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LE Magazine January 1997

Replacement of DHEA in aging men and women Potential remedial effects

Yen SS; Morales AJ; Khorram O Department of Reproductive Medicine, University of California, San Diego, La Jolla 92093, USA Ann N Y Acad Sci (U.S.) Dec 29 1995, 774 p128-42,

DHEA in appropriate replacement doses appears to have remedial effects with respect to its ability to induce an anabolic growth factor, increase muscle strength and lean body mass, activate immune function, and enhance quality of life in aging men and women, with no significant adverse effects. Further studies are needed to confirm and extend our current results, particularly the gender differences.

Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age

Aging in humans is accompanied by a progressive decline in the secretion of the adrenal androgens dehydroepiandrosterone (DHEA) and DHEA sulfate (DS), paralleling that of the GH-insulin-like growth factor-I (GH-IGF-I) axis. Although the functional relationship of the decline of the GH-IGF-I system and catabolism is recognized, the biological role of DHEA in human aging remains undefined. To test the hypothesis that the decline in DHEA may contribute to the shift from anabolism to catabolism associated with aging, we studied the effect of a replacement dose of DHEA in 13 men and 17 women, 40-70 yr of age. A randomized placebo-controlled cross-over trial of nightly oral DHEA administration (50 mg) of 6-month duration was conducted. During each treatment period, concentrations of androgens, lipids, apolipoproteins, IGF-I, IGF-binding protein-1 (IGFBP-1), IGFBP-3, insulin sensitivity, percent body fat, libido, and sense of well-being were measured. A s ubgroup of men (n = 8) and women (n = 5) underwent 24-h sampling at 20-min intervals for GH determinations. DHEA and DS serum levels were restored to those found in young adults within 2 weeks of DHEA replacement and were sustained throughout the 3 months of the study. A 2-fold increase in serum levels of androgens (androstenedione, testosterone, and dihydrotestosterone) was observed in women, with only a small rise in androstenedione in men. There was no change in circulating levels of sex hormone-binding globulin, estrone, or estradiol in either gender. High density lipoprotein levels declined slightly in women, with no other lipid changes noted for either gender. Insulin sensitivity and percent body fat were unaltered. Although mean 24-h GH and IGFBP-3 levels were unchanged, serum IGF-I levels increased significantly, and IGFBP-1 decreased significantly for both genders, suggesting an increased bioavailability of IGF-I to target tissues. This was associated with a remarkable increase in perceived physical and psychological well-being for both men (67%) and women (84%) and no change in libido. In conclusion, restoring DHEA and DS to young adult levels in men and women of advancing age induced an increase in the bioavailability of IGF-I, as reflected by an increase in IGF-I and a decrease in IGFBP-1 levels. These observations together with improvement of physical and psychological well-being in both genders and the absence of side-effects constitute the first demonstration of novel effects of DHEA replacement in age-advanced men and women.

Taurine deficiency after intensive chemotherapy and/or radiation

Am J Clin Nutr; 55(3):708-11 1992

Taurine, a nonessential amino acid (AA), is the most abundant free AA in the intracellular space. We measured plasma AA concentrations in 36 patients 7-28 d after intensive chemotherapy and/or radiation. Plasma taurine concentrations were uniformly low in all patients (20.0 +/- 6.4 mumol/L, mean +/- SD). Plasma taurine in 11 healthy volunteer control subjects was 45.0 +/- 20.3 mumol/L (P less than 0.001). Other AA concentrations, specifically those of precursor AAs methionine and cystine, were normal. We prospectively measured plasma AA concentrations in 12 patients before starting and 6-10 d after completing intensive cytotoxic treatment. Values before treatment were 37.2 +/- 11.6, 109.6 +/- 30.7, and 18.5 +/- 4.8 for taurine, cystine, and methionine, respectively, and were 24.3 +/- 6.0, 111.2 +/- 23.8, and 24.0 +/- 14.5 after treatment. Pretreatment plasma taurine correlated directly with the magnitude of decrease in plasma taurine during cytotoxic treatment (n = 12, r = 0.85, P less than 0.01). Intensive cytotoxic chemotherapy and/or radiation leads to a reduction in plasma taurine concentrations without any change in its precursor AAs, methionine and cystine. The clinical relevance of plasma taurine depletion will need further study.

