68(1-2):19-23. Patients with the acquired immunodeficiency syndrome (AIDS) are characterized by a decrease in the number of T helper cells, a defect that is linked to the impaired immunologic competence. Vitamin A and its dietary precursor, beta-carotene, increase absolute T helper cell counts as well as indices of T cell function in both human and animal models. To determine if short-term beta-carotene treatment affects T lymphocyte subsets in patients with AIDS, a single-blind, non-randomized clinical trial of beta-carotene was performed in seven patients with AIDS. Enrollment criteria included no evidence of: a) active opportunistic infection: b) greater than 1 kilogram change in weight in the month preceding enrollment; c) chronic diarrhea or malabsorption; and d) hepatic disease or significant anemia. Beta-carotene was given with meals in two divided doses of 60 mg/day for four weeks; this was followed by no therapy for six weeks. Samples for total white blood cell, lymphocyte and T lymphocyte subset counts were measured at baseline, at the end of four weeks of treatment and another six weeks after treatment had stopped. P24 antigen, beta-2 microglobulin and liver function tests were also measured. All subjects tolerated the treatment well without evidence of toxicity. In response to beta-carotene, total lymphocyte counts rose by 66 percent (.05 < p < .10), and CD4+ cells rose slightly, but insignificantly, in the entire group. In all three of the patients who had baseline CD4+ cells greater than 10/microliters, however, the mean absolute increase in CD4+ cells in response to beta-carotene was 53 +/- 10 cells/microliters (p < .01). Six weeks off beta-carotene treatment, the absolute CD4+ cell count returned to pretreatment levels (p < .01). No change was observed in CD8+ cells. P24 antigen and beta-2 microglobulin did not change during treatment. These preliminary observations suggest that short-term treatment with beta-carotene may increase CD4+ cell counts in patients with AIDS who have greater than 10 cells/microliters
Combined Therapy with Zidovudine-Thymosin Alpha-1 Alpha Interferon in the Treatment of HIV-Infected Patients. Garaci ERGPLeal. 1992;
AIDS--past and future. Gottlieb MS. N Engl J Med. 2001 Jun 7; 344(23):1788-91.
AIDS--past and future. Gottlieb MS. N Engl J Med. 2001 Jun 7; 344(23):1788-91.
Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Guay LA, Musoke P, Fleming T, et al. Lancet. 1999 Sep 4; 354(9181):795-802. BACKGROUND: The AIDS Clinical Trials Group protocol 076 zidovudine prophylaxis regimen for HIV-1-infected pregnant women and their babies has been associated with a significant decrease in vertical HIV-1 transmission in non-breastfeeding women in developed countries. We compared the safety and efficacy of short-course nevirapine or zidovudine during labour and the first week of life. METHODS: From November, 1997, to April, 1999, we enrolled 626 HIV-1-infected pregnant women at Mulago Hospital in Kampala, Uganda. We randomly assigned mothers nevirapine 200 mg orally at onset of labour and 2 mg/kg to babies within 72 h of birth, or zidovudine 600 mg orally to the mother at onset of labour and 300 mg every 3 h until delivery, and 4 mg/kg orally twice daily to babies for 7 days after birth. We tested babies for HIV-1 infection at birth, 6-8 weeks, and 14-16 weeks by HIV-1 RNA PCR. We assessed HIV-1 transmission and HIV-1-free survival with Kaplan-Meier analysis. FINDINGS: Nearly all babies (98.8%) were breastfed, and 95.6% were still breastfeeding at age 14-16 weeks. The estimated risks of HIV-1 transmission in the zidovudine and nevirapine groups were: 10.4% and 8.2% at birth (p=0.354); 21.3% and 11.9% by age 6-8 weeks (p=0.0027); and 25.1% and 13.1% by age 14-16 weeks (p=0.0006). The efficacy of nevirapine compared with zidovudine was 47% (95% CI 20-64) up to age 14-16 weeks. The two regimens were well tolerated and adverse events were similar in the two groups. INTERPRETATION: Nevirapine lowered the risk of HIV-1 transmission during the first 14-16 weeks of life by nearly 50% in a breastfeeding population. This simple and inexpensive regimen could decrease mother-to-child HIV-1 transmission in less-developed countries
Immunotherapy of human immunodeficiency virus infection. Hadden JW. Trends Pharmacol Sci. 1991 Mar; 12(3):107-11. HIV infection results in the destruction of the thymus-dependent cellular immune system and death due to opportunistic infection and malignancy. Immunosuppressive influences (other sexually or blood-transmitted viruses, HIV-derived peptides, semen, poor nutrition, drugs, etc.) favor the progression of the disease. Although immunorestorative agents may be expected to delay progression of the disease, John Hadden argues that no agent has yet proven useful in reversing the immunodeficiency in full-blown AIDS. However, two thymomimetic drugs, isoprinosine and diethyldithiocarbamate, inhibit the development of infections in patients with pre-AIDS in large multicenter trials, and preliminary data from trials with two thymomimetic peptides, thymopentin and ImReg-1, in pre-AIDS patients are encouraging
Comparative study of the anti-HIV activities of ascorbate and thiol-containing reducing agents in chronically HIV-infected cells. Harakeh S, Jariwalla RJ. Am J Clin Nutr. 1991 Dec; 54(6 Suppl):1231S-5S. To elucidate the action of vitamin C on pathogenic human retroviruses, we investigated and compared the effects of noncytoxic concentrations of ascorbic acid (AA), its calcium salt (Ca-ascorbate), and two thiol-based reducing agents [glutathione (GSH) and N-acetyl-L-cysteine (NAC)] against human immunodeficiency virus (HIV)-1 replication in chronically infected T lymphocytes. Ca-ascorbate reduced extracellular HIV reverse transcriptase (RT) activity by about the same magnitude as the equivalent dose of AA. Long-term experiments showed that continuous presence of ascorbate was necessary for HIV suppression. NAC (10 mmol/L) caused less than twofold inhibition of HIV RT and conferred a synergistic effect (approximately eightfold inhibition) when tested simultaneously with AA (0.426 mmol/L). In contrast, nonesterified GSH (less than or equal to 1.838 mmol/L) had no effect on RT concentrations and did not potentiate the anti-HIV effect of AA. These results further support the potent antiviral activity of ascorbate and suggest its therapeutic value in controlling HIV infection in combination with thiols
Intestinal glutamine metabolism. Hartmann F, Plauth M. Metabolism. 1989 Aug; 38(8 Suppl 1):18-24.
