Kinetics of hydralazine (HP) and its metabolites, hydralazine pyruvic acid hydrazone (HPPAH) and 3-methyl-s-triazolo[3,4-a]phthalazine (MTP), was examined in five slow and five fast acetylators after single oral and intravenous doses of HP on separate occasions at least 1 wk apart. Blood samples were collected over a 10-hr period and levels of the drug and metabolites determined by sensitive high-performance liquid chromatographic -fluorescence assay. After intravenous administration HP plasma concentrations were fitted to a two-compartment model and the following mean kinetic parameters were obtained for the slow and fast acetylators: terminal half Ufes (t1/2s), 0.677 and 0.664 hr; total plasma clearances, 7.77 and 8.86 l/hr/kg; distribution pseudoequilibrium t½s, 4.80 and 5.40 min; volumes of plasma compartment, 2.53 and 3.01 l/kg; steady-state volumes of distribution, 5.71 and 6.37 l/kg; and apparent volume of distribution (calculated from total plasma clearance divided by β, where β is the compound rate constant expressing the rate of loss of drug from the body after pseudoequilibrium is achieved), 7.25 and 8.16 l/kg. None was different (i.e., statistically) for the two groups. Of those measured, the major plasma metabolite was HPPAH, which together with HP constituted most of the "apparent HP" measured by published nonspecific assays. The mean areas under the curve (AUCs) of MTP were 0.501 and 1.014 μm/l/hr (p < 0.01) in the slow and fast acetylators. After oral doses to the slow and fast acetylators, mean terminal HP t½s were 0.474 and 0.437 hr (p > 0.6) and bioavailability, 35.4% and 16.2% (p < 0.001). With this route of administration, HPPAH was the major plasma metabolite in the slow acetylators and MTP the major metabolite in the fast acetylators. The mean AUCs of MTP (corrected for dose differences) were 1.50 and 3.98 μm/l/hr (p < 0.001) in the slow and fast acetylators. Clinical Pharmacology and Therapeutics (1980) 28, 769–778; doi:10.1038/clpt.1980.234
Dimeric derivatives (compounds 7 to 9) of the influenza virus neuraminidase inhibitor zanamivir (compound 2), which have linking groups of 14 to 18 atoms in length, are approximately 100-fold more potent inhibitors of influenza virus replication in vitro and in vivo than zanamivir. The observed optimum linker length of 18 to 22 A, together with observations that the dimers cause aggregation of isolated neuraminidase tetramers and whole virus, indicate that the dimers benefit from multivalent binding via intertetramer and intervirion linkages. The outstanding long-lasting protective activities shown by compounds 8 and 9 in mouse influenza infectivity experiments and the extremely long residence times observed in the lungs of rats suggest that a single low dose of a dimer would provide effective treatment and prophylaxis for influenza virus infections.
Doxifluridine (5'-dFUR) is a prodrug of 5 fluorouracil (5-FU) synthesized in an attempt to improve the therapeutic index compared with 5-FU. In this phase I study, cohorts of three patients were treated by a 5-day continuous infusion with the dose increased daily, total doses ranging from 3.75 g/m2 to 20 g/m2/120 h. Twenty-nine patients received 54 courses (median 2, range 1–4). The dose-limiting toxicities were mucositis (Miller grade 3 in three patients and grade 4 in another) and grade 4 neutropenia and thrombocytopenia in two patients. Other toxicities included nausea, vomiting, and diarrhea, rash, and fever. Neurological toxicity was mild and no cardiovascular toxicity was recorded. Plasma and urine levels of 5'-dFUR and 5-FU were quantitated by high-performance liquid chromatography. Steady-state plasma levels between 167 ng/ml and 6,519 ng/ml were recorded and at these levels there was no evidence of saturation of doxifluridine metabolism. One patient at the maximum tolerated dose of 20 g/m2/120 h had a complete response in a nasopharyngeal carcinoma.