Effect of glutaurine and its derivatives and their combinations with radiation protective substances upon irradiated mice

Acta Radiol Oncol Radiat Phys Biol; 20(5):319-324 1981

The radiation protective effects of glutaurine (gamma-L-glutamyl-taurine, Litoralon), and of some of its derivatives, as well as of their combinations with substances of the amino-alkyl-thiol group, have been investigated in mice. The results suggest that glutaurine possesses a radiation protective effect in animals irradiated with LD50/30 of roentgen rays and 60Co gamma rays. The compound has a favorable effect also when administered after irradiation. Among the combinations best results were obtained by its simultaneous administration with subminimal doses of S-beta-aminoethyl-isothiuronium (AET) or cystamine. Some of its derivatives also exhibited considerable protection against irradiation with roentgen rays.

Effect of mixed gamma-neutron irradiation on taurine penetration through cellular membranes of rat peripheral blood leukocytes

Res. Inst. Biology and Biophysics, V. V. Kuibyshev Tomsk State Univ., Tomsk,

USSRCapacity of rat peripheral blood WBC for transmembrane transfer of taurine was studied in vitro in normal controls and 24 hr after mixed gamma-neutron (70%) irradiation (GNI: 350 rads). Four hr after GNI, the number of WBC decreased and equaled 31% of the initial level; the amount of taurine increased within the same period, and 24 hr after GNI it was 3x the initial level. At the same time, an increase in the protein content of WBC was seen. Irradiation was found to change the membrane permeability. It was noted that 24 hr after GNI, the system of taurine transport in the irradiated cells became more specific: the affinity to taurine increased, and the d,l-beta-alanine- dependent transfer system began to play a more important role. In another series of experiments, it was found that damage to cell membranes caused by WBC trypsinization decreased the taurine content 5x, showing that the greater part of taurine is localized inside the cells, where it apparently participates in metabolism.

Taurine and sh-group content in the platelets of irradiated rats

Radiobiologiia; 18(2):271-274

The association between the content taurine and SH-groups of platelets during radiation sickness was studied in albino rats. Animals were irradiated with 650 R and sacificed 1, 4, 7, 12 and 21 days later. The levels of taurine and SH-groups in separated platelets was measured per protein unit. The development of radiation sickness resulted in a sevenfold decrease in the content of platelet taurine on days 4-7 of irradiation and twofold decrease in SH-group content on day 12 of irradiation. On day 21,the content of both taurine and SH-groups showed normalization. The decrease in taurine and SH-groups content may have been due to radiation-induced elevation of protein adsorption on platelet membrane.

Effect of alkoxyglycerols on the frequency of injuries following radiation therapy for carcinoma of the uterine cervix