Glutathione deficiency is associated with impaired survival in HIV disease. Herzenberg LA, De Rosa SC, Dubs JG, et al. Proc Natl Acad Sci U S A. 1997 Mar 4; 94(5):1967-72. Glutathione (GSH), a cysteine-containing tripeptide, is essential for the viability and function of virtually all cells. In vitro studies showing that low GSH levels both promote HIV expression and impair T cell function suggested a link between GSH depletion and HIV disease progression. Clinical studies presented here directly demonstrate that low GSH levels predict poor survival in otherwise indistinguishable HIV-infected subjects. Specifically, we show that GSH deficiency in CD4 T cells from such subjects is associated with markedly decreased survival 2-3 years after baseline data collection (Kaplan-Meier and logistic regression analyses, P < 0.0001 for both analyses). This finding, supported by evidence demonstrating that oral administration of the GSH prodrug N-acetylcysteine replenishes GSH in these subjects and suggesting that N-acetylcysteine administration can improve their survival, establishes GSH deficiency as a key determinant of survival in HIV disease. Further, it argues strongly that the unnecessary or excessive use of acetaminophen, alcohol, or other drugs known to deplete GSH should be avoided by HIV-infected individuals
Inactivation of DNA polymerases of murine leukaemia viruses by calcium elenolate. Hirschman SZ. Nat New Biol. 1972 Aug 30; 238(87):277-9.
Selenium supplementation suppresses tumor necrosis factor alpha-induced human immunodeficiency virus type 1 replication in vitro. Hori K, Hatfield D, Maldarelli F, et al. AIDS Res Hum Retroviruses. 1997 Oct 10; 13(15):1325-32. Selenium is a nutritionally essential trace element that is important for optimal function of the immune system. It is incorporated into selenoproteins as the amino acid selenocysteine and it is known to inhibit the expression of some viruses. In this study, we show that selenium supplementation for 3 days prior to exposure to tumor necrosis factor alpha (TNF-alpha) partially suppresses the induction of human immunodeficiency virus type 1 (HIV-1) replication in both chronically infected T lymphocytic and monocytic cell lines. In acute HIV-1 infection of T lymphocytes and monocytes in the absence of exogenous TNF-alpha, the suppressive effect of selenium supplementation was not observed. However, selenium supplementation did suppress the enhancing effect of TNF-alpha on HIV-1 replication in vitro in acutely infected human monocytes, but not in T lymphocytes. Selenium supplementation also increased the activities of the selenoproteins, glutathione peroxidase (GPx) and thioredoxin reductase (TR), which serve as cellular antioxidants. Taken together, these results suggest that selenium supplementation may prove beneficial as an adjuvant therapy for AIDS through reinforcement of endogenous antioxidative systems
Methemoglobinemia from sniffing butyl nitrite
4. Horne MK, III, Waterman MR, Simon LM, et al. Ann Intern Med. 1979 Sep; 91(3):417-8.
Aspirin and thymosin increase interleukin-2 and interferon-gamma production by human peripheral blood lymphocytes. Hsia J, Sarin N, Oliver JH, et al. Immunopharmacology. 1989 May; 17(3):167-73. Interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) have recently been added to the arsenal of synthetic biological response modifiers with important immunomodulatory activities. In this paper we have assessed the effects of acetylsalicylic acid (aspirin), thymosin alpha and thymosin fraction 5 (TF5), a partially purified calf thymic preparation, on production of IFN-gamma in vitro. Stimulation by oral aspirin of IL-2 and IFN-gamma production by peripheral blood lymphocytes (PBLs) was also studied in healthy human volunteers. Aspirin, thymosin alpha 1 and TF5 were all observed to enhance phytohemagglutinin (PHA)-stimulated production of IFN-gamma. Peak IFN-gamma production by PHA-stimulated PBLs was observed after 24 h of incubation with TF5 and after 72 h with aspirin. Stimulation by aspirin and TF5 required the presence of macrophages, and was additive and dose-dependent. The additive effects of aspirin and TF5 suggest that these agents act by different mechanisms. Oral administration of aspirin in normal volunteers significantly enhanced production of both IFN-gamma and IL-2. PHA-stimulated IFN-gamma production was greatest 24 h after aspirin ingestion; in contrast, IL-2 production was optimal 10 h after aspirin ingestion. These observations suggest that oral aspirin is an effective biological response modifier in humans and raise the possibility of a novel combination approach to immunomodulation involving cyclooxygenase inhibitors and thymosins
Decreased serum dehydroepiandrosterone is associated with an increased progression of human immunodeficiency virus infection in men with CD4 cell counts of 200-499. Jacobson MA, Fusaro RE, Galmarini M, et al. J Infect Dis. 1991 Nov; 164(5):864-8. Dehydroepiandrosterone (DHEA) and its interconvertible sulfate derivative (DHEA-S) are human androgenic steroids that have been reported to inhibit viral expression and have been associated with a decreased risk of cancer. The relationship between serum DHEA and DHEA-S levels and subsequent progression to AIDS was investigated in a sample of human immunodeficiency virus (HIV)-infected men from the San Francisco Men's Health Study followed prospectively since 1984. Among 108 men seropositive for HIV at study entry and with CD4 lymphocyte counts of 200-499 microliters 24 months later, serum DHEA levels below the lower limit of normal (less than 180 ng/dl) at this later date were predictive of subsequent progression to AIDS (relative hazard = 2.34; 95% confidence interval = 1.18-4.63; P = .01) after controlling for hematocrit, age, and log absolute CD4 cell number in a Cox proportional hazards model. This is the first large prospective cohort in which an endocrinologic variable has been observed to independently predict progression to AIDS. These observations, in addition to recent in vitro data, suggest that DHEA might have a protective effect in HIV infection
HIV and AIDS: new developments-current perspectives on the HIV epidemic. Jaffe JW. Audio Dig Intern Med. 2001 Apr 7; 48(07)
[Effect of an immunomodulator, RU 41740, on experimental infections]. Joly V. Presse Med. 1988 Jul 27; 17(28):1430-2. RU 41740 is an immunomodulator of organic origin acting on cells of the immune system (B cells, T cells, phagocytic cells) and on mediators IL1-CSF). Its mode of action has been explored by means of experimental infections. The types of defence involved differ according to whether the experimental infection is caused by an extracellular or intracellular micro-organism. Candida albicans and Saccharomyces cerevisiae were used to produce fungal infections, while bacterial infections were obtained with Staph. aureus, E. coli, Strep. pneumoniae and other organisms. The influenza virus was used to produce a viral infection. In these experimental models, RU 41740 increased the survival time of the infected animals and reduced bacterial, fungal and viral proliferation. These effects were observed even in immunocompromised mice. These in vitro and in vivo studies have demonstrated that RU 41740 is effective whatever the type of body defence involved
