紫外分光光度法测定复方链霉素软膏中2组分的含量

目的:建立以紫外分光光度法测定复方链霉素软膏中硫酸链霉素和氨苯磺胺含量的方法。方法:采用麦芽酚-硫酸铁铵比色法,以硫酸铁铵为显色剂,于521nm波长处测定硫酸链霉素的吸收度;以0.1mol/L氢氧化钠溶液为溶剂,于251nm波长处测定氨苯磺胺的吸收度。结果:硫酸链霉素、氨苯磺胺检测浓度分别在200～950(r=0.9994)、1.464～7.784(r=0.9998)μg/ml范围内与吸收度呈良好的线性关系;平均加样回收率分别为99.1%(RSD=1.90%)、99.7%(RSD=1.60%)。结论:本方法简便、准确,可用于复方硫酸链霉素软膏的质量控制。     

Discovery of novel sulfonamides as potent and selective inhibitors against human and mouse 11β-hydroxysteroid dehydrogenase type 1

Several classes of non-steroid 11β-HSD1 inhibitors have been developed as promising treatments for Type 2 Diabetes (T2D). Using a human 11β-HSD1 selective inhibitor as a starting point, we designed and synthesized a new class of derivatives of 1-arylsulfonyl piperidine-3-carboxamides. It was found that the large lipophilic group on the amino moiety may lead to cross-species potency towards human and mouse, allowing drug development by evaluating compounds in rodent model. By exploring structure-activity-relationship, the (R)-(+)-bornylamine derivative is identified as the most potent inhibitor of mouse enzyme 11β-HSD1 with an IC(50) of 18 nM. Docking studies revealed the different possible interaction modes of the S-enantiomer and R-enantiomer bound to h11β-HSD1, and explained why the S-enantiomer is more active than the R-enantiomer. Finally, two potent and isoform-selective compounds, (+)-isopinocampheylamine derivative 8m and (R)-(+)-bornylamine derivative 8l, with suitable in vitro properties, could be selected for future PK/PD evaluation in rodent models. Then, 8l was subjected a pharmacodynamics study in vivo with rodent model. It was shown that 8l have 71% and 63% inhibition in adipose and liver tissue at 1h after administration, but it was a short-acting compound displaying a significant drop in potency in the subsequent 3h. This study not only provides compounds as novel h11β-HSD1 inhibitors, but also presents structure-activity relationships for designing potent human/mouse 11β-HSD1 inhibitors suitable for in vivo evaluation in rodent models.     

Low-Dose Acetazolamide in the Treatment of Premenstrual Dysphoric Disorder: A Case Series

The treatment of premenstrual dysphoric disorder (PMDD) is far from satisfactory, as there is a high proportion of patients who do not respond to conventional treatment. The antidiuretic sulfonamide, acetazolamide, inhibits carbonic anhydrase and potentiates GABAergic transmission; the latter is putatively involved in PMDD. We therefore tried acetazolamide in a series of women with intractable PMDD. Here, we describe a series of eight women diagnosed with DSM-IV-TR PMDD, five of whom had comorbidity with a mood disorder and one with an anxiety disorder, who were resistant to treatment and responded with symptom disappearance after being added-on 125 mg/day acetazolamide for 7-10 days prior to menses each month. Patients were free from premenstrual symptoms at the 12-month follow-up. We suggest that acetazolamide may be used to improve symptoms of PMDD in cases not responding to other treatments. GABAergic mechanisms may be involved in counteracting PMDD symptoms.     

Design, synthesis and anticancer evaluation of novel tetrahydroquinoline derivatives containing sulfonamide moiety

Sulfonamides posses many types of biological activities and have recently been reported to show substantial antitumor activity in vitro and/or in vivo. There are a variety of mechanisms for the anticancer activity and the most prominent of these is through the inhibition of carbonic anhydrase isozymes. The present work reports the synthesis of some novel quinoline and pyrimido[4,5-b]quinoline derivatives bearing a substituted or unsubstituted sulfonamide moiety. The design of the structures of these compounds complies with the general pharmacophore of the sulfonamide compounds that act as carbonic anhydrase (CA) inhibitors as this may play a role in their anticancer activity. All the newly synthesized compounds were evaluated for their in vitro anticancer activity against breast cancer cell line (MCF7). Most of the screened compounds showed interesting cytotoxic activities compared to a reference drug.     

