Steady-state pharmacokinetics of indinavir in cerebrospinal fluid and plasma among adults with human immunodeficiency virus type 1 infection.

To characterize steady-state indinavir pharmacokinetics in cerebrospinal fluid and plasma, 8 adults infected with human immunodeficiency virus underwent intensive cerebrospinal fluid sampling while receiving indinavir (800 mg every 8 hours) plus nucleoside reverse transcriptase inhibitors. Nine and 11 serial cerebrospinal fluid and plasma samples, respectively, were obtained from each subject. Free indinavir accounted for 94.3% of the drug in cerebrospinal fluid and 41.7% in plasma. Mean values of cerebrospinal fluid peak concentration, concentration at 8 hours, and area under the concentration-time profile calculated over the interval 0 to 8 hours [AUC(0-8)] for free indinavir were 294 nmol/L, 122 nmol/L, and 1616 nmol/L x h, respectively. The cerebrospinal fluid-to-plasma AUC(0-8) ratio for free indinavir was 14.7% +/- 2.6% and did not correlate with indexes of blood-brain barrier integrity or intrathecal immune activation. Indinavir achieves levels in cerebrospinal fluid that should contribute to control of human immunodeficiency virus type 1 replication in this compartment. The cerebrospinal fluid-to-plasma AUC(0-8) ratio suggests clearance mechanisms in addition to passive diffusion across the blood-cerebrospinal fluid barrier, perhaps by P-glycoprotein-mediated efflux.

Distribution of bile acid absorption and bile acid transporter gene message in the hamster ileum.

The apical, Na-dependent, ileal bile acid transporter (IBAT) is critical for the reabsorption of bile acids in the ileum. Bile acid transport capacities as well as the distribution of bile acid transporter messenger ribonucleic acid (mRNA) and transporter protein were studied along the axis of the ileum. Na-dependent and Na-independent taurocholate uptake was measured in the hamster ileum using an everted-sleeve technique. The distribution of IBAT mRNA and protein were mapped by in-situ hybridization, immunohistochemistry, and Western blotting. Na-dependent and Na-independent bile acid uptake rates were highest 1-4 cm before the ileocecal valve (maxima 780 and 120 pmol/mm2 per min, respectively) and decreased proximally and distally. Na-independent absorption was increased in the last 6 cm of the ileum. IBAT mRNA and protein expression were linked closely to the distribution of uptake capacity. IBAT mRNA was more abundant near the crypt-villus junction whereas the protein was expressed evenly along the villus axis. We conclude that Na-dependent and Na-independent bile acid absorption capacities both have distinct distribution curves in the hamster ileum. All ileocytes on villi in the high-uptake area of the ileum express IBAT mRNA and protein.

Single-dose pharmacokinetics of indinavir and the effect of food.

Indinavir sulfate is a human immunodeficiency virus type 1 (HIV-1) protease inhibitor indicated for treatment of HIV infection and AIDS in adults. The purpose of this report is to summarize single-dose studies which characterized the pharmacokinetics of the drug and the effect of food in healthy volunteers. Indinavir concentrations in plasma and urine were obtained by high-pressure liquid chromatography and UV detection assay methods. The results indicate that indinavir was rapidly absorbed in the fasting state, with the time to the maximum concentration in plasma occurring at approximately 0.8 h for all doses studied. Over the 40- to 1,000-mg dose range studied, concentrations in plasma and urinary excretion of unchanged drug increased greater than dose proportionally. The nonlinear pharmacokinetics were attributed to the dose-dependent oxidative metabolism of first-pass metabolism as well as to metabolism in the systemic circulation. Renal clearance slightly exceeded the glomerular filtration rate, suggesting a net tubular secretion component. At high concentrations in plasma, tubular secretion appeared to be lowered because there was a trend for a decreased renal clearance. Administration of 400 mg of indinavir sulfate following a high-fat breakfast resulted in a blunted and decreased absorption (areas under the concentration-time curves [AUCs], 6.86 microM.h in the fasted state versus 1.54 microM.h in the fed state; n = 10). However, two types of low-fat meals were found to have no significant effect on the absorption of 800 mg of indinavir sulfate (AUCs, 23.15 microM.h in the fasted state versus 22.71 and 21.36 microM.h, respectively, in the fed state; n = 11). Immediately following dosing, the concentrations of indinavir in urine often exceeded its intrinsic solubility. To reduce the risk of nephrolithiasis, it is recommended that indinavir sulfate be administered with water.

