Absorption and excretion of tolmetin in arthritic patients.

The absorption, kinetics, biotransformation, and excretion of tolmetin and its metabolites were studied in patients with rheumatoid arthritis (RA) to evaluate the effects of the disease on tolmetin disposition. Five RA patients were stabilized on tolmetin sodium (300 mg, 4 times daily for 14 days) before receiving a single oral solution dose of tolmetin-14C sodium (300 mg as the acid) on day 15. Tolmetin was rapidly and completely absorbed (peak time, 20 to 60 min) and eliminated rapidly from plasma with a biphasic decay curve (t1/2beta congruent to 2.1 hr). MCPA, the oxidative metabolite, appeared more slowly (peak time, 40 to 90 min) but was eliminated rapidly in a biphasic manner (t1/2beta congruent to 1.7 hr). The terminal elimination phases for both tolmetin and MCPA demonstrated a curvature which suggested possible nonlinearity in the kinetic disposition of the drug. There were no apparent effects of the disease on the kinetics of tolmetin or MCPA. Tolmetin, MCPA, and tolmetin glucuronide were recovered quantitatively in urine (0 to 72 hr) with most of the exretion occurring in the 0- to 24-hr period. A significant increase, relative to data on normal subjects, in the renal clearance of both tolmetin and MCPA was noted. Concomitant increase in the apparent volume of distribution secondary to reported decreases in the plasma protein binding of tolmetin appeared to be the reason for increased renal clearance of tolmetin.

Importance of the aromatic ring in adrenergic amines. 2. Synthesis and adrenergic activity of some nonaromatic six- and eight-membered ring analogs of beta-phenylethanolamine.

The synthesis of beta-phenylethanolamine analogs in which the phenyl ring is replaced by cyclohexyl, cyclohexen-4-yl, cyclooctyl, cyclooctenyl, cycloocta-1,3-dien-2-yl, cycloocta-1,5-dienyl, and cyclooctatetraenyl was accompanied by conversion of the corresponding aldehydes to the cyanohydrins followed by reduction with lithium aluminum hydride. A preparatively useful synthesis of 1-formylcyclooctatetraene is described utilizing the photocycloaddition of methyl propiolate to benzene followed by reduction to the alcohol and oxidation with MnO2. All compounds, as their hydrochloride salts, exhibited indirect adrenergic activity on the rat vas deferens. On the reserpinized rat vas deferens all compounds potentiated the effects of exogenous norepinephrine. The results are in agreement with the conclusion that the more saturated the ring moiety, the greater the affinity for the amine uptake site of the vas deferens and suggest that there is no important interaction between the drug and this uptake site that involves pi-complex formation.

Toxicological evaluation of oligonucleotide therapeutics.

In this brief review, guidance is provided for the safety evaluation of phosphorothioate oligonucleotides. This novel class of compounds has proved to be challenging for the preclinical development scientist, as systemic exposure can evoke sometimes dramatic responses, in terms of general functional parameters, laboratory data (hematology, clinical chemistry) and histopathology of target organs. The polyanionic profile of these compounds is discussed vis-à-vis historical data for related structures. Dose-related responses in various laboratory test species are described. The liver, kidneys and immune system are major target organs, and an experimental perspective is provided for understanding each of these in determining a safe starting dose for clinical trials with novel compounds.

Clinical studies in patients with solid tumors using a second-generation antisense oligonucleotide (GEM 231) targeted against protein kinase A type I.