QSAR analysis of caffeoyl naphthalene sulfonamide derivatives as HIV-1 integrase inhibitors

Human immunodeficiency virus type 1 (HIV-1) integrase is a potential target for anti-HIV therapy. It is an essential enzyme required for replication of the acquired immunodeficiency syndrome (AIDS) virus. Caffeoyl naphthalene sulfonamide derivatives act against HIV integrase and thus have the potential to become a part of an anti-HIV drug regimen. Although caffeoyl naphthalene sulfonamide derivatives have all the features required of good anti-HIV agents such as the presence of bis-catechol moieties, polyaromatic rings, and a central linker, they do not perform well as anti-HIV agents in cell-based assays, that is, they do not stop viral replication at nontoxic concentration. We carried out a quantitative structure–activity relationship (QSAR) study of caffeoyl naphthalene sulfonamide derivatives via the software WIN CAChe 6.1 and STATISTICA to improve its activity. QSAR reveals that if partition coefficient, connectivity index, and shape index of these molecules are altered, the activity is likely to increase. On the basis of the QSAR model, we designed a new series of compounds, calculated the activities, and found that they were more potent than the existing compounds.     

Voltammetric investigation of new polythiophene derivatives possessing electrochemically cleavable arylsulfonamide groups as precursors for solid phase electrosynthesis

New thiophene derivatives substituted by electrochemically cleavable sulfonamide groups have been synthesised and their electrochemical behaviour has been investigated in acetonitrile. The anodic oxidation of phenyl (I)- and naphthyl (II)sulfonamide-substituted thiophenes yielded corresponding polymer films exhibiting p- and n-doping processes. The cathodic cleavage of the SN bond grafted to the polymer backbone was performed by applying a potential lower than ?2.5 V (versus Ag ∣ 10^?1 M Ag⁺) to the polymer. The efficiency of this solid-state electrochemical reaction was found to be strongly lowered when the film thickness was increased. It was demonstrated that the decrease of this parameter was less important when a copolymer electroformed from II or a phenylsulfonamide-substituted terthiophene (III) was involved. The recycling properties of this type of material were illustrated by the grafting of an aminoferrocene moiety after the cathodic cleavage step to poly(II-co-3-methylthiophene).     

Phase I trial of chloroguinoxaline sulfonamide,with correlation of its pharmacokinetics and pharmacodynamics

To define a maximum tolerable dose, chloroquinoxaline sulfonamide (CQS) was given as a 1-h infusion every 28 days to cancer patients for whom no effective standard therapy was available. Doses were escalated in cohorts of at least three patients each. Plasma for characterization of the pharmacokinetics of free and total CQS was obtained during and after the initial infusion and, when possible, during and after subsequent infusions of CQS if the dose had been reduced. A total of 101 courses of CQS in 55 patients were evaluated. Dose levels ranged from 18 to 3,700 mg/m². The dose-limiting toxicity was hypoglycemia, first recognized at the 3,700-mg/m² dose. When dose-limiting hypoglycemia was recognized, patients were entered at successively lower doses, with close monitoring of plasma glucose and insulin concentrations being done in 26 patients. grade 1–3 hypoglycemia occurred within 4 h of the termination of CQS infusion and cleared by 24 h. Symptomatic hypoglycemia was more frequent at doses of CQS above 1,000 mg/m² Concomitant administration of 5% gyciosion being done in 26 patients. Grade 1–3 hypoglycemia close monitoring of plasma glucose and insulin concentrations being done in 26 patients. Grade 1–3 hypoglycemia occurred within 4 h of the termination of CQS infusion and cleared by 24 h. Symptomatic hypoglycemia was more frequent at doses of CQS above 1,000 mg/m². Concomitant administration of 5% glucose did not ameliorate the hypoglycemia associated with CQS doses of >1,000 mg/m². The total calorie intake, percentage of ideal body weight, or percentage of weight lost did not explain the incidence or severity of hypoglycemia in 12 patients in whom these data were obtained. Cardiac tachyarrhythmias occured in 7 patients who received CQS at doses of 1,000 mg/m², and tachyarrhythmia was associated with hypoglycemia in 3 patients. Other toxicities were sporadic, but the frequency of toxicity was higher at CQS doses of 1,000 mg/m². These toxicities included fever, rash, lightheadedness, leukopenia, thrombocytopenia, alopecia, diarrhea, nausea, and vomiting. All toxicities were reversible. Mean peak plasma [CQS] and AUC increased with dose, with a suggestion that peak plasma [CQS] plateaued at higher doses. The decline in plasma [CQS] was fitted to a three-compartment, open linear model. The terminal half-life ranged from 28 to 206 h. Total body clearance ranged from 44 to 881 ml/h with no evidence of saturation. Urinary excretion of the parent compound in 24 h averaged <5%. CQS not bound to plasma protein (free CQS) comprised 1%–17% of total plasma CQS and was not related to dose. A relationship was defined between the magnitude of hypoglycemia and CQS pharmacokinetic parameters. The percentage of decrease in plasma [glucose], i.e., (predose [glucose]-nadir [glucose]/predose [glucose])×100, correlated with both free and total peak plasma [CQS]. The relationship was described by the Hill equation:Effect=(Emax) (peak) ^H/(peak ₅₀)^H+(peak)^H, where the maximal effect (Emax) equals the maximal possible percentage of decrease in plasma [glucose] equals 100%,peak ₅₀ is the peak total [CQS] at whichE is half-maximal (326 mg/l), andH is the Hill constant, a measure of the sigmoidicity of the relationship (1.06). The relationship fit the data precisely with a mean absolute error (MAE) of 10.42 and was unbiased with a mean error (ME) of –0.06. The recommended phase II dose of CQS is 1,000 mg/m². Because the magnitude of hypoglycemia after CQS administration is related to peak plasma [CQS], repetitive CQS doses of 1,000 mg/m² would probably be tolerated better than single large doses of equivalent intensity.Abbreviations CQS Chloroquinoxaline sulfonamide - AUC area under the plasma concentration x time curve - CLTB total body clearance - MAE mean absolute error - ME mean error - DNA deoxyribonucleic acid - BCNU carmustine [N, N-bis(2-chloroethyl)-N-nitrosourea] - ECOG Eastern Cooperative Oncology Group - WBC white blood cell count - PLT platelet count - ALT alanine aminotransferase - AST aspartate aminotransferase - PT prothrombin time - PTT partial thromboplastin time - EKG electrocardiogram - D5W 5% dextrose in water - HPLC high-performance liquid chromatography - BEE basal energy expenditure This work was supported in part by contract N-01-CM-07303 awarded by the National Cancer Institute, Department of Health and Human Services. One of the authors (B.A.C.) is the recipient of American Cancer Society Clinical Oncology Career Development Award 90-127     