Long-term survivors of HIV-1 infection. Klein MR, Miedema F. Trends Microbiol. 1995 Oct; 3(10):386-91. The clinical course and outcome of HIV-1 infection are highly variable. A full spectrum of pathology has been observed, from rapid progression to AIDS within months of HIV-1 seroconversion, to asymptomatic survival for more than a decade. This phenomenon probably reflects the multiphasic and multifactorial nature of the virus-host interactions. Obviously, interest in the extremes now recognized in HIV-1 disease progression is growing, with the hope that mechanisms of protection may be found
Immune enhancing effect of a growth hormone secretagogue. Koo GC, Huang C, Camacho R, et al. J Immunol. 2001 Mar 15; 166(6):4195-201. Growth hormone (GH) has been known to enhance immune responses, whether directly or through the insulin like growth factor-1, induced by GH. Recently a nonpeptidyl small m.w. compound, a GH secretagogue (GHS), was found to induce the production of GH by the pituitary gland. In this study, we examined the effect of GHS in immunological functions of 5- to 6-wk-old and 16- to 24-month-old mice. In young mice, we observed a significant increase in PBLs, but T and B cell-proliferative responses were not consistently enhanced. The old mice, treated with GHS for 3 wk, did not show increases in peripheral lymphocytes, but they exhibited a statistically significant increase in thymic cellularity and differentiation. When inoculated with a transplantable lymphoma cell line, EL4, the treated old mice showed statistically significant resistance to the initiation of tumors and the subsequent metastases. Generation of CTL to EL4 cells was also enhanced in the treated mice, suggesting that GHS has a considerable immune enhancing effect, particularly in the old mice. We have also found that GHS promoted better thymic engraftment in bone marrow transplant of SCID mice. We found more cycling cells in the spleens of treated mice, suggesting that GHS may exert its immune enhancing effect by promoting cell division in lymphoid cells. These observations ascribe to GHS a novel therapy possible for aging, AIDS, and transplant individuals, whose immune functions are compromised
Characteristics of HIV-infected men with low serum testosterone levels. Kopicko JJ, Momodu I, Adedokun A, et al. Int J STD AIDS. 1999 Dec; 10(12):817-20. Low levels of serum testosterone may have negative implications on morbidity in HIV-infected men. The purpose of this study was to determine demographic and clinical characteristics that predict low serum testosterone among men attending our HIV clinic. A cross-sectional study of 587 HIV-positive male patients who presented at the Louisiana State University HIV Outpatient (HOP) Clinic between August 1997 and January 1999 was conducted. Demographic and clinical characteristics were collected and analysed. Of the 587 men studied, 119 (20.3%) had a serum testosterone level below 400 ng/dl. Significantly more men with low serum testosterone levels had a presence of opportunistic infection (especially HIV wasting syndrome, oesophageal candidiasis, or dementia), CD4+ cell counts below 200 cells/mm3, or were taking megestrol acetate. Early detection of low serum testosterone will allow for expedient testosterone supplementation therapy, which could improve morbidity and quality of life for HIV-infected men
Randomised, double-blind, placebo-controlled trial of ditiocarb sodium ('Imuthiol') in human immunodeficiency virus infection. Lang JM, Touraine JL, Trepo C, et al. Lancet. 1988 Sep 24; 2(8613):702-6. 83 patients with human immunodeficiency virus (HIV) infection (CDC groups II, III, or IV-A) were randomised in a crossover trial of sodium-diethyldithiocarbamate (ditiocarb sodium, 'Imuthiol') (10 mg/kg body weight given orally once a week) against placebo. Each arm of the trial lasted 16 weeks. The disease did not progress to CDC-defined acquired immunodeficiency syndrome in the ditiocarb group but did so in 4 patients in the placebo group (3 between week 0 and 16, 1 between week 17 and 32). Ditiocarb was also associated to a significantly greater extent than placebo with relief of constitutional symptoms, improvement in clinical status (including shrinkage of enlarged spleen and lymph nodes), and improvement in immune function (as measured by CD4+ cell count and skin test reactivity). When placebo was replaced by ditiocarb, similar improvements were observed, whereas symptoms slowly reappeared and CD4+ cell levels progressively declined when ditiocarb treatment was replaced by placebo
Thymosin alpha 1 modulates the expression of high affinity interleukin-2 receptors on normal human lymphocytes. Leichtling KD, Serrate SA, Sztein MB. Int J Immunopharmacol. 1990; 12(1):19-29. In this report we demonstrate that thymosin alpha 1 (T alpha 1), a synthetic peptide composed of 28 amino acid residues, and thymosin fraction 5 (TF5) enhance the number of high affinity interleukin 2 receptors (IL-2R) expressed by human peripheral blood lymphocytes in response to in vitro stimulation with phytohemagglutinin (PHA). Thymosins did not, however, alter the affinity of the IL-2R for its ligand. Dose-response studies using a wide range of concentrations indicated a bimodal distribution of responsiveness to T alpha 1. In most experiments the high and low concentration peaks of activity were observed at 10(-8) M and 10(-12) M, respectively, although peak responses were observed at different T alpha 1 concentrations in different donors. No effects were elicited by thymosins in the absence of mitogenic stimulation. Thymosin enhancement of PHA-induced high affinity IL-2R expression directly correlated with increased levels of Tac antigen expression, as determined by flow cytometry, and enhanced interleukin 2 (IL-2) production. Since the biological effects of IL-2 are associated with the occupancy of high affinity IL-2R, the findings presented in this report strongly suggest that thymosins play a significant role in the regulation of immune responses through the modulation of high affinity IL-2R expression
