Effect of glutamine on methotrexate efficacy and toxicity

OBJECTIVE: To examine the effect of oral glutamine (GLN) on the efficacy and toxicity of methotrexate (MTX). SUMMARY BACKGROUND DATA: The use of high-dose chemotherapy regimens is limited by the severity of their toxicities. Oral GLN has been shown to decrease the gut toxicity seen with MTX treatment while enhancing its tumoricidal effect. METHODS AND RESULTS: Studies were done in laboratory rats and in breast cancer outpatients. Fischer 344 rats were randomized to 48 hours of prefeeding with GLN (1 g/kg/day) or an isonitrogenous amount of glycine. Rats were killed 24 hours after receiving a 20-mg/kg intraperitoneal dose of MTX. In the GLN group, there was a threefold increase in total MTX in the tumor as compared with the control group, and this increase was in both the diglutamated and pentaglutamated MTX. Inversely, there was a significant decrease in the total polyglutamated MTX in the gut in the GLN group. Given the results of this preclinical study, the authors performed a phase I trial. Nine patients diagnosed with inflammatory breast cancer received GLN (0.5 g/kg/day) during MTX neoadjuvant therapy, escalating from doses of 40 mg/m2 to 100 mg/m2 weekly for 3 weeks, followed by a doxorubicin-based regimen. No toxicity of oral GLN was detected. No patient showed any sign of chemotherapy-related toxicity. One patient had a grade I mucositis. Except for one, all patients responded to the chemotherapy regimen. Median survival was 35 months. CONCLUSIONS: These studies suggest that GLN supplementation is safe in its administration to the tumor-bearing host receiving MTX. By preferentially increasing tumor retention of MTX over that of normal host tissue, GLN may serve to increase the therapeutic window of this chemotherapeutic age.     

Social and medical rehabilitation of patients subjected to surgery on account of aneurysms of the anterior connecting artery

The report contains data concerning occupational and social rehabilitation of 46 patients operated on for aneurysma of the anterior communicative artery. It was established that the occupational prognosis depends upon the severity of the hemmorhage, character of surgical operation. Of significance are the conditions of work, time after the surgical operation. The authors mark that in 2/3 of the operated on patients the working capacity is being restored. A spontaneous restoration of diaturbed functions is slow and is not always sufficient. With this purpose it is expedient to repeat courses of a general tonic and special rehabilitative therapy. A favourable factor in the readaptation of patients is their early engagement in working activities. The authors give their recommendations for medical labour expert testimony for this category of patients.     

Studies on the antitesticular action of DL-6-(N-2-pipecolinomethyl)-5-hydroxy-indane (PMHI) in the rat

Both prepubertal and adult rats were treated with a single oral dose of either 60 mg or 120 mg of dl-6-(N-pipecolinomethyl)-5-hydroxy indane maleate (PMHI) per kg of body weight. Their testicular weights were drastically reduced compared with those of the controls. A follow-up, beginning on the third day post-treatment and continuing for a period of 50 days, showed that the body weight growth of PMHI-treated rats was not retarded. The hormonal profile indicated that, except for FSH which showed a transitory elevation in PMHI-treated immature rats, the serum levels of LH, estrogen, and testosterone were indistinguishable from those of the controls. Testicular histology revealed that the spermatogenic process in PMHI-treated rats recovered at a dose-related rate. EM sections of testes of adult rats indicated that cytoplasmic vacuolation appeared in the Sertoli cells 5 h post-treatment. The consequent cascade of arrested spermiogenesis included abnormal acrosomal condensation of spermatids and sloughing of polynucleated spermatids. Some spermatocytes also seemed to be affected, but spermatogonia and Leydig cells remained intact. These results indicate the PMHI acts primarily on Sertoli cells and causes arrest in the spermiogenetic stage of the spermatids. At a higher and toxic dose of PMHI, however, the earlier germinal elements might also be affected, due to the extensive damage to the supporting Sertoli cells.     

Left ventricular mass index in patients of end stage renal disease (non-diabetic) on regular haemodialysis

Echocardiography in patients of end stage renal failure (non diabetic) on regular haemodialysis revealed increase in left ventricular mass index in comparison to healthy controls. Anaemia, chronic uraemic state and hypertension were the probable contributory factors.     

Bioequivalence of a highly variable drug: an experience with nadolol

PURPOSE: To assess the bioequivalence of nadolol 40mg and 160mg tablets (Zenith-Goldline Pharmaceuticals) using Corgard 40mg and 160mg tablets (Bristol-Meyers Squibb) as reference products, to estimate the effect of food in the gastrointestinal tract on nadolol bioavailability, and to evaluate the effectiveness of standard pharmacokinetic metrics AUCt, AUC infinity, and Cmax in bioequivalence determinations. METHODS: Four bioequivalence studies were conducted as described in the FDA Guidance. Four additional studies of varying designs were conducted to establish bioequivalence of the 40mg tablet in terms of Cmax. RESULTS: Fasted and food-effect studies of the 160mg tablet clearly established bioequivalence and revealed an unexpected reduction in nadolol bioavailability from test and reference products in the presence of food. The food-effect study of the 40mg tablet (80mg dose) revealed a similar reduction in bioavailability from each product. Fasted studies of the 40mg tablet (80mg dose) established bioequivalence in terms of AUCt and AUC infinity. However, Cmax criteria proved extremely difficult to meet in the initial 40mg fasted study because of the large variability, leading to additional studies and ultimately requiring an unreasonable number of subjects. CONCLUSIONS: Final results clearly established bioequivalence of both strengths and characterized an unexpected food effect which did not appear to be formulation-related. However, the Cmax of nadolol is only slightly sensitive to absorption rate and the relatively large variability of Cmax reduces its effectiveness as a bioequivalence metric. Findings suggest that bioequivalence criteria for highly variable drugs should be reconsidered.     

An evaluation of the spectrum of Plasmodium vivax subpopulations by the results of an experimental study of late relapses in Delhi]

Enhancement of DNA vaccine immunogenicity is a current topic of high priority in the field of applied immunology, especially as a means of controlling HIV infection. The adjuvant effect of Ubenimex (UBX), an anti-cancer immunomodulator, on a DNA AIDS vaccine which we developed was examined in a murine model. UBX was formulated into a preparation containing DNA plasmids encoding env and rev genes of HIV-1 strain III(B), and was inoculated intramuscularly into BALB/c mice. The sera obtained with this mixture had 2(3)-2(5) times higher specific IgG titres than those obtained without the use of the adjuvant. UBX also elicited both a stronger HIV-1-specific DTH reaction, as measured by the footpad swelling test, and stronger cytotoxic T lymphocyte activity, as assayed by the 51Cr-release method, compared with responses using DNA alone. The cytokine secretion profile of restimulated immune lymphoid cells showed that UBX raised IL-2 and interferon-gamma levels and decreased IL-4 production. HIV-1-specific immunoglobulin subtype analysis demonstrated that UBX stimulated IgG2a production but suppressed synthesis of IgG1 and IgE. These results indicate that activation of the T-helper type 1 subset was induced by UBX, suggesting a mechanism of immunomodulation mediated by this agent. We conclude that UBX acts as an immunologic adjuvant for DNA vaccination against HIV-1. UBX may be a suitable adjuvant for clinical use because of its lack of antigenicity and low toxicity.