芳环上96种常用取代基的Q型聚类分析法

本文对芳环上96种常用取代基采用L(A)、π、F、R、σ_m和σ^p六种化学结构参数,以相似系数Cosθ_ik作为分类统计量,对取代基进行Q型标准化聚类分析。根据实际需要分成5群、10群及18群。可供药物研究者选择合成对象作参考。本文采用自编ALGOL-60语言程序在国产709机上完成全部计算。     

Anticonvulsant potency of common antiepileptic drugs in the gerbil

In gerbils, 'minor' (myoclonic) and 'major' (clonic-tonic) seizures were induced by blowing at the animals with compressed air. The anticonvulsant ED50 of the following drugs was determined after oral administration against both types of seizures: phenytoin, phenobarbital, carbamazepine, sodium valproate, ethosuximide, and diazepam. Valproate, ethosuximide, and diazepam were most potent against 'minor' seizures which could not or only partially be suppressed by phenytoin or carbamazepine, respectively. The 'grand mal' drugs phenytoin, phenobarbital, and carbamazepine were, on the other hand, more potent against 'major' than against 'minor' seizures. When phenobarbital was administered for several days, a strong induction of hepatic microsomal enzymes occurred.     

The effects of medical marijuana laws on potency

BackgroundMarijuana potency has risen dramatically over the past two decades. In the United States, it is unclear whether state medical marijuana policies have contributed to this increase.MethodsEmploying a differences-in-differences model within a mediation framework, we analyzed data on n = 39,157 marijuana samples seized by law enforcement in 51 U.S. jurisdictions between 1990 and 2010, producing estimates of the direct and indirect effects of state medical marijuana laws on potency, as measured by Δ⁹-tetrahydrocannabinol content.ResultsWe found evidence that potency increased by a half percentage point on average after legalization of medical marijuana, although this result was not significant. When we examined specific medical marijuana supply provisions, results suggest that legal allowances for retail dispensaries had the strongest influence, significantly increasing potency by about one percentage point on average. Our mediation analyses examining the mechanisms through which medical marijuana laws influence potency found no evidence of direct regulatory impact. Rather, the results suggest that the impact of these laws occurs predominantly through a compositional shift in the share of the market captured by high-potency sinsemilla.ConclusionOur findings have important implications for policymakers and those in the scientific community trying to understand the extent to which greater availability of higher potency marijuana increases the risk of negative public health outcomes, such as drugged driving and drug-induced psychoses. Future work should reconsider the impact of medical marijuana laws on health outcomes in light of dramatic and ongoing shifts in both marijuana potency and the medical marijuana policy environment.     

The effects of cigarette smoking on human sexual potency

Forty-two male cigarette smokers, age 18 to 44, were randomly assigned to high-nicotine, low-nicotine, or control groups in a study relating cigarette smoking to sexual response. Subjects watched erotic film segments while their penile diameters, heart rates, and finger pulse amplitudes were continuously recorded by a polygraph. Subjects in the smoking groups smoked relatively high-nicotine (.9 mg) or very low-nicotine (.002 mg) cigarettes prior to watching the last two films, while control subjects ate candy. Smoking two high-nicotine cigarettes in immediate succession significantly decreased the rate of penile diameter change relative to the other conditions. These effects were not seen after a single cigarette was smoked. High-nicotine cigarettes caused significantly more vasoconstriction and heart rate increase than did low-nicotine cigarettes, which did not differ from control conditions.     

Sensory effects of capsaicin congeners I. Relationship between chemical structure and pain-producing potency of pungent agents.

A quantitative method for measuring the efficiency of pungent agents of capsaicin-type by the pain reaction elicited on the eye of rats is described. About 50 derivatives -- most of them amides or esters of homovanillic acid -- were tested by this method and the share of different chemical groups of the molecule in the pungent action was analyzed. It turned out that the presence of an acylamide linkage or alkyl chain is not essential for pungency, since acylamide linkage can be replaced by an esteric group and the alkyl chain by cycloalkyl rings. The importance of OH group on the aromatic ring is confirmed. On the basis of the findings a hypothetical pharmacological receptor for capsaicin on pain sensory nerve endings is presented.     