Neuroimmunotherapy with low-dose subcutaneous interleukin-2 plus melatonin in AIDS patients with CD4 cell number below 200/mm3: a biological phase-II study. Lissoni P, Vigore L, Rescaldani R, et al. J Biol Regul Homeost Agents. 1995 Oct; 9(4):155-8. A phase-II pilot clinical study was performed to evaluate the effects of low-dose subcutaneous IL-2 with the pineal hormone melatonin (MLT) in AIDS patients with CD4 counts below 200/mm3. The study included 11 patients. IL-2 was given subcutaneously at 3 million IU/ day in the evening for 6 days/week for 3 weeks. MLT was given orally at 40 mg/day in the evening every day, starting 7 days prior to IL-2. The treatment was substantially well tolerated, and in particular no cardiovascular or pulmonary complication occurred. An increase in CD4 cell number greater than 30% occurred in 4/11 (36%) patients, and CD4 cell mean values observed during the study were significantly higher with respect to those found before. In addition, the treatment induced a significant increase in mean number of lymphocytes, eosinophils, T lymphocytes, NK cells,
Serum selenium, plasma glutathione (GSH) and erythrocyte glutathione peroxidase (GSH-Px)-levels in asymptomatic versus symptomatic human immunodeficiency virus-1 (HIV-1)-infection. Look MP, Rockstroh JK, Rao GS, et al. Eur J Clin Nutr. 1997 Apr; 51(4):266-72. OBJECTIVES: Antioxidant defense status was investigated in HIV-infected patients by measuring serum selenium, erythrocyte glutathione peroxidase (GSH-Px) activity, plasma thiol (-SH) and glutathione (GSH) concentrations along with the assessment of the clinical stage and surrogate markers of HIV-disease. DESIGN, SETTING AND SUBJECTS: Serum selenium levels were determined cross-sectionally in 104 sequentially selected HIV-infected patients (83 outpatients and 21 patients with ongoing AIDS defining events). The patients were classified into three stages of the disease, I, II and III according to the 1993 Centers For Disease Control (CDC) classification system for HIV-infection. GSH-Px activities, plasma SH and plasma GSH concentrations were determined in a subset of 24 patients at stage I and 12 patients at stage III with an active AIDS-defining disease. RESULTS: Mean serum selenium levels were lower in CDC stage II (68.7 +/- 20.9 micrograms/l; P < 0.01; n = "34)" and stage III (51.4 +/- 14.7 micrograms/l; P < 0.01; n = "37)" HIV-infected patients than in healthy subjects (89.2 +/- 20.9 micrograms/l; n = "72)" and stage I patients (82.3 +/- 20.5; microgram/l; n = "33)." Serum selenium levels were positively correlated with CD4-count (r = "0.42;" P < 0.001; n = "104)" and inversely with levels of soluble tumor necrosis factor receptors type II (r = "-0.58;" P < 0.01; n = "35)," neopterin (r = "-0.5;" P < 0.001; n = "80)" and beta 2-microglobulin (r = "-0.4;" P < 0.001; n = "94)." Hepatitis C virus (HCV) and HIV-coinfected patients at CDC stages I and II showed markedly lower selenium concentrations compared to HIV-infected patients without concomitant HCV-infection. Serum selenium and GSH-Px activity in hospitalized AIDS patients was significantly lower as compared to asymptomatic patients and healthy subjects, whereas plasma SH and GSH concentrations were lower in both, asymptomatic -and AIDS-patients, than in the controls. CONCLUSION: The results show that stages I-III of HIV-disease are characterized by significant impairments of antioxidative defenses provided by selenium, GSH-Px, SH-groups and GSH
The role of oxidative imbalance in progression to AIDS: effect of the thiol supplier N-acetylcysteine. Malorni W, Rivabene R, Lucia BM, et al. AIDS Res Hum Retroviruses. 1998 Nov 20; 14(17):1589-96. In this study we investigate the redox profile of HIV+ patients at different stages of disease with regard to immunological parameters, i.e., the number of circulating CD4+ and CD8+ lymphocytes. For this purpose, peripheral blood mononuclear cells (PBMCs) obtained from healthy donors, HIV+ patients in the asymptomatic phase, long-term nonProgressors (LTNPs), and AIDS patients have been considered. Cells have been exposed in vitro to the prooxidizing agent menadione, which is able to induce superoxide anion formation, and the susceptibility of the cells to the induced oxidative stress was estimated. Moreover, the possibility that the susceptibility of the cells to oxidative stress might be reduced by preexposing them to the antioxidizing agent N-acetylcysteine (NAC) has also been analyzed. The results obtained can be summarized as follows: (1) treatment with the prooxidant agent is capable of inducing massive morphological alterations in PBMCs. In particular, a significant correlation was found between the decrease in number of CD4+ lymphocytes in patients at different stages of disease and the susceptibility of their PBMCs to oxidative stress; (2) preincubation with NAC was able to preserve partially the ultrastructural characteristics of PBMCs isolated from HIV+ patients. In particular, a direct relationship was found between the efficacy of NAC protection and CD4 counts; (3) evaluation of the plasma index of peroxidation and the number of circulating CD4 lymphocytes indicates the existence of a positive correlation between "systemic" oxidative imbalance and stage of the disease; and (4) cells from LTNPs display either oxidative susceptibility or oxidative markers similar to those of healthy donor cells. Our study suggests that the redox profile of patients may be considered a predictive marker of AIDS progression and that the acute infection and the asymptomatic phase of the disease may represent a useful period in which the combined use of antiretroviral and antioxidant drugs may be beneficial
Tumor necrosis factor-alpha/cachectin enhances human immunodeficiency virus type 1 replication in primary macrophages. Mellors JW, Griffith BP, Ortiz MA, et al. J Infect Dis. 1991 Jan; 163(1):78-82. Macrophages are important target cells for human immunodeficiency virus type 1 (HIV-1). The ability of HIV-1 to productively infect macrophages may be influenced by endogenous cytokines that alter the activation state of these cells. In this study, the effect of tumor necrosis factor-alpha/cachectin (TNF alpha), a cytokine with macrophage-activating properties, on HIV-1 replication in primary blood monocyte-derived macrophages was examined. Treatment of macrophages with recombinant human TNF alpha (rTNF alpha), starting before or after HIV-1 infection, consistently enhanced viral production fivefold or greater above control (P less than .01). rTNF alpha was active at low concentrations (0.05-50 ng/ml) and increased the replication of both lymphocyte-tropic (human T lymphotropic virus type IIIB) and macrophage-tropic (human T lymphotropic virus type III BaL) strains of HIV-1. These findings provide additional evidence that TNF alpha may play a role in the pathogenesis of HIV-1 infection by upregulating viral expression in macrophages
Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Mellors JW, Rinaldo CR, Jr., Gupta P, et al. Science. 1996 May 24; 272(5265):1167-70. The relation between viremia and clinical outcome in individuals infected with human immunodeficiency virus-type 1 (HIV-1) has important implications for therapeutic research and clinical care. HIV-1 RNA in plasma was quantified with a branched-DNA signal amplification assay as a measure of viral load in a cohort of 180 seropositive men studied for more than 10 years. The risk of acquired immunodeficiency syndrome (AIDS) and death in study subjects, including those with normal numbers of CD4+ T cells, was directly related to plasma viral load at study entry. Plasma viral load was a better predictor of progression to AIDS and death than was the number of CD4+ T cells
S-adenosylmethionine and Pneumocystis carinii. Merali S, Vargas D, Franklin M, et al. J Biol Chem. 2000 May 19; 275(20):14958-63. We previously reported that S-adenosylmethionine (AdoMet), a key molecule in methylation reactions and polyamine biosynthesis, enhances axenic culture of the AIDS-associated opportunistic fungal pathogen Pneumocystis carinii. Here we report that AdoMet is absolutely required for continuous growth. Two transporters are present, one high affinity, K(m) = 4.5 microm, and one low affinity, K(m) = 333 microm. The physiologically relevant high affinity transporter has a pH optimum of 7.5 and no related natural compounds compete for uptake. Transport is 98% inhibited at 4 degrees C, 24% inhibited by 20 mm sodium azide, and 95% inhibited by the combination of 20 mm sodium azide and 1 mm salicylhydroxamic acid; thus transport is active and dependent on both a cytochrome chain and an alternative oxidase. In vitro, AdoMet is used at a rate of 1. 40 x 10(7) molecules cell(-1) min(-1). AdoMet synthetase activity was not detected by a sensitive radiolabel incorporation assay capable of detecting 0.1% of the activity in rat liver. In addition, the AdoMet plasma concentration of rats is inversely correlated with the number of P. carinii in the lungs. These findings demonstrate that P. carinii is an AdoMet auxotroph. The uptake and metabolism of this compound are rational chemotherapeutic targets
Thymosin alpha-1 prevents lung carcinogenesis. Moody TBMGA. FASEB J. 1998; 12(A1457.)
Thymosin alpha 1 down-regulates the growth of human non-small cell lung cancer cells in vitro and in vivo. Moody TW, Fagarasan M, Zia F, et al. Cancer Res. 1993 Nov 1; 53(21):5214-8. The effect of thymosin alpha 1 (THN alpha 1) and its NH2-terminal fragment (THN1-14) and COOH-terminal fragment (THN15-28) on non-small cell lung cancer (NSCLC) growth was evaluated. Using an anti-THN alpha 1 antibody, receptors were identified on NSCLC cells that were pretreated with 10(-6) M THN alpha 1. [3H]Arachidonic acid was readily taken up by NSCLC cells and THN alpha 1 significantly increased the rate of arachidonic acid release. THN1-15 slightly stimulated but THN15-28 and THN beta 4 did not alter arachidonic acid release from NCI-H1299 cells. In clonogenic growth assays in vitro, THN alpha 1 (10(-6) M) significantly decreased NSCLC colony number whereas THN1-14, THN15-28, and THN beta 4 were less potent. Using growth assays in vivo, THN alpha 1 (10 micrograms s.c./day) but not THN1-14, THN15-28, or THN beta 4 inhibited significantly NSCLC xenograft formation in nude mice. These data suggest that biologically active THN alpha 1 receptors are present on NSCLC cells and that native THN alpha 1 inhibits the growth of human NSCLC
Dehydroepiandrosterone as predictor for progression to AIDS in asymptomatic human immunodeficiency virus-infected men. Mulder JW, Frissen PH, Krijnen P, et al. J Infect Dis. 1992 Mar; 165(3):413-8. The steroid hormone dehydroepiandrosterone (DHEA) has been reported to protect against certain viral infections in animal models and to be a modest inhibitor of human immunodeficiency virus type 1 (HIV-1) infection in vitro. Serum DHEA levels were determined in 41 asymptomatic HIV-1-seropositive subjects, who progressed to AIDS within 5 years after entering a cohort study, in 41 HIV-1-seropositive controls, who remained asymptomatic, and in 41 HIV-1-seronegative controls. At entry, DHEA levels were higher in the seronegative group (median, 13.3 nmol/l) than in either the seropositive nonprogressors (median, 9.2 nmol/l; P = .01) or the progressors (median, 7.2 nmol/l; P less than .001). DHEA levels in the progressors approximately 5 months before the diagnosis of AIDS were lower than the levels in the nonprogressors after the same follow-up (median, 5.6 vs. 8.8 nmol/l; P = .007). DHEA levels less than 7 nmol/l and CD4+ cell counts less than 0.5 x 10(9)/l both proved to be independent predictors for disease progression in HIV-1-infected men
Nonspecific oral immunity in individuals with HIV infection. Muller F, Holberg-Petersen M, Rollag H, et al. J Acquir Immune Defic Syndr. 1992; 5(1):46-51. Lactoferrin, lysozyme, interferon, and neopterin levels were determined in parotid saliva from 44 individuals with different clinical stages of human immunodeficiency virus (HIV) infection and 19 HIV-seronegative controls. The secretory output of individual components was calculated according to the fluid flow rate. No parotid interferon activity was found in any of the HIV-infected subjects or controls, and no significant differences in parotid lysozyme or neopterin outputs were observed. The lactoferrin output was significantly decreased in HIV-seropositive subjects in parallel with their markedly reduced parotid secretory IgA output. This combined deficiency of parotid lactoferrin and secretory IgA may well contribute to the frequent oral infections seen in subjects with HIV infection
Virological and immunological effects of antioxidant treatment in patients with HIV infection. Muller F, Svardal AM, Nordoy I, et al. Eur J Clin Invest. 2000 Oct; 30(10):905-14. BACKGROUND: Intracellular oxidative stress in CD4+ lymphocytes due to disturbed glutathione homeostasis may lead to impaired lymphocyte functions and enhanced HIV replication in patients with HIV infection, especially in those with advanced immunodeficiency. The aim of the present study was to assess whether short-term, high-dose antioxidant treatment might have effects on immunological and virological parameters in patients with HIV infection. MATERIALS AND METHODS: In this pilot study, we examined virological and immunological effects of antioxidant combination treatment for 6 days with high doses of N-acetylcysteine (NAC) and vitamin C in 8 patients with HIV infection. The following were assayed before, during and after antioxidant treatment: HIV RNA plasma levels; numbers of CD4+, CD8+, and CD14+ leukocytes in blood; plasma thiols; intracellular glutathione redox status in CD4+ lymphocytes and CD14+ monocytes; lymphocyte proliferation; lymphocyte apoptosis and plasma levels of tumour necrosis factor (TNF)alpha; soluble TNF receptors and neopterin in plasma. RESULTS: No significant changes in HIV RNA plasma levels or CD4+ lymphocyte counts in blood were noted during antioxidant treatment in the patient group. However, in the 5 patients with the most advanced immunodeficiency (CD4+ lymphocyte counts < 200 x 106 L(-1)), a significant rise in CD4+ lymphocyte count, a reduction in HIV RNA plasma level of 0.8 log, an enhanced lymphocyte proliferation and an increased level of intracellular glutathione in CD4+ lymphocytes were found. No change in lymphocyte apoptosis was noted. CONCLUSIONS: Short-term, high-dose combination treatment with NAC and vitamin C in patients with HIV infection and advanced immunodeficiency lead to immunological and virological effects that might be of therapeutic value