Acta Obstet Gynecol Scand; 56(4):441-448 1977

The occurrence of complications of intracavitary and external radiotherapy of cervical carcinoma was studied in 657 patients given radium only (controls), 595 patients treated prophylactically with shark liver oil alkoxyglycerols (preparation AT-18: 0.6 g/day, po) before (for 7 days), during, and after (for 1-3 mo) radiotherapy, and 523 patients given a 'non-prophylactic' course of alkoxyglycerols during and after radiotherapy. The follow-up period was greater than 5 yr in 1,496 patients (including all controls) and 3.5 yr in 279 patients. Radiation damage to the bladder, ureters, intestine, and rectum and complex damage caused by tumor growth, with or without radiation injury, were studied. High-dose radium (intrauterine, greater than 100 mg; vaginal application, greater than 90 mg) caused an unexpectedly large number of radiation injuries, but this was greatly reduced by alkoxyglycerol therapy, especially prophylactic therapy. In all groups studied, prophylactic and non-prophylactic therapy greatly reduced radiation injuries. Only prophylactic therapy reduced complex damage (by about 60% in the high-dose radium group, about 67% in the total group). The data suggested that prophylactic alkoxyglycerol therapy could transform complex damage to a radiation injury by inhibiting the tumor-growth component of complex injuries. Since about 99% of the patients with complex injuries died within 5 yr, such prophylactic therapy could increase the 5-yr survival rate. In vivo radioprotective activity of Panax ginseng and diethyldithiocarbamate In Vivo; 7(5):467-70 1993 Studies were performed to determine whether the water fraction and the alkaloid fraction of Panax ginseng protect against radiation damage to jejunal crypts of N:GP(s) mice and induction of micronuclei (MN) in cytokinesis-blocked (CB) lymphocytes of C57BL/6 mice after in vivo irradiation with 60Co gamma-rays. The radioprotective effect of ginseng was compared with the effect of diethyldithiocarbamate (DDC). Jejunum was protected by the water fraction (2 mg/ml of drinking water) (P 0.001) and the alkaloid fraction (5.4 mg/day, P.O.) (P 0.005), both pre-and post-treatment, and by DDC (1000 mg/kg B.W., single I.P., 30 minutes before 15 Gy irradiation) (P 0.001). The frequency of radiation (3 Gy)-induced micronuclei in spleen lymphocytes was also reduced by pretreatment of water fraction, alkaloid fraction of ginseng (P 0.025) and DDC (P 0.001). The data suggested that the water fraction and alkaloid fraction of Panax ginseng may reduce cell damage caused by gamma-rays, especially damage to DNA molecules, and play a role in the repair or regeneration process of damaged cells.

Inhibition of mutagenesis and transformation by root extracts of panax ginseng in vitro

Planta Med; 57(2):125-8 1991

The root extract of Panax ginseng was investigated for its inhibitory effects on DNA synthesis, mutagenicity, and cellular transformation using V79 and NIH 3T3 cells. DNA synthesis measured by the [3H]thymidine incorporation into V79 Chinese hamster lung cells was significantly decreased by the addition of ginseng extract (0-1 microgram/ml) to the medium. However, ginseng extract was found to increase the rate of DNA excision repair synthesis in V79 cells in response to treatment with UV radiation or methyl methanesulfonate. The extract also showed decreased mutation frequency when mutagenicity was examined using V79 cells at the hypoxanthine-guanine phosphoribosyl transferase locus as resistance to 6-thioguanine after exposure to methyl methanesulfonate. We also found that the components of ginseng extract continue to exert an inhibitory effect on the transformation of NIH 3T3 cells initiated by 3-methylchloanthrene, methyl methanesulfonate, and 1-methyl-3-nitro-1-nitrosoguanidine.

Restoration of radiation injury by ginseng-some properties of the radioprotective substances

J Radiat Res (Tokyo); 22(3):336-343

Some properties of the radioprotective substance ginseng extract (GE) were studied in male 4-wk-old JCL-ICR mice. Prior to injection GE was dissolved in physiological saline and insolubles discarded after centrifugation. Mice injected with only physiological saline served as controls. The 30-day survival ratio was measured in both groups. Methanol-soluble GE did not protect the irradiated animals. Acid or alkali (0.12 N) inactivated GE at 60 C. GE radioprotective activity was stable after heating in physiological saline at pH 7 in a boiling-water bath for 15 min. GE was separated into two fractions by CM-cellulose column chromatography. Fraction CM-A was significantly efficacious at p less than 0.05, and CM-B was effective at p less than 0.001; doses were proportional to yield. UV spectrum and biuret tests suggested the presence of protein in the CM-B fraction. Supernatant obtained after heating the CM-B solution at pH 7 was separated into fractions G-I, G-II, and G-III by gel chromatography with a Sephadex G-75 column. G-I (0.44 mg/animal) and G-III (0.84 mg/animal) were significantly efficacious, but G-II (0.47 mg/animal) was not. The active component in ginseng had been thought to be ginseng saponin. Examination of the methanol-soluble fraction showed that the radioprotective component of GE is not saponin. Purification of the radioprotective substance is needed to clarify the chemical structure.