Estimating potency for the Emax-model without attaining maximal effects

The most widely applied model relating drug concentrations to effects is the Emax model. In practice, concentration-effect relationships often deviate from a simple linear relationship but without reaching a clear maximum because a further increase in concentration might be associated with unacceptable or distorting side effects. The parameters for the Emax model can only be estimated with reasonable precision if the curve shows sign of reaching a maximum, otherwise both EC50 and Emax estimates may be extremely imprecise. This paper provides a solution by introducing a new parameter (S0) equal to Emax/EC50 that can be used to characterize potency adequately even if there are no signs of a clear maximum. Simulations are presented to investigate the nature of the new parameter and published examples are used as illustration.     

Relative contributions of affinity and intrinsic efficacy to aryl hydrocarbon receptor ligand potency

Models of receptor action are valuable for describing properties of ligand-receptor interactions and thereby contribute to mechanism-based risk assessment of receptor-mediated toxic effects. In order to build such a model for the aryl hydrocarbon receptor (AHR), binding affinities and CYP1A induction potencies were measured in PLHC-1 cells and were used to determine intrinsic efficacies for 10 halogenated aromatic hydrocarbons (HAH): 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7, 8-tetrachlorodibenzofuran (TCDF), and eight polychlorinated biphenyls (PCB). TCDD, TCDF, and non-ortho-substituted PCBs 77, 81, 126, and 169 behaved as full agonists and displayed high-intrinsic efficacy. In contrast, the mono- and di-ortho-substituted PCBs bound to the AHR but displayed lower or no intrinsic efficacy. PCB 156 was a full agonist, but with an intrinsic efficacy 10- to 50-fold lower than non-ortho-substituted PCBs. PCB 118 was a very weak partial agonist. PCBs 105 and 128 were shown to be competitive antagonists in this system. The model was then used to predict CYP1A induction by binary mixtures. These predictions were tested with binary mixtures of PCB 126, 128, or 156 with TCDD. Both PCB 156 (a low-intrinsic efficacy agonist) and PCB 128 (a competitive antagonist) inhibited the response to TCDD, while the response to TCDD and PCB126 was additive. These data support the following conclusions: 1) only 1-2% of the receptors in the cell need be occupied to achieve 50% of maximal CYP1A induction by one of the high-intrinsic efficacy agonists, demonstrating the existence of "spare" receptors in this system; 2) the insensitivity of fish to ortho-substituted PCBs is due to both reduced affinity and reduced intrinsic efficacy compared to non-ortho-substituted PCBs; 3) PCB congeners exhibit distinct structure-affinity and structure-efficacy relationships. Separation of AHR ligand action into the properties of affinity and intrinsic efficacy allows for improved prediction of the behavior of complex mixtures of ligands, as well as mechanistic comparisons across species and toxic endpoints.     

Statistical analysis of the long-term effects of recombinant human deoxyribonuclease on pulmonary function in cystic fibrosis patients

The problem of evaluating the long-term effects of recombinant human deoxyribonuclease (rhDNase) on forced expiratory volume in one second (FEV1) in cystic fibrosis (CF) patients was considered. A two-stage mixed effects model, incorporating relevant predictive variables, captured the diverse patterns of decline of FEV1 for patients with different demographic characteristics. Based on the results of modeling the dropout process, it is clear that the probability of early dropout was closely related to patient's responsiveness to rhDNase treatment. Failure to consider the existence of informative censoring severely biased the estimates of the rate of decline and affected the interpretation of the results.     

Effect of halogenated substituents on the metabolism and estrogenic effects of the equine estrogen,equilenin