Disposition of indinavir, a potent HIV-1 protease inhibitor, after an oral dose in humans.

Indinavir, N-[2(R)-hydroxy-1(S)-indanyl]-5-[2(S)-tertiary- butylaminocarbonyl-4-(3-pyridylmethyl)piperazino]-4(S)- hydroxy-2(R)-phenylmethylpentanamide (L-735,524,MK-639, ayl-4- Crixivan), is a potent and specific inhibitor of the HIV-1(3 protease for the treatment of AIDS. Disposition of [14C]indinavir was investigated in six healthy subjects after single oral administration of 400 mg. AUC, Cmax, and Tmax values for indinavir were 492 microM x min, 4.7 microM, and 50 min, respectively. The AUC value for the total radioactivity in plasma was 1.9 times higher than that of indinavir, indicating the presence of metabolites. The major excretory route was through feces, and the minor through urine. Mean recovery of radioactivity in the feces was 83.4%. In the urine, mean recoveries of the total radioactivity and unchanged indinavir were 18.7% and 11.0% of the dose, respectively. HPLC radioactivity and LC-MS/MS analyses of urine showed the presence of indinavir and low levels of quaternary pyridine N-glucuronide (M1), 2',3'-trans-dihydroxyindanylpyridine N-oxide (M2), 2',3'-trans-dihydroxyindan (M3) and pyridine N-oxide (M4a) analogs, and despyridylmethyl analogs of M3 (M5) and indinavir (M6). M5 and M6 were the major metabolites in urine. The metabolic profile in plasma was similar to that in urine. Quantitatively, the metabolites in feces accounted for >47% of the dose, which along with the urinary excretion of approximately 19%, suggested that the absorption of the drug was appreciable. In the feces, radioactivity was predominantly due to M3, M5, M6, and the parent compound. Thus, in urine and feces, the prominent metabolic pathways were oxidations and oxidative N-dealkylations. Excretion of the quaternary N-glucuronide metabolite in the urine, which is a minor metabolite in human, was specific to primates.

Pancreatic expression and secretion of human islet amyloid polypeptide in a transgenic mouse.

Islet amyloid polypeptide (IAPP) is a secretory product of the pancreatic beta-cell, which is the primary constituent of the islet amyloid that develops in type II diabetes. To study the role the inherent amyloidogenicity of human IAPP (hIAPP) plays in the formation of islet amyloid deposits and to investigate a possible hormonal role for IAPP, transgenic mice expressing hIAPP were developed. The transgene was composed of a fragment of an hIAPP cDNA linked to the rat insulin II promoter. One line of transgenic mice expressed the transgene and synthesized hIAPP in their pancreatic islets. IAPP-like immunoreactivity in pancreatic extracts and plasma were two- to threefold greater in the transgenic mice compared with nontransgenic control mice. Although plasma concentrations of immunoreactive insulin (IRI) and glucose were equal in transgenic and control mice, the pancreatic content of IRI was nearly twofold greater in the transgenic animals, and proinsulin mRNA was significantly elevated, suggesting increased rates of insulin biosynthesis. Pancreatic samples obtained from transgenic mice up to 19 months of age had no evidence of islet amyloid. These results indicate that an increased level of synthesis of the amyloidogenic hIAPP is not sufficient to cause islet amyloid deposition. However, the increased synthesis and storage of insulin in the islets of the transgenic mice are consistent with either a direct regulatory effect of IAPP on the beta-cell or indirect stimulation of insulin production through IAPP-induced insulin resistance.

Norfloxacin: review of safety studies.

The tolerability profile of norfloxacin, the first of a new generation of fluoroquinolone carboxylic acid antibacterials, has been defined in numerous laboratory animal and human trials. Whether administered for moderate or protracted periods, norfloxacin has been relatively safe in animals over a wide range of doses. There has been no evidence of a teratogenic effect in any of the animal species tested (rat, rabbit, mouse, monkey) at six to 50 times the human dose (400 mg twice daily). However, norfloxacin has been shown to produce embryonic loss in monkeys when given in doses 10 times the maximal human dose, resulting in peak plasma levels that are two to three times those obtained in humans. Although there are no adequate and well-controlled studies in pregnant women, norfloxacin is not recommended for use in this population because it, like other drugs in this class, causes arthropathy in immature animals. In animals, norfloxacin is neither mutagenic nor carcinogenic, and, in clinical trials, norfloxacin-related adverse experiences have been uncommon. Those that have occurred have been generally mild, requiring discontinuation of therapy in less than 1 percent of patients. The most frequently reported side effects have been nausea, dyspepsia, headache, and dizziness. Administration of 400 mg of norfloxacin at two or three times a day has been associated with reasonably good gastrointestinal tolerance.