Restoration of radiation injury by ginseng- Responses of x-irradiated mice to ginseng extract

J Radiat Res (Tokyo); 22(3):323-335

The radioprotective effect of ginseng extract (GE) in JCL-ICR mice and hematological recovery of irradiated native and splenectomized mice were studied. Six-wk-old male mice were irradiated with 720 or 550 R. Within 3 min after irradiation, mice were injected ip with GE dissolved in 0.2 ml physiological saline. Control mice were injected only with saline after irradiation. Injection of 5.0 mg GE 2.5 hr before or after exposure to 720 R was significantly efficacious, but injection 1 day after treatment was not. Administration of 5.5 mg GE 2 or 1 day prior to irradiation was more efficacious than administration immediately after irradiation. The 30-day survival ratio of mice irradiated with 720 R was 5, 45, 75 and 82.5% for mice injected with 0, 1.8, 3.4, and 6.8 mg GE, respectively. The difference between control and GE groups was significant. Splenic wt of irradiated mice decreased to approx 1/3 normal on days 2-10 in the control group. The decrease was less in the GE group. Thymic wt decreased after irradiation by approx 30% from day 0 to day 30. Recovery of thymic wt was not stimulated by GE extract. GE-stimulated recovery of splenic DNA, and of thrombocyte and erythrocyte counts was observed; GE did not markedly affect leukocyte counts. GE increased the 30-day survival ratio of splenectomized mice. Only thrombocyte counts after exposure were stimulated by GE in splenectomized mice.

Recovery of thrombocyte counts after exposure is assumed to be one of the most important factors in restoration after bone marrow death. Substances stimulating recovery from radiation injury

Radioisotopes; 27(11):666-675 1978

Studies on radiation damage and recovery, and on substances that stimulate recovery are reviewed. Separation and testing of active extracts from the root of Panax ginseng, which stimulate recovery from radiation damage in mice are described. Various doses of ginseng extract (GEX) were given (mostly ip) to JCL-ICR mice (6 wk old; 40 mice per group), immediately after irradiation (IR) at various levels. The effects on the 30-day survival rates were studied. At a GEX dose of 6.8 mg and an IR dose of 720 R, the 30-day survival rate was 82.5%. At a GEX dose of 5.0 mg, no significant differences in the 30-day survival rate were found, whether GEX was injected ip or iv. At a GEX dose of 5.8 mg and an IR dose of 550 R, improvement began about the 10th day (WBC, RBC, platelet count). In non-irradiated mice, there was no particular effect of GEX on the blood. In mice splenectomized 1 wk before IR (770 R), 6.0 mg of GEX improved the 30-day survival rate compared with saline treated controls. The WBC and RBC did not recover in splenectomized mice that were irradiated, but the platelet count increased. A marked increase in the spleen wt of non-irradiated mice, associated with the administration of GEX, was eliminated by a final heat treatment of extract liquor and removal of the precipitant. Administration of 5.0 mg GEX was most effective in increasing the 30-day survival rate when given 1-2 days before irradiation. The administration of GEX 24 hr after irradiation resulted in a 30-day survival rate compared with that of controls.

Acemannan Immunostimulant in combination with surgery and radiation therapy on spontaneous canine and feline fibrosarcomas

J Am Anim Hosp Assoc; 31(5):439-47 1995

Eight dogs and five cats with histopathologically confirmed fibrosarcomas were treated with Acemannan Immunostimulanta in combination with surgery and radiation therapy. These animals had recurring disease that had failed previous treatment, a poor prognosis for survival, or both. Following four to seven weekly acemannan treatments, tumor shrinkage occurred in four (greater than 50%; n = 2) of 12 animals, with tumors accessible to measurement. A notable increase in necrosis and inflammation was observed. Complete surgical excision was performed on all animals between the fourth and seventh week following initiation of acemannan therapy. Radiation therapy was instituted immediately after surgery. Acemannan treatments were continued monthly for one year. Seven of the 13 animals remain alive and tumor-free (range, 440+ to 603+ days) with a median survival time of 372 days. The data suggests that Acemannan Immunostimulant may be an effective adjunct to surgery and radiation therapy in the treatment of canine and feline fibrosarcomas.