Thymosin treatment of chronic hepatitis B: a placebo-controlled pilot trial. Mutchnick MG, Appelman HD, Chung HT, et al. Hepatology. 1991 Sep; 14(3):409-15. Chronic hepatitis B is a severe and frequently progressive disease. We assessed the safety and efficacy of thymosin fraction 5 and thymosin-alpha 1 in a prospective, placebo-controlled trial in 12 patients with chronic hepatitis B. All patients had histological and biochemical evidence of active liver disease for at least 6 mo before treatment and were positive for serum hepatitis B virus DNA and HBsAg. Seven patients received thymosin fraction 5 or thymosin-alpha 1 and five patients received placebo twice weekly for 6 mo. By the conclusion of the study (1 yr), serum aminotransferase levels had improved significantly in thymosin-treated patients, but not in the placebo group. Six (86%) of the thymosin treated patients and one (20%) patient given placebo cleared hepatitis B virus DNA from serum (p less than 0.04, Fisher's exact test). After treatment, replicative forms of hepatitis B virus DNA were present in the liver specimens of four of five placebo-treated patients but in only one of seven thymosin-treated patients (p less than 0.04, Fisher's exact test). Response to thymosin therapy was associated with significant improvements in peripheral blood lymphocyte and CD3 and CD4 counts and in in vitro production of interferon-gamma over initial values. No significant side effects were observed in patients given thymosin or in placebo-treated patients. Clinical, biochemical and serological improvement in patients responding to thymosin were sustained during 26 +/- 3 mo of follow-up. The results of this pilot trial suggest that thymosin therapy promotes disease remission and cessation of hepatitis B virus replication in patients with chronic viral infection
Regulation of the activity of caspases by L-carnitine and palmitoylcarnitine. Mutomba MC, Yuan H, Konyavko M, et al. FEBS Lett. 2000 Jul 28; 478(1-2):19-25. L-Carnitine facilitates the transport of fatty acids into the mitochondrial matrix where they are used for energy production. Recent studies have shown that L-carnitine is capable of protecting the heart against ischemia/reperfusion injury and has beneficial effects against Alzheimer's disease and AIDS. The mechanism of action, however, is not yet understood. In the present study, we found that in Jurkat cells, L-carnitine inhibited apoptosis induced by Fas ligation. In addition, 5 mM carnitine potently inhibited the activity of recombinant caspases 3, 7 and 8, whereas its long-chain fatty acid derivative palmitoylcarnitine stimulated the activity of all the caspases. Palmitoylcarnitine reversed the inhibition mediated by carnitine. Levels of carnitine and palmitoyl-CoA decreased significantly during Fas-mediated apoptosis, while palmitoylcarnitine formation increased. These alterations may be due to inactivation of beta-oxidation or to an increase in the activity of the enzyme that converts carnitine to palmitoylcarnitine, carnitine palmitoyltransferase I (CPT I). In support of the latter possibility, fibroblasts deficient in CPT I activity were relatively resistant to staurosporine-induced apoptosis. These observations suggest that caspase activity may be regulated in part by the balance of carnitine and palmitoylcarnitine
Glutamine metabolism in lymphocytes: its biochemical, physiological and clinical importance. Newsholme EA, Crabtree B, Ardawi MS. Q J Exp Physiol. 1985 Oct; 70(4):473-89. Glutamine is utilized at a high rate (fourfold higher than that of glucose) by isolated incubated lymphocytes and produces glutamate, aspartate, lactate and ammonia. The pathway for glutamine metabolism includes the reactions catalysed by glutaminase, aspartate aminotransferase, oxoglutarate dehydrogenase, succinate dehydrogenase, fumarase, malate dehydrogenase and phosphoenolpyruvate carboxykinase. In fact little if any of the carbon of the glutamine that is used is converted to acetyl-CoA for complete oxidation. For this reason, the oxidation of glutamine is only partial and, in an analogous manner to the terminology used to describe the partial oxidation of glucose to lactate as glycolysis, the term glutaminolysis is used to describe the process of partial glutamine oxidation. The role of glutaminolysis in lymphocytes and perhaps other rapidly dividing cells is to provide both nitrogen and carbon for precursors for synthesis of macromolecules (e.g. purines and pyrimidines for DNA and RNA) and also energy. However, the rate of glutamine utilization by lymphocytes is markedly in excess of the precursor requirements (which are at most 4%) and if glutamine was vitally important in energy production it would be expected that more would be converted to acetyl-CoA for complete oxidation via the Krebs cycle. Indeed most of the energy for lymphocytes may be obtained by the complete oxidation of fatty acids and ketone bodies. Consequently the role of the high rate of glutaminolysis in lymphocytes and other rapidly dividing cells may be identical to that of glycolysis: the high rates provide ideal conditions for the precise and sensitive control of the rate of use of the intermediates of these pathways for biosynthesis when required. High rates of glycolysis and glutaminolysis can be seen as part of a mechanism of control to permit synthesis of macromolecules when required without any need for extracellular signals to make more glucose or glutamine available for these cells. In order to maintain a high rate of glutaminolysis despite fluctuation in the plasma level of glutamine, the flux through the glutaminolytic pathway can be controlled and the key processes in the lymphocyte that may play a role in this process include glutamine transport across the cell and mitochondrial membranes, glutaminase and oxoglutarate dehydrogenase. Changes in the intracellular concentration of Ca2+ may play a role in control of one or more of these reactions.(ABSTRACT TRUNCATED AT 400 WORDS)
Infectious diseases. China awakens to fight projected AIDS crisis. Normile D. Science. 2000 Jun 30; 288(5475):2312-3.