GEM 231 is a second-generation antisense oligonucleotide targeted against the RIalpha regulatory subunit of cAMP-dependent protein kinase type I (PKA-I). Excessive expression of PKA-I is associated with cell proliferation and transformation, and increased levels of secreted extracellular PKA (ECPKA) are found in the serum of cancer patients. Preclinical studies have demonstrated single-agent antitumor activity of GEM 231 in a variety of human cancer xenograft models, and additive or synergistic antitumor activity has been observed with taxane and/or camptothecin-based combinations. Based on prior safety (MTD) data demonstrating dose-dependent, reversible, and cumulative transaminitis, and high peak plasma concentration (Cmax)-dependent changes in activated partial thromboplastin time (aPTT) with GEM 231 2-h twice-weekly infusions, an alternative schedule of GEM 231 given as a single agent was evaluated in patients with advanced solid tumors. Fourteen patients (median age approximately 60 yrs) with advanced solid malignancies received a total of 78 weeks of therapy. GEM 231 was infused via a CADD pump at 80 mg/m2/day (d) for 3 d/wk (n = 1), then for 5 d/wk at 80 (n = 3), 120 (n = 8), and 180 mg/m2/d (n = 2). One cycle was defined as 4 weeks of therapy. Apparent dose dependency for the occurrence of transaminitis was readily reversible. At 180 mg/m2/d, 2 of 2 patients had cycle 1 dose-limiting toxicity (DLT) transaminitis. One patient treated at 120 mg/m2/d experienced grade 3 transaminase elevations after 8 weeks of therapy, but when serum transaminase values rapidly improved he resumed treatment at 80 mg/m2/d for 6 weeks until tumor progression was documented. Another patient at 120 mg/m2/d developed grade 3 esophagitis after 3 weeks, limiting further dosing. One patient (lung cancer) demonstrated stable disease for 9 weeks. Overall, plasma aPTT was minimally prolonged and changes were transient, peaked at the end of each infusion, and were not associated with spontaneous bleeding. A constitutive symptom (e.g., low-grade fatigue) was common, cumulative, and reversible following discontinuation of therapy. Serum ECPKA was measured by enzymatic assay and Western blotting from blood drawn at the beginning and end of each infusion. Serum ECPKA levels demonstrated a trend to decline with the treatment. In addition to single agent schedules, combination trials were undertaken to assess safety and possible interaction of GEM 231 with taxanes (paclitaxel, docetaxel), given once every 3 weeks (one cycle). While trials using the 2-h twice-weekly GEM 231 infusions are ongoing, preliminary results from both studies show that it is safe to combine paclitaxel or docetaxel with GEM 231. Overall, it is also feasible to administer GEM 231 in combination with taxane or nontaxane chemotherapy (e.g., camptothecins). Phase I combination studies are currently underway to further explore the clinical, pharmacokinetic, and biologic profile of GEM 231 with chemotherapy.

Review of the pharmacokinetics and metabolism of zomepirac in man and animals.

Zomepirac has been shown to be rapidly and completely absorbed after oral administration to man. Urinary excretion is the principal route for removal of zomepirac and its metabolites in man and in animals. Zomepirac is highly bound to plasma protein. The pharmacokinetics of zomepirac after single and multiple doses in man can be adequately described by a two-compartment oral absorption model. There is a linear relationship between dose and peak plasma concentration, AUC, and urinary excretion of zomepirac. The bioavailability of zomepirac was unaffected by single or repeated doses of antacid. The rhesus monkey has been shown to be a good predictive animal model for zomepirac's metabolism and pharmacokinetics in man, with glucuronidation found to be the principal route of metabolism in both species.

Quantitation of the antimalarial agent, mefloquine, in blood, plasma, and urine using high-pressure liquid chromatography.

Sensitive and specific assays are described for the quantitation of mefloquine in whole blood, plasma, and urine specimens using high-pressure liquid chromatography. Specimens were extracted with ethyl acetate and concentrated before chromatography. Whole blood and plasma extracts were chromatographed on a polar bonded phase partitioning column, and urine extracts were chromatographed on a bonded reversed-phase partitioning column. The sensitivity of the assays for mefloquine was 0.05 microgram/ml of whole blood or plasma and 0.25 microgram/ml of urine using 5-ml samples. The assays are suitable for studying mefloquine pharmacokinetics in humans.

The comparative metabolism and disposition of penfluridol-3H in the rat, rabbit, dog, and man.

Penfluridol, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol, was well absorbed by the rat, rabbit, dog, and man after single oral doses of drug in solution. Penfluridol and its metabolites were widely distributed in tissues of male rats and cleared slowly. The terminal plasma t 1/2 for penfluridol was greater than 40 hr for the rabbit, 227 hr for the dog, and 199 hr for man. Fecal excretion of total radioactivity predominated in the rat, rabbit, and dog whereas in man excretion was evenly divided between urine and feces. The major biotransformation pathways of penfluridol in the rat, rabbit, dog, and man were oxidative N-dealkylation followed by beta-oxidation, conjugation of penfluridol, and conjugation of the acidic metabolites.

Plasma levels, biotransformation and excretion of oxatomide (R 35 443) in rats, dogs and man.

Plasma levels, biotransformation and excretion of oxatomide were studied after single oral doses of 14C-oxatomide in male rats, dogs and humans. Oxatomide was very well absorbed, and almost completely metabolized in the three species. Excretion of the metabolites was very rapid and complete within a few days; the 14C label was excreted more in the faeces (54-62%) than in the urine (27-40%). Major metabolic pathways of oxatomide were oxidative N-dealkylations at the piperazine nitrogens and at the benzimidazolone nitrogen in rats and man, and also aromatic hydroxylation at the benzimidazolone moiety in man. The main urinary metabolite in the three species was 2,3-dihydro-2-oxo-1H-benzimidazole-1-propanoic acid, resulting from the oxidative N-dealkylation at the 1-piperazine nitrogen.