Acemannan-containing wound dressing gel reduces radiation-induced skin reactions in C3H mice

Int J Radiat Oncol Biol Phys; 32(4):1047-52 1995

PURPOSE: To determine (a) whether a wound dressing gel that contains acemannan extracted from aloe leaves affects the severity of radiation-induced acute skin reactions in C3H mice; (b) if so, whether other commercially available gels such as a personal lubricating jelly and a healing ointment have similar effects; and (c) when the wound dressing gel should be applied for maximum effect.

METHODS AND MATERIALS: Male C3H mice received graded single doses of gamma radiation ranging from 30 to 47.5 Gy to the right leg. In most experiments, the gel was applied daily beginning immediately after irradiation. To determine timing of application for best effect, gel was applied beginning on day -7, 0, or +7 relative to the day of irradiation (day 0) and continuing for 1, 2, 3, 4, or 5 weeks. The right inner thigh of each mouse was scored on a scale of 0 to 3.5 for severity of radiation reaction from the seventh to the 35th day after irradiation. Dose-response curves were obtained by plotting the percentage of mice that reached or exceeded a given peak skin reaction as a function of dose. Curves were fitted by logit analysis and ED50 values, and 95% confidence limits were obtained.

RESULTS: The average peak skin reactions of the wound dressing gel-treated mice were lower than those of the untreated mice at all radiation doses tested. The ED50 values for skin reactions of 2.0-2.75 were approximately 7 Gy higher in the wound dressing gel-treated mice. The average peak skin reactions and the ED50 values for mice treated with personal lubricating jelly or healing ointment were similar to irradiated control values. Reduction in the percentage of mice with skin reactions of 2.5 or more was greatest in the groups that received wound dressing gel for at least 2 weeks beginning immediately after irradiation. There was no effect if gel was applied only before irradiation or beginning 1 week after irradiation.

CONCLUSION: Wound dressing gel, but not personal lubricating jelly or healing ointment, reduces acute radiation-induced skin reactions in C3H mice if applied daily for at least 2 weeks beginning immediately after irradiation.

Usefulness of coenzyme Q10 in clinical cardiology: a long-term study

Langsjoen H; Langsjoen P; Langsjoen P; Willis R; Folkers K
University of Texas Medical Branch, Galveston 77551, USA.
Mol Aspects Med (ENGLAND) 1994, 15 Suppl ps165-75,

Over an eight year period (1985-1993), we treated 424 patients with various forms of cardiovascular disease by adding coenzyme Q10 (CoQ10) to their medical regimens. Doses of CoQ10 ranged from 75 to 600 mg/day by mouth (average 242 mg). Treatment was primarily guided by the patient's clinical response. In many instances, CoQ10 levels were employed with the aim of producing a whole blood level greater than or equal to 2.10 micrograms/ml (average 2.92 micrograms/ml, n = 297). Patients were followed for an average of 17.8 months, with a total accumulation of 632 patient years. Eleven patients were omitted from this study: 10 due to non-compliance and one who experienced nausea. Eighteen deaths occurred during the study period with 10 attributable to cardiac causes. Patients were divided into six diagnostic categories: ischemic cardiomyopathy (ICM), dilated cardiomyopathy (DCM), primary diastolic dysfunction (PDD), hypertension (HTN), mitral valve prolapse (MVP) and valvular heart disease (VHD). For the entire group and for each diagnostic category, we evaluated clinical response according to the New York Heart Association (NYHA) functional scale, and found significant improvement. Of 424 patients, 58 per cent improved by one NYHA class, 28% by two classes and 1.2% by three classes. A statistically significant improvement in myocardial function was documented using the following echocardiographic parameters: left ventricular wall thickness, mitral valve inflow slope and fractional shortening. Before treatment with CoQ10, most patients were taking from one to five cardiac medications. During this study, overall medication requirements dropped considerably: 43% stopped between one and three drugs. Only 6% of the patients required the addition of one drug. No apparent side effects from CoQ10 treatment were noted other than a single case of transient nausea. In conclusion, CoQ10 is a safe and effective adjunctive treatment for a broad range of cardiovascular diseases, producing gratifying clinical responses while easing the medical and financial burden of multidrug therapy.