Short-term growth hormone administration at the time of opportunistic infections in HIV-positive patients. Paton NI, Newton PJ, Sharpstone DR, et al. AIDS. 1999 Jul 9; 13(10):1195-202. OBJECTIVES: A 12-week course of recombinant human growth hormone is an effective but expensive therapy for established HIV-related wasting. Wasting in HIV disease is often episodic, coinciding with bouts of acute opportunistic infection. We hypothesized that a short course of growth hormone, targeted at the time of opportunistic infection, might improve protein metabolism thereby reducing lean tissue loss. METHODS: HIV-infected men with acute opportunistic infections, who received standard antimicrobial treatment for their infection as well as intensive nutritional counselling and oral energy supplements, were randomized to receive growth hormone or placebo for 14 days. Principal assessments were protein metabolism (measured by 13C-leucine infusion), body composition (measured by DEXA) and safety. RESULTS: There were no significant changes in outcome parameters in the placebo group (n = 11). In the growth hormone group (n = 9), protein catabolic rate decreased by 60% in the fasted state (P = 0.02 versus placebo), lean body mass increased by 2.2 kg (P = 0.03 versus baseline) and fat mass decreased by 0.7 kg (P = 0.002 versus baseline). There was no increase in adverse or serious adverse events in the growth hormone as compared with the placebo group. CONCLUSIONS: A two-week course of growth hormone at the time of acute opportunistic infection in HIV-infected patients improves protein metabolism and body composition during therapy and appears to be safe. This may represent a rational and economical approach to the use of growth hormone therapy
Nutrients and HIV: part two--vitamins A and E, zinc, B-vitamins, and magnesium. Patrick L. Altern Med Rev. 2000 Feb; 5(1):39-51. There is compelling evidence that micronutrient deficiencies can profoundly affect immunity; micronutrient deficiencies are widely seen in HIV, even in asymptomatic patients. Direct relationships have been found between deficiencies of specific nutrients, such as vitamins A and B12, and a decline in CD4 counts. Deficiencies appear to influence vertical transmission (vitamin A) and may affect progression to AIDS (vitamin A, B12, zinc). Correction of deficiencies has been shown to affect symptoms and disease manifestation (AIDS dementia complex and B12; diarrhea, weight loss, and zinc), and certain micronutrients have demonstrated a direct anti-viral effect in vitro (vitamin E and zinc). The previous article in this series focused on selenium and beta carotene deficiencies in HIV/AIDS. This literature review elucidates how deficiencies of the micronutrients zinc, magnesium, vitamins A, E, and specific B vitamins relate to HIV symptomology and progression, and clearly illustrates the need for nutritional supplementation in HIV disease
The efficacy of inosine pranobex in preventing the acquired immunodeficiency syndrome in patients with human immunodeficiency virus infection. The Scandinavian Isoprinosine Study Group. Pedersen C, Sandstrom E, Petersen CS, et al. N Engl J Med. 1990 Jun 21; 322(25):1757-63. We performed a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of inosine pranobex (Isoprinosine) [corrected] in the treatment of patients with human immunodeficiency virus (HIV) infection but without manifest acquired immunodeficiency syndrome (AIDS). A total of 866 patients were enrolled in 21 centers in Denmark and Sweden. The patients were stratified in three groups according to their CD4+ cell count and randomly assigned to receive either inosine pranobex (1 g three times a day) (n = 429) or matching placebo (n = 437) for 24 weeks. Of the 831 patients who could be evaluated, AIDS developed in 17 in the placebo group as compared with 2 in the inosine pranobex group (P less than 0.001; odds ratio, 8.6 [95 percent confidence limits, 2.2 and 52.6]). There were no significant differences between the groups with respect to changes in CD4+ cell count or the development of other HIV-related conditions, with the exception of thrush, which developed in fewer patients in the inosine pranobex group (P = 0.05). No serious side effects were observed. We conclude that treatment with inosine pranobex delays progression to AIDS in patients with HIV infection. The duration of this beneficial effect, the optimal dose, and the mode of action of inosine pranobex remain to be clarified
Glutathione levels in antigen-presenting cells modulate Th1 versus Th2 response patterns. Peterson JD, Herzenberg LA, Vasquez K, et al. Proc Natl Acad Sci U S A. 1998 Mar 17; 95(6):3071-6. Current thinking attributes the balance between T helper 1 (Th1) and Th2 cytokine response patterns in immune responses to the nature of the antigen, the genetic composition of the host, and the cytokines involved in the early interaction between T cells and antigen-presenting cells. Here we introduce glutathione, a tripeptide that regulates intracellular redox and other aspects of cell physiology, as a key regulatory element in this process. By using three different methods to deplete glutathione from T cell receptor transgenic and conventional mice and studying in vivo and/or in vitro responses to three distinct antigens, we show that glutathione levels in antigen-presenting cells determine whether Th1 or Th2 response patterns predominate. These findings present new insights into immune response alterations in HIV and other diseases. Further, they potentially offer an explanation for the well known differences in immune responses in "Th1" and "Th2" mouse strains
Isoprinosine and Imuthiol, two potentially active compounds in patients with AIDS-related complex symptoms. Pompidou A, Delsaux MC, Telvi L, et al. Cancer Res. 1985 Sep; 45(9 Suppl):4671s-3s. Isoprinosine and Imuthiol are immunomodulators with a unique effect on T-cells. The possibility of using them in treating patients with acquired immunodeficiency syndrome related complex (ARC) was initially examined regarding their in vitro effects on peripheral blood mononuclear cells. In six ARC patients Isoprinosine (100 micrograms/ml) and Imuthiol (10 pg/ml) induced in vitro an early chromatin activation as measured by nuclear refringency test and potentiated phytohemagglutinin (5 micrograms/ml) in the same 20-min assay in the absence of fetal calf serum. In all patients an early phytohemagglutinin induced chromatin dispersion was observed with a dose related response before interleukin 2 production can occur. Isoprinosine and Imuthiol increased significantly both the percentage and the absolute number of T4+ cells when peripheral blood mononuclear cells were incubated for 4 days in RPMI supplemented with 10% fetal calf serum. No changes in T8+ cells were noted. Three homosexual ARC patients were then treated p.o. with Imuthiol (5-10 mg/kg/week) for 4 to 6 months. Without any deleterious effect a clinical improvement (in terms of adenopathy and opportunistic infection regression) and restoration of the response to recall antigens were observed in all three patients. One patient with less than 500 T4+ lymphocytes/mm3 exhibited a complete restoration of OKT profiles. In such patients clinical and immunological effects of Isoprinosine have already been reported by others. Altogether these preliminary results indicate that more data should be obtained on the effects of these two agents in ARC patients
In-vitro inhibition of LAV/HTLV-III infected lymphocytes by dithiocarb and inosine pranobex. Pompidou A, Zagury D, Gallo RC, et al. Lancet. 1985 Dec 21; 2(8469-70):1423.