Estrogen replacement therapy has been correlated with an increased risk for developing breast and endometrial cancers. One potential mechanism of estrogen carcinogenesis involves metabolism of estrogens to 2- and 4-hydroxylated catechols, which are further oxidized to electrophilic/redox active o-quinones that have the potential to both initiate and promote the carcinogenic process. Previously, we showed that the equine estrogens, equilin and equilenin, which are major components of the estrogen replacement formulation Premarin (Wyeth-Ayerst), are primarily metabolized to the catechol, 4-hydroxyequilenin. This catechol was found to autoxidize to an o-quinone causing oxidation and alkylation of DNA in vitro and in vivo. To block catechol formation from equilenin, 4-halogenated equilenin derivatives were synthesized. These derivatives were tested for their ability to bind to the estrogen receptor, induce estrogen sensitive genes, and their potential to form catechol metabolites. We found that the 4-fluoro derivatives were more estrogenic than the 4-chloro and 4-bromo derivatives as demonstrated by a higher binding affinity for estrogen receptors alpha and beta, an enhanced induction of alkaline phosphatase activity in Ishikawa cells, pS2 expression in S30 cells, and PR expression in Ishikawa cells. Incubation of these compounds with tyrosinase in the presence of GSH showed that the halogenated equilenin compounds formed less catechol GSH conjugates than the parent compounds, equilenin and 17beta-hydroxyequilenin. In addition, these halogenated compounds showed less cytotoxicity in the presence of tyrosinase than the parent compounds in S30 cells. Also, as stated above, the 4-fluoro derivatives showed similar estrogenic effects as compared with parent compounds; however, they were less toxic in S30 cells as compared to equilenin and 17beta-equilenin. Because 17beta-hydroxy-4-halogenated equilenin derivatives showed higher estrogenic effects than the halogenated equilenin derivatives in vitro, we studied the relative ability of the 17beta-hydroxy-4-halogenated equilenin derivatives to induce estrogenic effects in the ovariectomized rat model. The 4-fluoro derivative showed higher activity than 4-chloro and 4-bromo derivatives as demonstrated by inducing higher vaginal cellular differentiation, uterine growth, and mammary gland branching. However, 17beta-hydroxy-4-fluoroequilenin showed a lower estrogenic activity than 17beta-hydroxyequilenin and estradiol, which could be due to alternative pharmacokinetic properties for these compounds. These data suggest that the 4-fluoroequilenin derivatives have promise as alternatives to traditional estrogen replacement therapy due to their similar estrogenic properties with less overall toxicity.     

常见精神障碍类化学药品口服制剂药学研究的一般考虑

精神障碍类化学药品为近年来仿制药申报热点。检索相关文献和国外审评报告,并结合具体案例,对常见精神障碍类化学药品活性成分的理化性质（生物药剂学分类、粒径分布、晶型）进行汇总分析,并对此类药品口服常释制剂和调释制剂的典型生产工艺（干法直压工艺、多层压片工艺、流化床微丸包衣工艺）中的药学关注点进行讨论,综合提出结合药物特点加强药学研究的建议,以期对精神障碍类化学仿制药注册申报提供一定的参考。     

The effects of drugs acting at the GABAA-receptor/ionophore after chemical kindling with the benzodiazepine receptor ligand FG 7142.

Repeated administration of the beta-carboline benzodiazepine receptor ligand FG 7142 produces sensitization to its effects so that full seizures develop (chemical kindling); initially it is only pro-convulsant. The present study investigated alterations in the function of drugs which act at the different sites at the gamma-aminobutyric acid (GABA) benzodiazepine receptor complex, after repeated administration of FG 7142. In FG 7142 kindled mice decreased anticonvulsant and hypothermic effects of the GABA agonist muscimol were observed. The hypothermic effects of the GABA agonist progabide were reduced. In contrast a small increase in the hypothermic effect of pentobarbitone was seen. The convulsant effects of bicuculline and picrotoxin were unaltered when they were given intravenously but marginally increased when they were given by the intraperitoneal route. No changes were seen in the hypothermic effects of these drugs. No significant changes were seen in the convulsant or hypothermic effects of pentylenetetrazol. These results suggest that kindling with FG 7142 may alter GABA receptor function.     

Sulfur mustard as a carcinogen: application of relative potency analysis to the chemical warfare agents H, HD, and HT

A relative potency method for assessing potential human health effects from exposures to relatively untested chemicals is presented and documented. The need for such a method in evaluating the carcinogenic potential of the chemical warfare agent sulfur mustard (agent HD) from a limited data base is specifically addressed. The best-estimate potency factor for sulfur mustard relative to benzo[a]pyrene is 1.3, with an interquartile range of 0.6 to 2.9. The method is applied to (1) the estimated fence-boundary air concentrations of mustard during operation of a proposed agent incinerator at Aberdeen Proving Ground (APG), Maryland, and (2) the current approved general population exposure level of 1 X 10(-4) mg HD/m3 and the occupational exposure level of 3 X 10(-3) mg HD/m3. Maximum estimates of excess lifetime cancer risk for individuals at sites along the APG boundary range between 3 X 10(-8) and 1 X 10(-7). Lifetime cancer risk estimates less than or equal to 10(-6) are not now regulated by the U.S. Environmental Protection Agency or the Food and Drug Administration. Maximum estimates of excess lifetime cancer risk assuming daily exposure to the approved standards during the proposed 5 years of incinerator operation are on the order of 10(-5) for the general public and 10(-4) for the worker population. These values are considered upper limit estimates.     