Norfloxacin versus co-trimoxazole in the treatment of recurring urinary tract infections in men.

Norfloxacin is a lipid-soluble weak organic acid bound to plasma proteins to a low extent. Norfloxacin has a pKa1 from 6.2 to 6.4 and a pKa2 from 8.7 to 8.9. Mean concentrations of norfloxacin in prostatic tissue have been reported as 1.7 mg/kg. Recurrent urinary tract infection (UTI) in men is frequently associated with prostatic infection, and chronic prostatitis is both difficult to diagnose and to treat. One hundred and twenty-nine patients were entered into a randomized, open controlled, comparative multiclinic study of the efficacy and safety of norfloxacin vs. co-trimoxazole in male patients with recurrent UTI. Norfloxacin 400 mg and co-trimoxazole 160/800 mg were given twice daily for 4 to 6 weeks. One hundred and nine patients were considered evaluable for efficacy. Norfloxacin effected bacteriologic eradication in 56 of 60 (93%) patients; co-trimoxazole effected eradication in 39 of 49 (67%) patients. This difference in bacteriologic outcome had statistical significance (p less than 0.05). A subset of these patients had prostatic fluid cultures pre- and post-therapy. The eradication rate was 23 of 25 (92%) for norfloxacin and 10 of 15 (67%) for co-trimoxazole. Bacteria isolated were (norfloxacin/co-trimoxazole): E. coli 27/25; K-E-S 14/13; Proteus spp. 7/5; Ps. aeruginosa 2/0; other gram-negative bacilli 4/3; gram-positive cocci 7/3. Four patients, one on norfloxacin and three on co-trimoxazole had drug-related clinical and/or laboratory adverse experiences. None was serious. Norfloxacin appears to be an effective drug for the treatment of recurrent UTI in men.

World-wide clinical experience with norfloxacin: efficacy and safety.

This review covers 2346 norfloxacin treated patients in clinical trials world wide. These studies show that 400 mg of norfloxacin b.i.d. was effective and compared favorably with other standard oral agents in the treatment of urinary tract infections, including complicated and recurrent infections in men. This regimen given b.i.d. or t.i.d. was also effective in the treatment of acute gastroenteritis due to common gastrointestinal pathogens such as enterotoxigenic Escherichia coli, Salmonella spp., Shigella spp., Campylobacter spp. as well as less common organisms. A single 800 mg dose was effective in the treatment of gonorrhoea including patients with extra genito-urinary involvement and penicillinase producing strains of Neisseria gonorrhoeae. Preliminary data from ongoing trials have also shown that norfloxacin is effective in the prophylaxis of traveller's diarrhoea and infections in the granulocytopenic patient. These various regimens of norfloxacin were well tolerated with a low incidence (less than 3%) of drug related adverse experiences. The most common adverse experiences were nausea, headache, dizziness, rash, elevation of liver enzymes and eosinophilia.

Multiclinic comparative study of norfloxacin and trimethoprim-sulfamethoxazole for treatment of urinary tract infections.

Three hundred seventy patients with upper or lower urinary tract infections were entered into a multicenter, open comparative study. A total of 190 patients were treated with norfloxacin, and 180 patients were treated with trimethoprim-sulfamethoxazole. The percentage of strains susceptible to norfloxacin (99%) was significantly greater (P less than 0.001) than the percentage of strains susceptible to trimethoprim-sulfamethoxazole (90%). The percentages of patients with bacteriological outcomes of eradication were greater in the norfloxacin group (97%) than in the trimethoprim-sulfamethoxazole group (90%). The difference was significant (P less than 0.05). Seven patients (three treated with norfloxacin, four treated with trimethoprim-sulfamethoxazole) experienced early reinfection. Of 370 patients entered into the study, 20 patients experienced clinical adverse effects that were probably or definitely related to the study drug; 6 patients were in the group that received norfloxacin, and 14 were in the group that received trimethoprim-sulfamethoxazole. Study antimicrobial agents were discontinued because of clinical adverse effects in eight patients (norfloxacin, one patient; trimethoprim-sulfamethoxazole, seven patients). Three patients receiving norfloxacin and four patients receiving trimethoprim-sulfamethoxazole had laboratory adverse effects which were classified as probably or definitely drug related. None of the clinical or laboratory adverse effects was serious.