Arvind B. Rege

Pharmacokinetics and long-term tolerance to ribavirin in asymptomatic patients infected with human immunodeficiency virus.

Single‐dose and steady‐state pharmacokinetics of the antiviral agent ribavirin were studied in seven male, asymptomatic, human immunodeficiency virus‐seropositive subjects. After a single 400 mg intravenous infusion, mean terminal plasma half‐life (t½) was 27.1 hours, mean volume of distribution was 802 L, and mean total plasma clearance was 26.1 L/hr. Renal clearance was 39% of total clearance and it exceeded creatinine clearance. Oral bioavailability was 44.6%. With long‐term dosing (400 mg orally twice a day) ribavirin accumulated, reaching steady state in 2 to 4 weeks in plasma and red blood cells. Red blood cell concentrations greatly exceeded plasma concentrations (60:1). Plasma concentrations at steady state (trough) were 10‐ to 14‐fold higher than the corresponding single‐dose concentrations. The terminal t½ (washout) after 16 weeks greatly exceeded the t½ observed after a single oral dose (151 versus 29.6 hours). Ribavirin‐induced reductions in hemoglobin ranging from 0.8 to 3.5 gm/dl were well tolerated. There was no significant reduction in CD4 lymphocytes during treatment with ribavirin for 16 weeks in subjects who had more than 200 CD4 cells at entry and who also remained free of opportunistic infections during 24 weeks of observation.

High-pressure liquid chromatography/electrochemical detection method for monitoring MDA and MDMA in whole blood and other biological tissues

The drug Ecstasy (3,4-methylenedioxymethamphetamine (MDMA)) is one of several hallucinogenic amphetamine derivatives reported to be serotonergic neurotoxins. The following is a description of a new high-pressure liquid chromatographic (HPLC) analytical method for the analysis of MDMA, 3,4-methylenedioxyamphetamine (MDA) and N-ethyl-3,4-methylenedioxyamphetamine (MDE) from whole blood. Upon separation of MDMA, MDA and MDE by HPLC, quantitation is achieved by use of electrochemical detection. Retention times for MDA, MDMA, and MDE are 6.5, 9.2, and 10.3 min, respectively, allowing for a complete chromatographic run every 15 min. The sensitivity of the method is 1 ng/ml which allows for measurement of MDA, MDMA, or MDE in microsamples of whole blood. The volume of blood required is very small (200 microliters); therefore, there is minimal blood loss in repeated blood sampling from small animals. Assay linearity was demonstrated from 1 ng/ml to at least 1 microgram/ml. The coefficients of variation for both intra-assay and inter-assay comparisons were less than 9%. Other HPLC methods have been previously described for the analysis of amphetamine derivatives, but this new method offers greater sensitivity, rapid turn-around time and ease of use.

Urinary excretion of 6‐hydroxychlorzoxazone as an index of CYP2E1 activity

To determine whether the urinary excretion of 6‐hydroxychlorzoxazone is an index of CYP2E1 activity in vivo.

Cavernous Tissue Antibiotic Levels in Penile Prosthesis Surgery

A comparison of the delivery of several antibiotics (vancomycin, gentamicin and aztreonam) to the tissue site of prosthesis implantation was studied using cavernous tissue levels for each antibiotic. A total of 32 patients underwent penile prosthesis implantation. Intravenous antibiotics were administered 1 to 2 hours preoperatively, with vancomycin and aztreonam given to patients at the Tulane University Medical Center, and vancomycin and gentamicin given to patients at the New Orleans Veterans Administration Hospital. At operation the urine, serum and cavernous tissue were concurrently sampled and later analyzed for antibiotic concentration. The mean cavernous tissue level for vancomycin was 55.5 +/- 5.5 ng./mg. (standard deviation) for 20 patients, while the mean cavernous tissue levels for aztreonam and gentamicin were 8.9 +/- 2.1 ng./mg. for 10 patients and 4.7 +/- 1.2 ng./mg. for 12 patients, respectively. When the delivery of antibiotic to cavernous tissue was compared (quantitated as ng. antibiotic per mg. tissue per mg. drug administered), a statistically significant value (p less than 0.01) was observed with vancomycin (0.11 ng./mg./mg.) greater than gentamicin (0.06 ng./mg./mg.) or aztreonam (0.01 ng./mg./mg.), and with no significant difference observed between aztreonam or gentamicin. These findings suggest that cavernous tissue levels may be used as a method to determine optimal antibiotic prophylaxis against penile prosthesis infection.

The Role of Serum Inhibitors of Erythroid Colony-Forming Cells in the Mechanism of the Anemia of Renal Insufficiency

Uremic toxins have been the subject of investigation for several years to determine their role in the signs and symptoms of uremia. Substances that are known to accumulate in body fluids to produce symptoms of uremia in patients with renal insufficiency were outlined by Schreiner and Maher in 19611 and Bergstrom and Bittar in 1969.2 The success of regular hemodialysis in relieving the symptoms of uremia indicates that toxic substances below 5,000 daltons molecular weight must be removed. Jebsen et al.3 found that prolonged dialysis can reverse the peripheral neuropathy independent of changes in BUN and creatinine. Thus, there appears to be very little correlation between the toxic manifestations of uremia and plasma levels of creatinine, urea, and uric acid. Babb et al.4 postulated that uremic products in the middle molecular range of 1,000 to 2,000 daltons may be the cause of the toxic manifestations of neuropathy. It is the purpose of this chapter to examine plasma fractions below 1,000 daltons to attempt to characterize the uremic toxins responsible for the anemia of renal insufficiency. In addition, assay of sera from several predialysis patients with anemia of renal insufficiency for erythropoietin (Ep) using a sensitive radioimmunoassay for erythropoietin was carried out. The anemia of renal insufficiency is a hypoproliferative state of the bone marrow associated with a normocyte normochromic anemia. Anemia is one of the most common presenting symptoms in patients with end-stage renal disease and is usually alleviated to some degree by hemodialysis. However, a large number of patients require frequent blood transfusions even when being chronically dialyzed. Improvements in ferrokinetics and erythropoiesis have been reported in patients after dialysis 5–7 without an increase in plasma erythropoietin levels, indicating that dialysis may be removing toxic substances that are involved in the mechanism of the suppressed erythropoiesis in renal disease. Androgen therapy8–13 and infusions of erythropoietin-rich plasma14,15 have been reported during the past several years to relieve the anemia of renal insufficiency.