Penfluridol: a neuroleptic drug designed for long duration of action.

1. Penfluridol is a unique, long-acting, oral neuroleptic belonging to the diphenylbutylpiperidines. The synthesis of penfluridol represented the result of a well-planned scientific search for a highly lipophilic compound structurally related to haloperidol and pimozide. 2. Because of its unusual lipophilicity, penfluridol distributes extensively in fatty tissues following oral administration. This depot effect produces a very slow release of drug from the tissues, and results in a very long duration of activity. 3. Penfluridol is extensively metabolized by oxidative N-dealkylation to afford, as isolated metabolites, the beta-glucuronide conjugate of the diphenylbutyric acid derivative A1 and the unconjugated basic piperidine moiety B1. It is assumed, at this time, that the pharmacological activity is attributable to the parent compound. 4. When administered clinically at oral doses of 20 to 100 mg/week, penfluridol has been found to be an effective antipsychotic agent. This frequency of dosing is consistent with the pharmacokinetic behavior of the drug in man, and does not appear to result in any inappropriate accumulation of the drug in patients. Wide variations in steady-state levels and plasma elimination half-life have been observed in patient populations.

Pharmacokinetics and metabolism of an oligodeoxynucleotide phosphorothioate (GEM91) in cynomolgus monkeys following intravenous infusion.

The pharmacokinetics and metabolism of an antisense oligonucleotide phosphorothioate (GEM91) were studied in cynomolgus monkeys following intravenous infusion. [35S]-Labeled GEM91 was administered to 12 monkeys by means of a 2-hour intravenous infusion at a dose of 4 mg/kg. Plasma pharmacokinetic analysis revealed that the maximum plasma concentration was 41.7 microg equivalents/ml, which was achieved in 2.13 hours. The plasma elimination half-life was 55.8 hours based on radioactivity levels. Urinary excretion represented the major pathway of elimination, with 70% of the administered dose excreted in urine over 240 hours. The oligonucleotide was widely distributed to tissues. The highest concentrations were observed in the liver and kidney. Analysis of the extracted oligonucleotide following post-labeling with [32p] on polyacrylamide gel electrophoresis showed the presence of both intact and degraded oligonucleotide in plasma, kidney, liver, spleen, and lymph nodes. Based on the methods used for post-labeling (either 3'-end or 5'-end), different patterns of bands were observed on polyacrylamide gel electrophoresis, suggesting metabolic modification of the administered oligonucleotide.

The absorption, distribution, and excretion in mice of a quinolinemethanol antimalarial, 2,8-bis(trifluoromethyl)-4-(1-hydroxy-3-(N-t-butylamino)propyl)quinoline phosphate (WR 184,806).

Approximately 75% of the radioactivity derived from WR 184806-14C was excreted in the feces with the remainder in the urine after po administration. At least 77-85% of the dose was absorbed by 2-8 hr; lungs, liver, skeletal muscle, kidneys, small intestine (less contents) and residual carcass were major sites of deposition of total radioactivity. Within these tissues the radioactivity present was predominantly as WR 184,806 rather than its metabolites. Peak blood plasma levels of WR 184,806 occurred at 2-4 and 7-10 hr. The peak erythrocyte level of WR 184,806 occurred at 6 hr. The presence in the urine and feces of unchanged WR 184,806 was confirmed by thin-layer chromatography and inverse isotope dilution.

The metabolism of zomepirac sodium. II. Isolation and identification of the urinary metabolites in rat, mouse, rhesus monkey, and man.

The metabolism of the oral analgesic agent, zomepirac sodium, sodium 5-(4-chlorobenzoyl)-1,4-dimethyl-1 H-pyrrole-2-acetate dihydrate, was studied in healthy male humans, rhesus monkeys, Wistar rats, and Swiss mice. The major urinary metabolites of zomepirac (Z) (80--95% of the dose) in these species were identified on the basis of a combination of chromatographic and spectroscopic data. Z was present as a major product in all species. Hydroxyzomepirac (HMZ) was a major component in rat and mouse, but a minor one in man, and it was absent in the monkey. 4-Chlorobenzoic acid (CBA) was identified as a major metabolite in rat (present as conjugates) and mouse and a minor one in monkey and man. Zomepirac glucuronide (ZG) was present as the major metabolite in man, monkey, and mouse, and present at trace levels in the rat. 4-Chlorohippuric acid, the glycine conjugate of CBA, was found in trace amounts only in the monkey. Thus, the metabolism of zomepirac in man and monkey is mainly characterized by glucuronide conjugation. The rat metabolizes zomepirac, mainly by oxidative pathways, to give HMZ and CBA. The mouse shows a balance of conjugation and oxidative pathways.