The Anticonvulsant Zonisamide Reduces Ethanol Self-Administration by Risky Drinkers

Objective: The purpose of this study is to examine the effects of zonisamide on ethanol self-administration and subjective effects in risky drinkers using a human laboratory paradigm. Method: We conducted a double-blind, placebo-controlled study of the effects of zonisamide 100 mg on ethanol self-administration and urge to drink in risky drinkers (N = 10) (). Result: During the second hour of a 2-hour self-administration session ethanol consumption was 50% lower in the zonisamide group as compared to the placebo group. Urge to drink was also significantly lower under the zonisamide condition. Conclusion: These results indicate that a single dose of zonisamide reduces urge to drink and the quantity of ethanol self-administered by risky drinkers during their second hour of access to alcohol. Scientific Significance: Zonisamide may help individuals drinking at risky levels reduce their intake of alcohol.     

Antimycotic Activity of Different Chemicals, Chaksine Iodide and Garlic/Antimykotische Aktivität von verschiedenen Chemikalien, Chaksinjodit und Knoblauch

Summary: Thirteen different fungi reported to produce keratomycosis in man, were tested for their susceptibility to in vitro antifungal action of alum, sulphacetamide, copper sulphate, silver nitrate, chaksine iodide and garlic. Interestingly, 2% alum, 30% sodium sulphacetamide, 0.2% copper sulphate and 0.1% silver nitrate inhibited the growth of all 13 fungi viz. Alternaria, Aspergillus flavus, Asp. fumigatus, Asp. niger, Candida albicans, Curvularia, Drechslera, Fusarium, Mucor, Penicillium, Rhizopus oryzae, Scopulariopsis and Syncephalastrum. Chaksine iodide, an alkaloid from an Indian medicinal herb, Cassia absus, at a concentration of 0.5% inhibited all fungi. Lower concentrations were either ineffective or effective against a few fungi only. Garlic (up to 1%) could inhibit none of the fungi. Repeated experiments yielded consistent findings.
Zusammenfassung: 13 verschiedene Pilze, die als Erreger einer Keratomykose des Menschen bekannt sind, wurden in vitro gegen folgende Substanzen getestet: Alaun, Sulfazetamid, Kupfersulfat, Silbernitrat, Chaksinjodit und Knoblauch.
Alle 13 Pilze wurden durch 2% Alaun, 30% Natriumsulfazetamid, 0,2% Kupfersulfat und 0,1% Silbernitrat gehemmt (Alternaria, Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Candida albicans, Curvularia, Drechslera, Fusarium, Mucor, Penicillium, Rhizopus oryzae, Scopulariopsis und Syncephalastrum). Chaksinjodit, ein Alkaloid aus einer indischen Heilpflanze, Cassia absus hemmte alle Pilze bei einer Konzentration von 0,5%. Niedrigere Konzentrationen waren entweder unwirksam oder nur gegen einige der Pilze wirksam. Knoblauch konnte in einer Konzentration bis zu 1% keine Pilze am Wachstum hindern. Die Wiederholung der Experimente führte zu entsprechenden Ergebnissen.