Methylation of 1,7-dihydro-9H-purine-2,8-dione, 2 8-diaminopurine, and 2-amino-7,9-dihydropurin-8-one in neutral medium gave 3,7,8,9-tetrahydro-1,3,9-trimethyl-2,8-dioxo-2H-purinium iodide, 2,8-diamino-1,7,9-trimethyl-9H-purinium di-iodide, and 2-amino-7,9-dihydro-7-methylpurin-8-one respectively. Methylation of the 2,8-dione and its 1-methyl derivative in alkaline medium in each case provided a 1 : 1 mixture of 1,7-dihydro-1,3,7-trimethyl-3H- and 1,7-dihydro-1,7,9-trimethyl-9H-purine-2,8-dione, which on further methylation in neutral medium gave 3,7,8,9-tetrahydro-1,3,7,9-tetramethyl-2,8-dioxo-2H-purinium iodide. Methylation of 1,7-dihydro-7-methyl-9H-purine-2,8-dione, obtained by nitrosation of 2-amino-7,9-dihydro-7-methylpurin-8-one, in alkaline medium gave a 1 : 9 mixture of the above trimethylpurinediones. The methylation patterns were established by reduction, hydrolytic cleavage, methylation with CD3I, and mass and 1H n.m.r. spectral comparisons.Reduction of these and related methylated purines with sodium borohydride produced 1,3,7-, 1,3,9-, and 1,7,9-trimethyl- and 1,3,6,9- and 1,3,7,9-tetramethyl-cis-perhydropurine-2,8-diones, and 1,7,9-trimethyl- and 1,6,7,9-tetramethyl-cis-2,8-diamino-4,5,6,9-tetrahydro-1H-purinium salts. Tafel's purone (perhydropurine-2,8-dione) and 2,8-diamino-4,5,6,9-tetrahydro-1H-purine were formed by electrolytic reduction of the respective purines, and had the cis-configuration at C-4 and C-5, similar to the above reduced purines, as shown by the patterns of 1H n.m.r. signals, and spectral comparisons with cis-perhydrocyclopenta[d]pyrimidin-2-one and cis-2-amino- 4,4a,5,6,7,7a-hexahydro-3H-cyclopenta[d]pyrimidine.
The effect of gabapentin on antipyrine clearance was assessed in 12 healthy male volunteers, using a known enzyme inducer, phenytoin, as control. Subjects received gabapentin 400 mg or phenytoin 100 mg three times daily for 2 weeks. Antipyrine tests were performed before, during, and after treatment with gabapentin or phenytoin. In contrast to phenytoin, chronic administration of gabapentin did not affect antipyrine clearance. Gabapentin appears to have little potential for drug interactions.
Catching flu: The influenza virus neuraminidase inhibitor zanamivir (red) is functionalized at the 7-position to give derivatives that retain a high affinity for the enzyme. When conjugated to biotin (green) or onto microspheres, such derivatives can be used to capture or aggregate influenza virus particles.
Abstract α‐Halogen‐cycloalkanone wie (I) werden beim Umsetzen mit Trialkylboranen wie (II) in Gegenwart von Basen wie K‐tert.‐butylat in THF bei 0°C unter Halogen‐Alkyl‐ Austausch in 2‐Stellung zu Derivaten wie (III) alkyliert, wobei die Reaktionsgeschwindigkeit mit Zunahme der Ringgröße der Ketone abnimmt.
Summary: Fifteen cancer patients were studied following repeated courses of doxorubicin (12-44 mg/m2) (together with other anticancer agents) to consider the possibility of enhanced metabolism as a cause of the previously reported reduction in doxorubicin plasma concentrations with repeated courses. Plasma doxorubicin and doxorubicinol concentrations were measured by a modified high-performance liquid chromatography/fluorescence method. The results presented confirmed the significant decline in doxorubicin plasma concentration-dose ratios measured 3 h after the 1-h infusion. Although the degree of this reduction varied markedly between patients, it was shown not to be associated with a rise in the plasma concentration-dose ratio of the major metabolite doxorubicinol or with altered renal and/or hepatic function, which may have influenced disposition. Alternative mechanisms that might explain the reduction in doxorubicin concentrations, such as increased doxorubicin clearance or volume of distribution, were not considered in the present study.
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