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LE Magazine July 2001

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Thymosin alpha-1

High doses of thymosin alpha-1 enhance the anti-tumor efficacy of combination chemo-immunotherapy for murine B16 melanoma.

BACKGROUND: We have reported previously that combined chemo-immunotherapy with cyclophosphamide (CY), thymosin alpha-1 (T alpha-1) and low dose interferon alpha,beta (IFN alpha beta) has significant anti-tumour effects. Here, using mouse B16 melanoma as a model, we tested whether increasing the dose of T alpha-1 could increase the anti-tumour activity of triple combination chemo-immunotherapy. MATERIALS AND METHODS: C57BL/6 mice were challenged subcutaneously with B16 melanoma cells and injected intraperitoneally with saline, CY (200 mg/kg, day 7), or CY with T alpha-1 (200, 600 or 6000 micrograms/kg/day, days 10-13) and IFN alpha beta (30,000 I.U., day 13). RESULTS: Chemo-immunotherapy with high dose (HD)-T alpha-1 caused complete tumour regression for 27.5 days after tumour cell injection (3.9 times longer than untreated controls) and delayed tumour relapse compared to all other groups. Moreover, it significantly increased the median survival time of treated mice, and cured an average of 23% of animals, while none was cured in any other group. Splenocytes from HD-T alpha-1-treated mice showed markedly increased cytotoxic activities against both YAC-l and autologous B16 tumour cells. HD-T alpha-1 treatment reversed the tumour-induced reduction in percentages of CD3 and CD4-positive splenocytes to non-tumour levels, and it increased percentages of CD8, B220 and IL-2R beta-positive cells to well beyond non-tumour controls. CONCLUSIONS: High doses of T alpha-1 improve anti-tumour efficacy of chemo-immunotherapy against B16 melanoma. These effects appear to be mediated by stimulation of the host immune response.

Anticancer Res 1998 Sep-Oct;18(5A):3571-8

Thymosin alpha-1 is chemopreventive for lung adenoma formation in A/J mice.

The effects of thymosin (THN) alpha-1 were investigated using the urethane injection carcinogenesis A/J mouse model. Lung adenomas were observed 2.5, 3, and 4 months after urethane injection (400 mg/kg i.p.) into female A/J mice. Daily administration of THN alpha-1 (0.4 mg/kg, s.c.) reduced lung adenoma multiplicity significantly, by approximately 45, 40, and 17%, respectively, 2.5, 3 and 4 months after urethane injection. Animals treated with THN alpha-1 had a significantly greater white cell density than control A/J mice. Endogenous THN alpha-1-like peptides were detected in the mouse lung. By radioimmunoassay and by Western blot, prothymosin alpha was detected in the mouse lung. By immunocytochemistry, THN alpha-1-like peptides were detected in all lung compartments including the bronchus, adenoma, bronchioles, and alveoli. These results indicate that exogenous THN alpha-1 prevents lung carcinogenesis in A/J mice.

Cancer Lett 2000 Jul 31;155(2):121-7

Immunomodulating activity of thymosin fraction 5 and thymosin alpha-1 in immunosuppressed mice.

We found that both thymosin from calf thymus and its constituent peptide alpha-1 prepared by chemical synthesis restore cell-mediated immunity following its suppression in mice by injection of 5-FU. Conditions suitable for assessing the thymosin activity by means of footpad reaction were established in such immunosuppressed mice. In this new animal model, thymosin alpha-1 peptide showed activity at a low dose of 5-50 micrograms/kg, which was 100-1,000 times less than that required for thymosin F-5 preparations. Further studies utilizing the adoptive transfer technique showed that alpha-1 peptide corrects the 5-FU-induced suppression of mature T cells, transferring the DTH response as well as that of macrophage function responsible for the expression of footpad reaction. Furthermore, regeneration of lymph node and bone marrow cells as well as CFU-c (progenitor cells of macrophages and granulocytes) was enhanced by thymosin alpha-1 in the 5-FU-treated mice. All these results indicate that thymosin alpha-1 accelerates the replenishment and maturation of haematopoietic cells, including not only T cells but also macrophages, when they have been severely damaged by the 5-FU treatment.

Cancer Immunol Immunother 1983;15(2):108-13

Thymosin alpha-1 exerts protective effect against the 5-FU induced bone marrow toxicity.

