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Biomedical subjects

S K Puri

Publications and source records attributed to S K Puri.

At least 73 records · Page 4Linked to original sources
PubMed1992

Cefotaxime and metabolite disposition in two pediatric continuous ambulatory peritoneal dialysis patients.

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.

Adolescent↗
PubMed1992

Differential sensitivity of the pre-erythrocytic stages of Plasmodium cynomolgi B to the prophylactic action of primaquine.

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.

Animals↗
PubMed1991

Effect of Plasmodium berghei infection and chloroquine on the hepatic drug metabolizing system of mice.

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.

Animals↗
PubMed1991

Pharmacokinetics of cefotaxime and its active metabolite in children with renal dysfunction.

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.

Adolescent↗
PubMed1991

Comparative evaluation of blood schizontocidal activity of quinine and quinidine against drug resistant rodent malaria.

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.

Animals↗
PubMed1990

Multiple dose pharmacokinetics, safety, and tolerance of velnacrine (HP 029) in healthy elderly subjects: a potential therapeutic agent for Alzheimer's disease.

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.

Administration, Oral↗
PubMed1990

Effects of interferon in malaria infection.

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.

Animals↗
PubMed1990

Disposition of roxithromycin in patients with normal and severely impaired renal function.

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.

Absorption↗
PubMed1990

Pattern of relapses in sporozoite induced Plasmodium cynomolgi B infection in rhesus monkeys.

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.

Animals↗
PubMed1990

Causal prophylactic activity of a new 8-aminoquinoline derivative against Plasmodium cynomolgi B in rhesus monkeys.

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).

Animals↗
PubMed1989

The effect of food on the bioavailability of velnacrine (HP 029) in healthy elderly men: a potential Alzheimer agent.

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.

Aged↗
PubMed1989

Single dose safety, tolerance, and pharmacokinetics of HP 029 in healthy young men: a potential Alzheimer agent.

1,2,3,4-tetrahydro-9-aminoacridin-1-ol maleate (HP 029) is a new cholinergic compound that has been shown to enhance memory in animals and therefore may be potentially effective in humans for the treatment of Alzheimer's disease (AD). The initial safety, tolerance, and pharmacokinetics of HP 029 after single oral doses were assessed in a randomized, double-blind, placebo controlled study in 70 healthy young men (eight dose groups). The test doses ranged from 5 to 200 mg. There were 9 subjects per dose group, 6 on HP 029 and 3 on placebo. The 5 and 100 mg dose groups had only 8 subjects. Plasma and urine samples were analyzed for nonconjugated HP 029 using an HPLC assay with a detection limit of 1 ng/ml. HP 029 was rapidly absorbed after oral dosing with mean peak plasma levels occurring between 0.75 and 1.2 hours. The mean peak levels ranged from 12.7 and 234.7 ng/ml after the 10 and 200 mg doses, respectively. There were dose related increases in peak plasma levels, AUCs, and the amounts of drug excreted in the urine. The mean plasma half-life was about 2.0 hours and was not affected by dose. About 6 to 11% of the dose was eliminated in the urine. HP 029 was renally cleared at a high rate and independent of dose. There were no clinically important or drug-related changes in any of the physical examinations, audiograms, or ophthalmologic examinations. There were only minor within-subject fluctuations in vital signs, ECGs, and laboratory values, none of which were clinically meaningful or drug related after any of the doses of HP 029.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Delay in emergence of mefloquine resistance in Plasmodium berghei by use of drug combinations.

Blood induced Plasmodium berghei infection in Swiss mice was exposed during successive passages to melfloquine alone or melfoquine in combination with dapsone or primaquine or erythromycin, and the level of resistance to melfoquine in four sub-lines was compared at ED90 level. Treatment with mefloquine alone resulted in a 201.14 fold increase in resistance after 21 passages. Use of drug combination (melfoquine + dapsone) delayed the acquisition of resistance as shown by a marginal increase of ED90 by 5.76 fold after 34 passages. Similarly, there was a 17.84 fold increase of resistance after 32 passages involving exposure to mefloquine-primaquine and a 112.28 fold increase after exposure to melfoquine-erythromycin combination for 31 passages. The study emphasizes that rational drug combinations should be developed to protect the melfoquine against the emergence of resistance in P. falciparum cases.

Animals↗
PubMed1989

Spectrum of the antimalarial activity of a new macrolide antibiotic midecamycin in mice and monkeys.

The antimalarial activity of a new macrolide antibiotic, midecamycin, has been evaluated against a sensitive strain of Plasmodium berghei, a chloroquine-resistant strain of P. yoelii nigeriensis and a simian parasite, P. cynomolgi B. The ED50 and ED90 values of this antibiotic administered in two divided daily doses were found to be 37.15 +/- 3.51 and 100.84 +/- 7.54 mg/kg, respectively, against P. berghei and 362.34 +/- 85.33 and 878.04 +/- 10.02 mg/kg, respectively, against P. yoelii nigeriensis. Doses above 45 mg/kg for 4 days significantly extended the mean survival time of treated mice infected with either of the two parasites. However, no appreciable blood schizontocidal (at 100 mg/kg X 7 days), anti-relapse (at 100 mg/kg X 7 days) or causal prophylactic activities (at 200 mg/kg X 3 days) were observed against P. cynomolgi infection in rhesus monkeys.

Animals↗
PubMed1989

Radical curative activity of a new 8-aminoquinoline derivative (CDRI 80/53) against Plasmodium cynomolgi B in monkeys.

An analogue of primaquine, N1-(3-acetyl-4-5-dihydro-2-furanyl)-N4-(6-methoxy-8-quinolinyl) 1,4-pentanediamine, CDRI Code 80/53), has been evaluated for anti-relapse activity against sporozoite induced Plasmodium cynomolgi B infection in rhesus monkeys. The compound has shown 100% curative anti-relapse activity at 1.25 mg/kg x 7 day dose schedule, thereby giving a primaquine index of 0.8. The compound is currently under Phase-I clinical trials.

Aminoquinolines↗
PubMed1989

Methemoglobin toxicity and hematological studies on malaria anti-relapse compound CDRI 80/53 in dogs.

Methemoglobin toxicities of primaquine and compound N1-(3-acetyl-4-5-dihydro-2-furanyl)-N4-(6-methoxy-8-quinolinyl) 1,4-pentanediamine, CDRI Code 80/53, have been compared in beagles. Primaquine administration at 3 mg/kg for 7 days produced significantly high (P less than 0.001) methemoglobinemia and the levels increased 10.55-fold. Compound 80/53 at 3.75 mg/kg x 7 days produced a marginal increase in methemoglobinemia (3.24-fold; P less than 0.02). The methemoglobin formed by primaquine administration was 3.65-fold (P less than 0.001) higher than that formed after administration of compound 80/53. There was no significant change in other hematological parameters and liver function tests.

Aminoquinolines↗