Olive Leaf Extract: A New/Old Healing Bonanza for Mankind. Privitera JR. NutriScreen Covina, CA. 1996
Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. Quinn TC, Wawer MJ, Sewankambo N, et al. N Engl J Med. 2000 Mar 30; 342(13):921-9. BACKGROUND AND METHODS: We examined the influence of viral load in relation to other risk factors for the heterosexual transmission of human immunodeficiency virus type 1 (HIV-1). In a community-based study of 15,127 persons in a rural district of Uganda, we identified 415 couples in which one partner was HIV-1-positive and one was initially HIV-1-negative and followed them prospectively for up to 30 months. The incidence of HIV-1 infection per 100 person-years among the initially seronegative partners was examined in relation to behavioral and biologic variables. RESULTS: The male partner was HIV-1-positive in 228 couples, and the female partner was HIV-1-positive in 187 couples. Ninety of the 415 initially HIV-1-negative partners seroconverted (incidence, 11.8 per 100 person-years). The rate of male-to-female transmission was not significantly different from the rate of female-to-male transmission (12.0 per 100 person-years vs. 11.6 per 100 person-years). The incidence of seroconversion was highest among the partners who were 15 to 19 years of age (15.3 per 100 person-years). The incidence was 16.7 per 100 person-years among 137 uncircumcised male partners, whereas there were no seroconversions among the 50 circumcised male partners (P<0.001). The mean serum HIV-1 RNA level was significantly higher among HIV-1-positive subjects whose partners seroconverted than among those whose partners did not seroconvert (90,254 copies per milliliter vs. 38,029 copies per milliliter, P="0.01)." There were no instances of transmission among the 51 subjects with serum HIV-1 RNA levels of less than 1500 copies per milliliter; there was a significant dose-response relation of increased transmission with increasing viral load. In multivariate analyses of log-transformed HIV-1 RNA levels, each log increment in the viral load was associated with a rate ratio of 2.45 for seroconversion (95 percent confidence interval, 1.85 to 3.26). CONCLUSIONS: The viral load is the chief predictor of the risk of heterosexual transmission of HIV-1, and transmission is rare among persons with levels of less than 1500 copies of HIV-1 RNA per milliliter
A double-blind, placebo-controlled trial of testosterone therapy for HIV-positive men with hypogonadal symptoms. Rabkin JG, Wagner GJ, Rabkin R. Arch Gen Psychiatry. 2000 Feb; 57(2):141-7. BACKGROUND: The goal was to evaluate the efficacy of testosterone in alleviation of hypogonadal symptoms (diminished libido, depressed mood, low energy, and depleted muscle mass) in men with symptomatic human immunodeficiency virus illness. METHODS: Seventy-four patients were enrolled in a double-blind, placebo-controlled 6-week trial with bi-weekly testosterone injections, followed by 12 weeks of open-label maintenance treatment. Major outcome measures were Clinical Global Impressions Scale ratings for libido, mood, energy, and erectile function; Hamilton Depression Rating Scale scores, and Chalder Fatigue Scale scores. Body composition changes were assessed with bioelectric impedance analysis. RESULTS: Seventy men completed the 6-week trial. Response rates, defined as much or very much improved libido, were 74% (28/38) for patients randomized to testosterone, and 19% (6/32) for placebo-treated patients (P<.001). Of the 62 completers with fatigue at baseline, 59% (20/34) receiving testosterone and 25% (7/28) receiving placebo reported improved energy (P<.01). Among the 26 completers with an Axis I depressive disorder at baseline, 58% of the testosterone-treated patients reported improved mood compared with 14% of placebo-treated patients (Fisher exact test = ".08)." With testosterone treatment, average increase in muscle mass over 12 weeks was 1.6 kg for the whole group, and 2.2 kg for the 14 men with wasting at baseline. Improvement on all parameters was maintained during subsequent open-label treatment for up to 18 weeks. CONCLUSION: Testosterone is well tolerated and effective in the short-term treatment of symptoms of clinical hypogonadism in men with symptomatic human immunodeficiency virus illness, restoring libido and energy, alleviating depressed mood, and increasing muscle mass
Inhibition of HIV progression by dithiocarb. German DTC Study Group. Reisinger EC, Kern P, Ernst M, et al. Lancet. 1990 Mar 24; 335(8691):679-82. 60 patients with HIV-1 infection in Walter Reed stages 2-4 were randomised to treatment with intravenous or oral dithiocarb (diethyldithiocarbamate, DTC) or placebo for 24 weeks in a paired double-blind design. 55 patients were evaluable at the end of the study: no patient who had received DTC but 6 placebo patie |