Perspectives on therapy of cardiovascular diseases with coenzyme Q10 (ubiquinone)

Mortensen SA
Department of Cardiology and Internal Medicine, Rigshospitalet B 2142, State University Hospital, Copenhagen
Clin Investig (GERMANY) 1993, 71 (8 Suppl) pS116-23,

A defective myocardial energy supply-due to lack of substrates and/or essential cofactors and a poor utilization efficiency of oxygen-may be a common final pathway in the progression of myocardial diseases of various etiologies. The vitamin- like essential substance coenzyme Q10, or ubiquinone, is a natural antioxidant and has a key role in oxidative phosphorylation. A biochemical rationale for using coenzyme Q10 as a therapy in heart disease was established years ago by Folkers and associates; however, this has been further strengthened by investigations of viable myocardial tissue from the author's series of 45 patients with various cardiomyopathies. Myocardial tissue levels of coenzyme Q10 determined by high-performance lipid chromatography were found to be significantly lower in patients with more advanced heart failure compared with those in the milder stages of heart failure. Furthermore, the myocardial tissue coenzyme Q10 deficiency might be restored significantly by oral supplementation in selected cases. In the author's open clinical protocol study with coenzyme Q10 therapy (100 mg daily) nearly two-thirds of patients revealed clinical improvement, most pronounced in those with dilated cardiomyopathy. Double-blind placebo-controlled trials have definitely confirmed that coenzyme Q10 has a place as adjunctive treatment in heart failure with beneficial effects on the clinical outcome, the patients' physical activity, and their quality of life. The positive results have been above and beyond the clinical status obtained from treatment with traditional principles-including angiotensin-converting enzyme inhibitors.

Coenzyme Q10: a new drug for cardiovascular disease

Greenberg S; Frishman WH Department of Medicine, Mt. Sinai Hospital and Medical Center, New York, New York J Clin Pharmacol (UNITED STATES) Jul 1990, 30 (7) p596-608,

Co-enzyme Q10 (ubiquinone) is a naturally occurring substance which has properties potentially beneficial for preventing cellular damage during myocardial ischemia and reperfusion. It plays a role in oxidative phosphorylation and has membrane stabilizing activity. The substance has been used in oral form to treat various cardiovascular disorders including angina pectoris, hypertension, and congestive heart failure. Its clinical importance is now being established in clinical trails worldwide.

Treatment of essential hypertension with coenzyme Q10

Langsjoen P; Langsjoen P; Willis R; Folkers K
Institute for Biomedical Research, University of Texas, Austin 78712, USA.
Mol Aspects Med (ENGLAND) 1994, 15 Suppl pS265-72,

A total of 109 patients with symptomatic essential hypertension presenting to a private cardiology practice were observed after the addition of CoQ10 (average dose, 225 mg/day by mouth) to their existing antihypertensive drug regimen. In 80 per cent of patients, the diagnosis of essential hypertension was established for a year or more prior to starting CoQ10 (average 9.2 years). Only one patient was dropped from analysis due to noncompliance. The dosage of CoQ10 was not fixed and was adjusted according to clinical response and blood CoQ10 levels. Our aim was to attain blood levels greater than 2.0 micrograms/ml (average 3.02 micrograms/ml on CoQ10). Patients were followed closely with frequent clinic visits to record blood pressure and clinical status and make necessary adjustments in drug therapy. Echocardiograms were obtained at baseline in 88% of patients and both at baseline and during treatment in 39% of patients. A definite and gradual improvement in functional status was observed with the concomitant need to gradually decrease antihypertensive drug therapy within the first one to six months. Thereafter, clinical status and cardiovascular drug requirements stabilized with a significantly improved systolic and diastolic blood pressure. Overall New York Heart Association (NYHA) functional class improved from a mean of 2.40 to 1.36 (P 0.001) and 51% of patients came completely off of between one and three antihypertensive drugs at an average of 4.4 months after starting CoQ10. Only 3% of patients required the addition of one antihypertensive drug. In the 9.4% of patients with echocardiograms both before and during treatment, we observed a highly significant improvement in left ventricular wall thickness and diastolic function.

