Biomedical subjects
Publications and source records attributed to S K Puri.
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Plasmodium knowlesi (a simian malarial parasite) infection resulted in elevation of hepatic oxidative stress in monkeys. Further, the antioxidant defence system of the host was also noticeably affected. The infected monkeys showed a marked increase in the levels of superoxide (O2-), lipid peroxidation (LPO), glutathione (GSH) and xanthine oxidase (XO), and decreased levels of superoxide dismutase (SOD) and catalase. Oral administration of chloroquine (20 mg kg body wt-1 for 3 days) to infected monkeys caused recovery trends in oxidative stress and antioxidant defences to almost normal a week after cessation of drug treatment.
Hexokinase, phosphofructokinase and pyruvate kinase, the regulatory enzymes of the glycolytic sequence, showed progressive increases in their activities with the rise of parasitaemia in Plasmodium knowlesi-infected rhesus monkey serum and red blood cells. Chloroquine therapy cleared the parasitaemia in 72 h and brought the elevated levels of these enzymes back to almost normal in about 30 days.
Almost all of the important enzymes of glycolytic sequence were studied in isolated schizonts of Plasmodium knowlesi as well as in normal and P. knowlesi parasitized rhesus red blood cells. Significant activities of all the glycolytic enzymes assayed were observed in cell-free schizonts and the levels of all were found to be considerably elevated in infected host erythrocytes, confirming that the consumption of glucose is dramatically increased in host red cells, consequent to malaria infection.
An observer-blind randomized, placebo-controlled, crossover study was conducted in 22 healthy male subjects. They received 2 g cefpirome or placebo intravenously following an overnight fast. One hour later they consumed a single 0.5 g/kg dose of alcohol. The treatments were reversed after a seven-day 'washout' period. Subjects were evaluated for any adverse events or 'disulfiram-like' symptoms. The effects of cefpirome on the pharmacokinetics of alcohol were also studied. There were no statistically significant differences in mean values for the various pharmacokinetic parameters for plasma alcohol between the cefpirome and placebo treatment groups. There were no side effects or 'disulfiram-like' reactions following consumption of alcohol in either group. A single iv dose of 2 g cefpirome was well-tolerated in healthy males and, moreover, pre-treatment with cefpirome did not adversely affect the metabolism of alcohol in these subjects.
OBJECTIVE: To characterize the pharmacokinetics of cefotaxime and desacetylcefotaxime in pediatric patients undergoing continuous ambulatory peritoneal dialysis (CAPD) after intraperitoneal administration of cefotaxime. DESIGN: Case series. SETTING: Ambulatory children from Children's Hospital nephrology clinic, Columbus, Ohio. PATIENT POPULATION: Two adolescents without peritonitis. METHODS: A single intraperitoneal dose of cefotaxime 500 mg per 1 L dianeal was given during CAPD. Cefotaxime and desacetyl-cefotaxime were measured in plasma, urine, and dialysate by HPLC. RESULTS: Maximum plasma concentration (Cmax) of cefotaxime was 11.94 and 13.08 mg/L and that of desacetylcefotaxime 5.73 and 5.33 mg/L. Time to reach maximum concentration (Tmax) of cefotaxime was 2.22 and 4.08 h, and that of desacetylcefotaxime was 5.33 and 5.73 h after instillation of the intraperitoneal cefotaxime dose. Systemic absorption of cefotaxime was 56.6 and 64.8 percent. Total clearance of cefotaxime was 62 and 79 mL/min/1.73 m2. Nonrenal clearance accounted for nearly 95 percent; renal and CAPD clearance contributed approximately 5 percent of the total clearance. Renal and CAPD clearance measurements of desacetylcefotaxime were similar to those for cefotaxime. Cefotaxime half-life was 1.83 and 2.49 h and desacetylcefotaxime half-life was 8.14 and 11.0 h. CONCLUSIONS: Cefotaxime was well absorbed and therapeutic serum concentrations were achieved after intraperitoneal administration. Renal and CAPD clearances for cefotaxime and desacetylcefotaxime were low. Cefotaxime nonrenal clearance was unaffected. Further studies are needed to establish appropriate intraperitoneal dosing guidelines of cefotaxime in pediatric CAPD patients.
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The sensitivity of the developing pre-erythrocytic stages of Plasmodium cynomolgi bastianelli to primaquine in single, two or three dose regimens administered at varying times during the incubation period has been investigated. The study reveals that the early pre-erythrocytic stages of the parasite are more susceptible to primaquine than the later stages. Regimens of 5.34 mg/kg x 1 dose on day 0 or day + 1; 2.67 mg/kg x 2 doses on days 0 and 1 and 1.78 mg/kg x 3 doses on days -1, 0, + 1 or days + 1, + 2, + 3 protected all the treated monkeys while identical regimens administered after day 3 of sporozoite inoculation were not curative.