Thymosin alpha-1 was shown to prevent the 5-fluorouracil (5-FU)-induced bone marrow toxicity in BDF1 mice, as determined by the cellularity, haemopoietic stem cells (CFU-s) and granulocyte-macrophage colony forming unit (GM-CFU). Furthermore, thymosin alpha-1 increased the levels of colony stimulating factor (CSF) in sera or in culture media of spleen cells derived from 5-FU-treated mice. The treatment of spleen cells with anti-Thy 1,2 antibody plus complement abolished completely the CSF production. The in vivo treatment of donor mice with anti-Thy 1,2 antibody following 5-FU abolished completely the capability of their bone marrow cells to save lethally irradiated recipients. Thymosin alpha-1 treatment prevented the damage by such combined treatment. The present study indicates that thymosin alpha-1 exerts its protective effect against the 5-FU-induced bone marrow toxicity, at least partially, through its effect on the maturation of immature T cells to functional T cells which produce various kinds of lymphokines including CSF.

Int J Immunopharmacol 1985;7(5):761-8

Combination thymosin alpha-1 and lymphoblastoid interferon treatment in chronic hepatitis C.

BACKGROUND: Monotherapy for chronic hepatitis C using interferon (IFN) results in a very small proportion of patients exhibiting a sustained response. Clinical trials assessing the benefit of combination drug therapy may provide evidence of improved treatment response over that seen with single drug treatment. AIM: To assess the response in patients with chronic hepatitis C to one year of combination treatment: thymosin alpha-1 (T alpha-1), 1 mg twice weekly, and lymphoblastoid (L)-IFN, 3 MU thrice weekly. PATIENTS AND METHODS: Fifteen patients with serum HCV RNA positive chronic hepatitis C were studied. Eleven patients were treatment naive and four had failed previous standard IFN therapy. Thirteen patients were HCV RNA serotype 1b. All patients were given combination T alpha-1 and L-IFN therapy for one year with a six month follow up period. RESULTS: Six months after initiation of treatment seven patients (47%) were sera HCV RNA negative and at completion of the one year treatment 11 (73%), including two who had failed previous standard IFN treatment, had negative serum HCV RNA. Six months after treatment, six patients (40%), including five with HCV type 1b, showed a sustained response characterized by a negative serum HCV RNA. CONCLUSIONS: The results of this open label trial suggest that there may be a potential benefit to combining an immune modulator (T alpha-1) with an antiviral (IFN) in the treatment of chronic hepatitis C. Verification of the observations in this study require completion of a randomised controlled study.

Gut 1996 Nov;39(5):679-83

Memantine

Pharmacologic rationale for memantine in chronic cerebral hypoperfusion, especially vascular dementia.

Memantine is a moderate-affinity, voltage-dependent, uncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors. In contrast to competitive NMDA antagonists, memantine is well tolerated in humans and is being developed for the treatment of dementia. The pathogenesis of vascular dementia (VaD) is largely unknown, and is likely multifactorial, but it involves the impairment of blood circulation as a common denominator. There is broad evidence for the efficacy of memantine in several animal models of ischemia. Memantine also acts on several secondary, potentially contributing factors in VaD such as neuronal depolarization, removal of magnesium block of NMDA receptors, chronic overstimulation of these receptors, and, possibly, mitochondrial dysfunction. Among others, it also has additional positive effects on long-term potentiation and cognition in standard animal models of impaired synaptic plasticity. Recently, clinical efficacy of memantine has been shown in an etiologically mixed population of severely demented patients, including those with VaD. Given the difficulties of diagnosing VaD in clinical practice, an optimal antidementive drug should be beneficial in both Alzheimer disease and VaD. Preclinical data presented in this paper indicate that such benefits can be achieved with memantine. In addition, phase II clinical data in dementia are summarized, and two ongoing pivotal trials in VaD are described. Suggestions for VaD guideline development are made regarding clinical instruments, and etiologies and severity stages are considered.

Alzheimer Dis Assoc Disord 1999 Oct-Dec;13 Suppl 3:S172-8

Efficacy and tolerability of memantine in patients with dementia syndrome. A double-blind, placebo controlled trial.

The efficacy and tolerability of memantine (1-amino-3,5-dimethyl-adamantane hydrochloride, Akatinol memantine; CAS 41100-52-1) was investigated in a double-blind, randomized clinical study versus placebo in 66 patients aged between 65 and 80 years predominantly suffering from mild to moderate vascular dementia. The target variables assessed were the baseline differences of the Sandoz Clinical Assessment Geriatric scale (SCAG) and Syndrom-Kurz-Test (SKT) total scores and the total time required in the subtests of Activity of Daily Living tests (ADL). Additional parameters assessed were the physician's global impression, the Mini Mental State Evaluation (MMSE), the Tapping and Trace tests for fine motor rating and the quality in performing the ADL tests. Adverse drug effects were recorded by DOTES/TWIS. 59 of the 66 patients included in the study terminated the trial (29 in the placebo and 30 in the memantine group). For the baseline differences of the SCAG total score a statistically significant improvement was observed already after 14 days of memantine treatment as compared to placebo. After 42 days this difference was still more pronounced and highly significant. Significant improvements after 14 and 42 days of memantine treatment could also be demonstrated for the SCAG subscales cognitive disturbances, lack of drive, emotional disturbances, social behaviour and somatic disturbances. Additionally, the efficacy of the drug could be confirmed by the SKT and ADL tests. Particularly striking in the ADL tests was the considerable improvement achieved in the quality of performing the tasks under memantine treatment.