The metabolism of zomepirac sodium. I. Disposition in laboratory animals and man.

Zomepirac sodium (ZS) is an orally active, nonnarcotic, analgesic agent. The disposition and pharmacokinetics of zomepirac (Z) were studied in rats, mice, rabbits, hamsters, rhesus monkeys, and healthy human subjects. Z was rapidly and completely absorbed by all animal species and man. Dose-related linear increases in the area under the curve for plasma Z vs. time were noted after increasing po doses of ZS to mice (2.5--7.5 mg/kg), rats (0.5--10 mg/kg), and rhesus monkeys (5--40 mg/kg). Daily administration of ZS to rats (10 mg/kg/day for 10 days) caused no biologically significant changes in the pharmacokinetic profile for Z. Assessment of Z's absolute bioavailability in monkeys (10 mg/kg, iv vs. po) indicated that po doses of ZS were completely bioavailable (F = 1.12 +/- 0.40). Plasma clearance ranged from ca. 4.5 ml/min/kg for the female hamster, rhesus monkey, and man to as low as 0.30 ml/min/kg for rats, mice, and rabbits. Terminal elimination half-lives averaged 5.3--6.6 hr for mouse, 2.8--6.5 hr for rat, 2.5 hr for rabbit, 2.3 hr for hamster, 12.7--25.5 hr for rhesus monkey, and 4 hr for man. The major route of excretion for Z and its metabolites was via the kidneys for all animals and man with the balance appearing in feces. Biliary excretion was qualitatively observed in rhesus monkeys and quantitated in rats (23.6% of dose in 27 hr). Formation of the acyl glucuronide of Z was the major metabolic pathway in man and rhesus monkey, was substantial in the mouse, was very minor in the rat and rabbit, and was nonexistent in the hamster. Rat, mouse, and hamster hydroxylate the 4-methyl group on the pyrrole ring to give hydroxyzomepirac (a biologically inactive metabolite), a minor metabolite in man and nonexistent in the rhesus monkey. The rodents also cleave Z to form 4-chlorobenzoic acid and its conjugates, minor metabolites in man and rhesus monkey.

Purified poloxamer 188 for treatment of acute vaso-occlusive crisis of sickle cell disease: A randomized controlled trial.

CONTEXT: Sickle cell disease (SCD) can cause severe painful episodes that are often thought to be caused by vaso-occlusion. The current therapy for these uncomplicated painful episodes includes hydration, oxygen, and analgesics. Purified poloxamer 188 may increase tissue oxygenation and thereby reduce inflammation, pain, and the overall duration of such painful episodes in patients with SCD. OBJECTIVE: To compare the duration of painful episodes in patients with SCD treated with purified poloxamer 188 to that of similar episodes experienced by patients who receive a placebo. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled, intention-to-treat trial conducted between March 1998 and October 1999 in 40 medical centers in the United States. PARTICIPANTS: Two hundred fifty-five patients with SCD (aged 9-53 years) who had a painful episode sufficiently severe to require hospitalization and narcotic analgesics. INTERVENTION: Patients were randomly assigned to receive an intravenous infusion of purified poloxamer 188, 100 mg/kg for 1 hour followed by 30 mg/kg per hour for 47 hours (n = 127), or a matching volume of saline placebo (n = 128). MAIN OUTCOME MEASURE: Duration of the painful episode, from randomization to crisis resolution. RESULTS: Mean (SD) duration of the painful episodes was 141 (42) hours in the placebo group compared with 133 (41) hours in those treated with purified poloxamer 188, a 9-hour reduction (P =.04). Subset analyses indicated an even more pronounced purified poloxamer 188 effect in children aged 15 years or younger (21 hours; P =.01) and in patients who were receiving hydroxyurea (16 hours; P =.02). Finally, the proportion of patients achieving crisis resolution was increased by purified poloxamer 188 (65/126 [52%] vs 45/123 [37%]; P =.02). Similar results were observed in children aged 15 years or younger (22/37 [60%] vs 10/36 [28%]; P =.009) and in patients who were also receiving hydroxyurea (12/26 [46%] vs 4/28 [14%]; P =.02). CONCLUSIONS: A decrease in the duration of painful episodes and an increase in the proportion of patients who achieved resolution of the symptoms were observed when the purified poloxamer 188-treated patients were compared with the patients receiving placebo. However, the difference between these groups was significant but relatively small. In subgroup analysis, a more significant effect on both parameters was observed in children and in patients who were receiving concomitant hydroxyurea. It is important to confirm both of these observations in further prospective trials.