The hepatic microsomal mixed-function oxidase (MFO) system was markedly impaired during Plasmodium berghei infection in mice. Cytochrome P-450 and other mono-oxygenases, viz. aniline hydroxylase, aminopyrine-N-demethylase and benzo(a)pyrene hydroxylase, were significantly decreased while microsomal heme showed a four-fold increase at peak parasitemia (greater than 50%). Oral treatment with chloroquine (16 mg kg-1 body wt for 4 days) of P. berghei-infected mice cleared the parasitemia within 72 h and almost normalized the altered levels of MFO indices, a week after cessation of treatment. The findings were further supported by the isoenzymic profile and drug-binding properties of terminal mono-oxygenase, cytochrome P-450.
We studied cefotaxime (CTX) and desacetylcefotaxime (dCTX) pharmacokinetics in 19 children (ages, 7 to 16 years) with various degrees of renal function. The patients were stratified into three groups according to 24-h urinary creatinine clearance (CLCR) values: group I, CLCR greater than 80 ml/min/1.73 m2 (n = 7); group II, CLCR from 30 to 80 ml/min/1.73 m2 (n = 6); and group III, CLCR less than 30 ml/min/1.73 m2 (n = 6). A single 50-mg/kg dose of CTX was given intravenously to each patient after which blood and urine samples were collected and analyzed for CTX and dCTX by high-performance liquid chromatography. Safety was assessed by pre- and poststudy blood chemistries and urinalysis. The mean values for total body clearance of CTX for groups I, II, and III were 158.1 +/- 38.8, 118.3 +/- 50.8, and 84.8 +/- 11.7 ml/min/1.73 m2, respectively (P less than 0.01). Renal clearance also decreased across groups, I, II, and III, with values of 77.5 +/- 20.2, 41.3 +/- 18.5, and 11.4 +/- 7.7 ml/min/1.73 m2 respectively (P less than 0.0001). Both the CTX fraction nonrenally cleared and elimination half-life increased with decreasing renal function. The CTX volume of distribution at steady state was not affected by renal disease. The renal clearance values of dCTX were 146.4 +/- 71.4, 64.5 +/- 32.1, and 14.4 +/- 8.7 ml/min/1.73 m2 for groups I, II, and III, respectively (P less than 0.0004). Elimination half-life values were 2.04 +/- 0.39, 3.87 +/- 1.93, and 6.19 +/- 3.22 h for the respective groups (P less than 0.006). Both the maximum concentration of dCTX in plasma and time to reach the maximum concentration of dCTX in plasma were increased with decreased CLCR. The results of this study indicate that dosage adjustment may be necessary for CTX in children with renal dysfunction. On the basis of the pharmacokinetics and antimicrobial activities of the parent drug and its metabolite, dosage reductions of 25 to 50% in children with moderate renal impairment (CLCR from 30 to 80 ml/min/1.73 m2) and 50 to 75% in children with severe renal impairment (CLCR < 30 ml/min/1.73 m2) are recommended.
Ayush-64, a new herbal antimalarial drug developed by the Central Council for Ayurveda and Siddha, was evaluated for direct parasiticidal action against P. berghei and P. yoelii nigeriensis in swiss mice and P. cynomolgi B and P. knowlesi in rhesus monkeys. No blood schizontocidal activity could be demonstrated against any of the four malaria parasites.
Blood schizontocidal activity of quinine and quinidine has been compared against sensitive as well as chloroquine/mefloquine/quinine resistant strains of Plasmodium berghei and a multiple resistant strain of P. yoelii nigeriensis in Swiss mice. Evaluation of results on ED50/ED90 basis has shown distinct superiority of quinidine over quinine against sensitive as well as drug resistant strain of rodent malaria.
The pharmacokinetics, safety, and tolerance of 1,2,3,4-tetrahydro-9-aminoacridin-1-olmaleate (HP 029) a potential therapeutic agent for Alzheimer's disease, were assessed after multiple oral doses in a randomized double-blind, placebo controlled, ascending dose study in 56 healthy elderly men (14 per dose group). The subjects in the first three groups received 25, 50, or 100 mg two times a day and a fourth group was administered 100 mg velnacrine tid for 28 days. All subjects received a final dose on day 29. Subjects were confined for continuous observation during the 36-day study period. Blood and urine samples were collected for the pharmacokinetic assessment. There were no clinically important changes in the safety variables in both age groups after any dose. There was no evidence of hepatotoxicity when elderly men were given 100 mg tid for 28 days. Nine subjects reported one or two episodes of gastrointestinal (diarrhea) side effects (6 in the 100 mg bid group and 3 in the 100 mg tid dose group) during a 29-day trial. None required treatment or were discontinued from study. These results indicate that the safety and tolerance up to 100 mg tid for 28 days in healthy elderly men are acceptable. Velnacrine was rapidly absorbed after oral administration. There were dose-related increases in Cmax, AUCs, and amount of drug excreted in urine. During multiple dosing, the Cmax increased as a function of dose. The tmax and t1/2 were not affected by dosage nor multiple dosing. Steady state levels of velnacrine were reached between days 2 and 3 with no evidence of further accumulation of velnacrine thereafter. Approximately 11-30% of the administered dose was excreted in the urine over the course of the study. The favorable pharmacokinetic characteristics and acceptable safety and tolerance of multiple dosing oral doses of velnacrine support further testing of this compound for efficacy and safety in Alzheimer's patients.