Arzneimittelforschung 1991 Aug;41(8):773-80

Evaluation of memantine for neuroprotection in dementia.

Memantine, a non-competitive NMDA antagonist, has been approved for use in the treatment of dementia in Germany for over ten years. The rationale for use is excitotoxicity as a pathomechanism of neurodegenerative disorders. memantine acts as a neuroprotective agent against this pathomechanism, which is also implicated in vascular dementia. HIV-1 proteins Tat and gp120 have been implicated in the pathogenesis of dementia associated with HIV infection and the neurotoxicity caused by HIV-1 proteins can be blocked completely by memantine. memantine has been investigated extensively in animal studies and following this, its efficacy and safety has been established and confirmed by clinical experience in humans. It exhibits none of the undesirable effects associated with competitive NMDA antagonists such as dizocilpine. The efficacy of memantine in a variety of dementias has been shown in clinical trials. Memantine is considered to be a promising neuroprotective drug for the treatment of dementias, particularly Alzheimer's disease for which there is no neuroprotective therapy available currently. It can be combined with acetylcholinesterase inhibitors which are the mainstay of current symptomatic treatment of Alzheimer's disease. Memantine has a therapeutic potential in numerous CNS disorders besides dementias which include stroke, CNS trauma, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), epilepsy, drug dependence and chronic pain. If memantine is approved by the FDA for some of these indications by the year 2005, it can become a blockbuster drug by crossing the US $1 billion mark in annual sales.

Expert Opin Investig Drugs 2000 Jun;9(6):1397-406

Effects of oral memantine administration on Parkinson symptoms. Results of a placebo-controlled multicenter study.

The effectiveness of memantine on the symptoms of Parkinson's disease was investigated in 67 patients (39 males, 28 females) mostly between 55 and 75 years. The study was multi-center placebo-controlled with four treatment groups, i. e. patients with and without pre- and after-treatment with other anti-Parkinson medication receiving either placebo or memantine as sole or additional medication. The analysis of 61 evaluable cases showed a positive statistically significant influence on the single symptom tremor as well as on the neurological overall symptomatology (Webster-scale total score). Despite the inadequately ascertained mode of action memantine promises success particularly in milder and initial forms of the Parkinson syndrome either used as monotherapy or as an adjuvant.

Dtsch Med Wochenschr 1984 Jun 22;109(25):987-90

Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine).

OBJECTIVES: To assess clinical efficacy and safety of memantine-an uncompetitive N-methyl-D-aspartate (NMDA) antagonist-in moderately severe to severe primary dementia. MATERIALS AND METHODS: Dementia was defined by DSM-III-R criteria and severity was assessed by the Global Deterioration Scale (stages 5-7) and the Mini-Mental State Examination (< 10 points). Primary endpoints were the Clinical Global Impression of Change (CGI-C) rated by the physician, and the Behavioural Rating Scale for Geriatric Patients (BGP), subscore 'care dependence', rated by the nursing staff. Secondary endpoints included the modified D-Scale (Arnold/Ferm). RESULTS: The ITT sample comprised 166 patients and 151 patients were treated per protocol. At 12-week ITT endpoint analysis, 82 received memantine 10 mg per day, 84 placebo. Dementia was in 49% of the Alzheimer type and in 51% of the vascular type (CT, Hachinski score). A positive response in the CGI-C was seen in 73% versus 45% in favour of memantine (stratified Wilcoxon p < 0.001), independent of the etiology of dementia. The results in the BGP subscore 'care dependence' were 3.1 points improvement under memantine and 1.1 points under placebo (p = 0.016). A coincident response of the two independent target variables was observed in 61.3% (memantine) versus 31.6% (placebo). Secondary endpoint analysis of the D-Scale assessing basic ADL functions support the primary results. Regarding the safety profile, no significant differences between treatment groups were observed. CONCLUSIONS: The results of this trial support the hypothesis that memantine treatment leads to functional improvement and reduces care dependence in severely demented patients.

Int J Geriatr Psychiatry 1999 Feb;14(2):135-46



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