Coenzyme Q10 in essential hypertension

Digiesi V; Cantini F; Oradei A; Bisi G; Guarino GC; Brocchi A; Bellandi F; Mancini M; Littarru GP
Third institute of Clinical Medicine and Medical Therapy, University of Florence Medical School, Italy
Mol Aspects Med (ENGLAND) 1994, 15 Suppl ps257-63

This study was undertaken to clarify the mechanism of the antihypertensive effect of coenzyme Q10 (CoQ10). Twenty-six patients with essential arterial hypertension were treated with oral CoQ10, 50 mg twice daily for 10 weeks. Plasma CoQ10, serum total and high-density lipoprotein (HDL) cholesterol, and blood pressure were determined in all patients before and at the end of the 10-week period. At the end of the treatment, systolic blood pressure (SBP) decreased from 164.5 +/- 3.1 to 146.7 +/- 4.1 mmHg and diastolic blood pressure (DBP) decreased from 98.1 +/- 1.7 to 86.1 +/- 1.3 mmHg (P 0.001). Plasma CoQ10 values increased from 0.64 +/- 0.1 microgram/ml to 1.61 +/- 0.3 micrograms/ml (P 0.02). Serum total cholesterol decreased from 222.9 +/- 13 mg/dl to 213.3 +/- 12 mg/dl (P 0.005) and serum HDL cholesterol increased from 41.1 +/- 1.5 mg/dl to 43.1 +/- 1.5 mg/dl (P 0.01). In a first group of 10 patients serum sodium and potassium, plasma clinostatic and orthostatic renin activity, urinary aldosterone, 24-hour sodium and potassium were determined before and at the end of the 10-week period. In five of these patients peripheral resistances were evaluated with radionuclide angiocardiography. Total peripheral resistances were 2,283 +/- 88 before treatment and 1,627 +/- 158 after treatment (P 0.02). Plasma renin activity, serum and urinary sodium and potassium, and urinary aldosterone did not change. In a second group of 11 patients, plasma endothelin, electrocardiogram, two-dimensional echocardiogram and 24-hour automatic blood pressure monitoring were determined.

Acetyl-L-carnitine in Alzheimer disease:

a short-term study on CSF neurotransmitters and neuropeptides
Bruno G; Scaccianoce S; Bonamini M; Patacchioli FR; Cesarino F; Grassini P; Sorrentino E; Angelucci L; Lenzi GL
Dipartimento di Scienze Neurologiche, Universita di Roma La Sapienza, Italy
Alzheimer Dis Assoc Disord (U.S.) Fall 1995, 9 (3) p128-31,

Acetyl-L-carnitine (ALCAR) is a drug currently under investigation for Alzheimer disease (AD) therapy. ALCAR seems to exert a number of central nervous system (CNS)-related effects, even though a clear pharmacological action that could explain clinical results in AD has not been identified yet. The aim of this study was to determine cerebrospinal fluid (CSF) and plasma biological correlates of ALCAR effects in AD after a short-term, high-dose, intravenous, open treatment. Results show that ALCAR CSF levels achieved under treatment were significantly higher than the ones at baseline, reflecting a good penetration through the blood-brain barrier and thus a direct CNS challenge. ALCAR treatment produced no apparent change on CSF classic neurotransmitters and their metabolite levels (homovanillic acid, 5-hydroxyindoleacetic acid, MHPG, dopamine, choline). Among CSF peptides, while corticotropin-releasing hormone and adrenocorticotropic hormone remained unchanged, beta-endorphins significantly decreased after treatment; plasma cortisol levels matched this reduction. Since both CSF beta-endorphins and plasma cortisol decreased, one possible explanation is that ALCAR reduced the AD-dependent hypothalamic-pituitary-adrenocortical (HPA) axis hyperactivity. At present, no clear explanation can be proposed for the specific mechanism of this action.