Earlier, we reported that prophylactic treatment with human interferon gamma (rHuIFN-gamma) protected monkeys against Plasmodium cynomolgi B malaria infection. We have tested the efficacy of rHuIFN-gamma on relapsing stage of experimental P. cynomolgi B malaria infection in rhesus monkeys. No effect of rHuIFN-gamma was seen against experimental relapsing stage compared with controls; however, it appears that chloroquine (CHL) may have interfered with the antimalarial effect of IFN, since treatment with CHL inhibits the antiviral activity of mouse alpha/beta IFN and polyinosinic-polycytidylic acid (poly I:C) against Semliki forest virus (SFV) in mice. These results may have clinical implications especially with the use of IFN against virus infection, cancer and in parasitic infections in malaria endemic areas where CHL is one of the most widely used antimalarial drugs. Our result also shows that CHL treatment enhances the virus replication in mice and suggest a possible connection between AIDS and malaria infection, since the spread of AIDS has been rapid in parts of tropical Africa that have a high incidence of malaria, and chloroquine has been frequently used in the chemotherapy of malaria.
The disposition of roxithromycin, an investigational macrolide antibiotic, was evaluated in 20 subjects, 10 with normal renal function (creatinine clearance [CLCR] of 116 +/- 17 ml/min [mean +/- standard deviation]) and 10 with severely impaired renal function (CLCR of 10.2 +/- 2.6 ml/min) after a single 300-mg oral dose. Plasma concentration-time data were analyzed in terms of a one- or two-compartment oral absorption model utilizing nonlinear regression analysis. The terminal elimination half-life was significantly prolonged in the group with severely impaired renal function (15.5 +/- 4.7 h) compared with that of the group with normal renal function (7.9 +/- 2.5 h). Apparent total body clearance was significantly reduced in the renally impaired (25.3 +/- 10.5 ml/min) in relation to the group with normal renal function (48.8 +/- 11.1 ml/min). The first-order absorption rate constants and apparent volumes of distribution did not differ between the two groups. These data indicate that the disposition of roxithromycin is significantly delayed in subjects with CLCRs of less than 15 ml/min and suggest that the roxithromycin dosing interval be doubled for these patients.
The pattern of sequential relapses in 10 rhesus monkeys following inoculation of sporozoites of Plasmodium cynomolgi B has been studied after administering curative dose of chloroquine (5 mg/kg base X 7 days) to eliminate blood parasitaemia after each relapse. Observation for periods ranging from 109 to 245 days showed that the interval between first six relapses was 19.3 +/- 6.77 days (1st relapse), 20.9 +/- 8.43 days (2nd relapse), 22.8 +/- 8.55 days (3rd relapse), 27.8 +/- 10.0 days (4th relapse), 31.67 +/- 11.50 days (5th relapse) and 32.5 +/- 16.26 days (6th relapse). The results of this study indicate a gradual extension of the relapse interval in successive relapses.
A new 8-aminoquinoline derivative, N1-(3-acetyl-4-5-dihydro-2 furanyl)-N4-(6-methoxy-8-quinolinyl)1,4-pentanediamine, synthesized at CDRI, Lucknow, showed causal prophylactic activity at 3.16 mg/kg x 3 doses (on day -1, 0 and +1) against sporozoite induced P. cynomolgi B infection in rhesus monkeys. Single dose of 10 mg/kg of this compound on day 0 also prevented establishment of patient infection. Activity of the compound was comparable to that of primaquine (with causal prophylactic activity at 1.78 mg/kg in three day test and at 10.0 mg/kg in single dose test).
Velnacrine (HP 029; 1,2,3,4-tetrahydro-9-aminoacridin-1-ol-maleate) is an investigational drug being studied in patients with Alzheimer's disease. In this open, randomized, crossover study, 24 healthy, elderly men were given 100 mg of velnacrine on two different study days to assess the influence of food on the bioavailability of velnacrine. On the first day, subjects received drug either after an overnight fast or 15 minutes after completing a standard breakfast. Seven days later, the treatments were crossed over. Blood and urine samples were collected at specific times and various intervals, respectively, from all subjects before and after drug administration for up to 24 hours. Plasma and urine concentrations of velnacrine were determined by an HPLC method. Administration of velnacrine with food resulted in slightly lower peak plasma levels of unconjugated velnacrine, (175 vs 213 ng/ml) and delayed times-to-peak plasma levels, (2.5 vs 1.5 h) without affecting the AUCs and the t 1/2 of the drug. The amount of unconjugated velnacrine excreted in urine was slightly higher when the drug was taken with food (19 vs 17 mg), but renal clearance was not altered. These results indicate that food delayed the rate but not the extent of velnacrine absorption. The minor differences in Cmax and tmax may not be clinically meaningful. Therefore, velnacrine can be administered with or without food.