4-Hydroxy-5,6-dihydropyrones as inhibitors of HIV protease: the effect of heterocyclic substituents at C-6 on antiviral potency and pharmacokinetic parameters.

Due largely to the emergence of multi-drug-resistant HIV strains, the development of new HIV protease inhibitors remains a high priority for the pharmaceutical industry. Toward this end, we previously identified a 4-hydroxy-5,6-dihydropyrone lead compound (CI-1029, 1) which possesses excellent activity against the protease enzyme, good antiviral efficacy in cellular assays, and promising bioavailability in several animal species. The search for a suitable back-up candidate centered on the replacement of the aniline moiety at C-6 with an appropriately substituted heterocyle. In general, this series of heterocyclic inhibitors displayed good activity (in both enzymatic and cellular tests) and low cellular toxicity; furthermore, several analogues exhibited improved pharmacokinetic parameters in animal models. The compound with the best combination of high potency, low toxicity, and favorable bioavailabilty was (S)-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one (13-(S)). This thiophene derivative also exhibited excellent antiviral efficacy against mutant HIV protease and resistant HIV strains. For these reasons, compound 13-(S) was chosen for further preclinical evaluation.     

Neuroleptics related to butaclamol. An investigation of the effects of chlorine substituents on the aromatic rings.

The synthesis of analogues of the antipsychotic drug butaclamol bearing chloro substituents on the benzene rings is described. On the basis of a perceived topographical similarity of a putative chlorophenylethylamine pharmacophore present in these analogues and in VUFB-10032 and doclothepin, agents related to octoclothepin which do not induce catalepsy, they have been tested for "noncataleptic" neuroleptic activity. None of the butaclamol analogues exhibit this type of activity. Depending on the position of the chlorine, the analogues either retained butaclamol-like activity or were inactive.     

The effects of linking substituents on the in vivo behavior of site-directed, peptide-based, diagnostic radiopharmaceuticals

A number of human cancers are known to over-express the gastrin-releasing peptide receptor (GRPr) on cell surfaces. The high specificity and affinity of bombesin (BBN), an amphibian analogue of mammalian gastrin-releasing peptide, for the GRPr makes it an ideal candidate for delivery of diagnostic probes, such as 99mTc radiometal, to tumor sites. An optimized targeting agent possesses high tumor uptake with minimal uptake in normal tissues. In this study, 99mTc-targeting vectors of bombesin using various amino acid/aliphatic pharmacokinetic modifiers or linking groups were evaluated to determine the effect of the spacer on receptor binding affinity, internalization/externalization and biodistribution. Conjugates of the general type [DPR-X-BBN] (X = amino acid/aliphatic pharmacokinetic modifier) were synthesized by solid phase peptide synthesis (SPPS) and metallated with either low-valent, radioactive Tc-99m(I) or non-radioactive Re(I)-tricarbonyl precursors. All of the new non-metallated and metallated conjugates were characterized by electrospray ionization mass spectrometry (ESI-MS). Receptor binding affinity, internalization/externalization and biodistribution studies in normal (CF-1) and tumor (human prostate PC-3-bearing mice) are reported. The effectiveness of targeting xenografted PC-3 tumors in rodents for two of the new 99mTc-BBN conjugates is demonstrated herein using small animal single photon emission computed tomography (SPECT).     

Paradoxical effects of N-cyanoalkyl substituents upon the activities of several classes of opioids.

The pharmacological effect of the N-(beta-cyanoethyl) moiety is dependent on the opioid on which it is substituted. It caused a large increase in antinociceptive potency, in (--)-3-hydroxymorphinan and (--)-normetazocine, as compared with the N-methyl opioid. These cyanoethyl compounds do not substitute for morphine in morphine-dependent monkeys. This moiety also appears to greatly increase the ability of the opiate receptor to differentiate enantiomers. An ca. 100,000-fold difference in binding was noted between the epimeric N-(beta-cyanoethyl)-3-hydroxymorphinans and the normetazocines. The levo enantiomers have little acute toxicity and showed excellent therapeutic ratios. In contrast, the N-(beta-cyanoethyl) moiety on normorphine, norcodeine, and noroxymorphone did not appear to improve their pharmacological properties. Homologous N-cyanoalkyl opioids were less potent antinociceptives.