Clinical and neurochemical effects of acetyl-L-carnitine in Alzheimer's disease

Pettegrew JW; Klunk WE; Panchalingam K; Kanfer JN; McClure RJ
Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh, School of Medicine, PA 15213, USA.
Neurobiol Aging (UNITED STATES) Jan-Feb 1995, 16 (1) p1-4,

In a double-blind, placebo study, acetyl-L-carnitine was administered to 7 probable Alzheimer's disease patients who were then compared by clinical and 31P magnetic resonance spectroscopic measures to 5 placebo-treated probable AD patients and 21 age-matched healthy controls over the course of 1 year. Compared to AD patients on placebo, acetyl-L-carnitine-treated patients showed significantly less deterioration in their Mini-Mental Status and Alzheimer's Disease Assessment Scale test scores. Furthermore, the decrease in phosphomonoester levels observed in both the acetyl-L-carnitine and placebo AD groups at entry was normalized in the acetyl-L-carnitine-treated but not in the placebo-treated patients. Similar normalization of high-energy phosphate levels was observed in the acetyl-L-carnitine-treated but not in the placebo-treated patients. This is the first direct in vivo demonstration of a beneficial effect of a drug on both clinical and CNS neurochemical parameters in AD.

Neuroprotective activity of acetyl-L-carnitine:
studies in vitro

Forloni G; Angeretti N; Smiroldo S
Unit of Neurobiology of Alzheimer, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy
J Neurosci Res (UNITED STATES) Jan 1994, 37 (1) p92-6,

The neuroprotective properties of acetyl-L-carnitine (ALCAR) were investigated in primary cell cultures from rat hippocampal formation and cerebral cortex of 17-day-old rat embryos. Chronic exposure to ALCAR (10-50 microM for 10 days) reduced the cell mortality induced by 24 hr fetal calf serum deprivation. Protection was partial when the neuronal cells, chronically treated with ALCAR (50 microM), were exposed to glutamate (0.25-1 mM) and kainic acid (250-500 microM) for were characterized with the subjects in two states of Vitamin-C nutriture: a depleted state, which was achieved by 4-5 wk of compliance with a Vitamin-C-restricted diet of less than 10 mg/d and a supplemented state, in which the subjects were given 500 mg Vitamin-C/d for 3 wk. Plasma and urine samples were collected for 72 h after the dose of Vitamin-C from depleted subjects and for 24 h from supplemented subjects and analyzed for Vitamin-C. Several of the pharmacokinetic indices measured were different in depleted vs supplemented subjects but none exhibited any age-related differences. This indicates that Vitamin-C nutriture affects Vitamin-C pharmacokinetics but age does not.

The excretion of large Vitamin-C loads in young and elderly subjects: an ascorbic acid tolerance test

Neale RJ; Lim H; Turner J; Freeman C; Kemm JR
Department of Applied Biochemistry and Food Science, University of Nottingham, Loughborough
Age Ageing (ENGLAND) Jan 1988, 17 (1) p35-41,

An ascorbic acid tolerance test is described for assessing Vitamin-C status. The test is simple to administer and suitable for elderly patients. It involves giving an oral load of 1 g ascorbic acid in water and then measuring urinary excretion of Vitamin-C over the next 6h. The excretion pattern at dosing has been studied in ten young subjects. The result of the ascorbic acid tolerance test in these young subjects was significantly different after supplementation with 1g ascorbic acid daily for 1 month. Two series of elderly patients were also studied with the ascorbic acid tolerance test. They had low initial plasma ascorbic acid levels and much less Vitamin-C was excreted in the urine after dosing. Seven of these elderly patients were then supplemented with 1g ascorbic acid for 1 month. After supplementation the initial plasma levels and their response to the ascorbic acid tolerance test became similar to that seen in younger subjects.