Synthesis, chemical, and biological properties of vinylogous hydroxamic acids: dual inhibitors of 5-lipoxygenase and IL-1 biosynthesis.

Vinylogous hydroxamic acids (3-(N-hydroxy-N-alkylamino)-2-propen-1-ones, VHA) were prepared as antiinflammatory agents. The synthesis, chemical properties, and in vitro biological activities of these relatively unexplored compounds are described. The VHAs were prepared by condensation of the appropriate N-substituted hydroxylamine with any of the three reagents: a 1,3-dicarbonyl compound (method A); a vinylogous amide (method B); or an alkynone (method C). The VHAs exist as one or more tautomers in solution with the relative proportions of each being dependent upon the structure of the VHA, solvent, and pH. VHAs undergo some of the typical reactions of hydroxamic acids as well as those of vinylogous amides. VHAs are active as inhibitors of 5-lipoxygenase and of IL-1 biosynthesis in vitro, which do not inhibit other enzymes of the arachidonic acid cascade. They have been shown by ESR studies to bring about inhibition of soybean type 1 15-lipoxygenase by reduction of the active site iron.     

Prediction of phenotype for acetylation and for debrisoquine hydroxylation by DNA-tests in healthy human volunteers

Summary The debrisoquine/sparteine-type polymorphism of drug oxidation and the polymorphism for acetylation are two common inherited variations in human drug metabolism. The phenotypes for hydroxylation and acetylation can be predicted be newly developed methods based on mutation-specific amplification of DNA by the polymerase chain reaction (PCR), which also allow for identification of heterozygous carriers of one mutant allele.In the present study, the results of genotyping of 81 healthy European volunteers were compared with the phenotype obtained by the classical biochemical approach using debrisoquine and caffeine as probe drugs.Genotyping correctly predicted all 73 extensive metabolisers (EMs) and 6 out of 8 poor metabolisers (PMs) of debrisoquine. All 48 rapid acetylators and 33 of 35 slow acetylators were predicted.Overall, the DNA analysis result matched the in vivo phenotype in 97.5 % of individuals.     

Evaluation of CHIP (iproplatin) in recurrent pediatric malignant solid tumors

CHIP (325 mg/M²), a second generation cisplatin derivative, was administered intravenously every 3 weeks to 85 pediatric patients with recurrent sarcomas (19), osteosarcomas (20), neuroblastoma (23), germ cell tumors (10), and other malignant tumors (7). Thirty-eight of them had been previously exposed to cisplatin. Partial remissions were only observed in 3 of 23 (13% SE=7%) patients having neuroblastoma. Severe thrombocytopenia (65%) and neutropenia (35%) were the dose limiting factors.     

Effects of chain-length and unsaturation on affinity and selectivity at muscarinic receptors.

1. Lengthening the chain in diphenylacetylcholine decreases affinity for muscarinic cholinoceptors in guinea-pig ileum. Diphenylacetoxypropyldimethylamine and its quaternary trimethylammonium salt are roughly equiactive: the dimethylamine and the piperidine have some selectivity for ileum compared with atria, but are not as active nor as selective as 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) methobromide (MeBr). With the weaker diphenylacetoxybutyl compounds the base is more active than the quaternary salt. 2. The diphenylacetoxybutyl-, cis-butenyl and trans-butenyl compounds have similar affinities. The quaternary salts are less active than the tertiary bases, but they are less selective than the butynyl analogues studied in earlier work. 3. 1,1-Diphenyl-1-hydroxy-2,4-hexadiynyl dimethylamine and its trimethylammonium salt are inactive in concentrations below 100 microM, as are the (+)-camphor-sulphonyl ester of 4-hydroxy-N-methyl piperidine and its methiodide. The (+/-)-phenylcyclopentylacetyl ester of 4-hydroxy-N-methylpiperidine methobromide is more active than its cyclohexyl analogue and than 4-DAMP MeBr but it is less selective than 4-DAMP MeBr. 4. The high selectivity of p-fluoro-hexahydrosila-diphenidol is confirmed but this compound has relatively low affinity (for ileum log K = 7.8). 5. The results indicate steric constraints to binding at muscarinic receptors which could be used to check molecular modelling of the receptor based on its known amino acid sequence. The group binding the charged nitrogen is probably at the mouth of a cavity which can accommodate two large rings (as in 4-DAMP MeBr) but with a depth less than about 7 A so that the rod-like hexadiynes cannot fit.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diagnostic sonography of the fetal genitourinary tract

Fetal diagnosis has vastly improved over the last decade. Ultrasound has become the imaging modality of choice. As real-time equipment has improved technologically, the ability to deduce subtle abnormalities has greatly increased. The fetal genitourinary tract may be evaluated for renal dysplasias, anomalies, or obstruction. Points of obstruction and, at times, the exact cause of obstruction may be deduced. Abnormalities of the ureter, bladder, urethra, scrotum, or reproductive system can be detected.     

Quality of life and Kaposi sarcoma: using preference techniques to value the health gains from treatment

The goal of this work was to investigate preference techniques to value potential health gains from treatments of Kaposi sarcoma (KS). The study was designed to take the form of face-to-face interviews with a sample of men with a history of HIV/AIDS ( n=15) or HIV/AIDS and KS ( n=17). The main outcome measure was quality of life (QoL) associated with various KS disease states expressed on a scale from 0 (death) to 1 (perfect health), obtained though time trade-off (TTO) and rating scale techniques. For cutaneous lesions only, the mean TTO preference score value was 0.27. In other words, the men were willing to trade a life expectancy of 5 years for a shorter period (1.4 years) in perfect health. More severe KS health states were rated lower (0.07-0.09). The mean rating scale value for cutaneous lesions only was 0.11 and ranged from -0.10 to -0.04 for the more severe conditions; these values were systematically lower than the TTO ( P=0.014). A large overall potential gain in QoL from treatment (partial response minus stable disease) was found for each condition to be reflected in both the TTO (from 0.31 to 0.55) and the rating scale (from 0.38 to 0.44). Respondents associate KS health states with extremely poor QoL and indicate that large gains are possible through modest treatment effects. While TTO returns higher values than the rating scale, potential gains from treatments were similar. The techniques appear to be suitable for application to QoL and economic evaluation of treatments of KS.