Neonatal programming of ethylmorphine demethylase and corticosteroid 5 alpha-reductase by testosterone, dihydrotestosterone, and estradiol. Effects of an anti-estrogen, an anti-androgen, and an inhibitor of estrogen synthetase

The neonatal imprinting of ethylmorphine demethylase and corticosteroid 5 alpha-reductase was studied. Males, castrated at birth (day 1), were injected (sc) with testosterone, dihydrotestosterone, or estradiol on days 2, 4, and 6 and with testosterone (2 mg/rat/day) on days 50-59. Microsomes were prepared on day 60. All three steroids, at greater than or equal to 0.73 mumol/pup, increased the apparent Vmax and decreased the apparent Km of the demethylase to values that did not differ (p less than 0.05) from those of intact adult males. Analogously, all steroids, at greater than or equal to 0.73 mumol/pup, decreased the apparent Vmax of the reductase to intact male values; its apparent Km was increased to adult male values by both androgens (at greater than or equal to 0.37 mumol/pup) and by estradiol (at greater than or equal to 0.73 mumol/pup). Flutamide (1.45 mumol/pup) failed to alter these effects indicating that androgen receptors are not involved in the imprinting process. Nafoxidine (1.45 mumol/pup) blocked the effects of all three steroids, indicating that androgens and estrogens both imprint via the estrogen receptor. An inhibitor of androgen aromatase, 1,4,6-androstatriene-3, 17 dione, blocked the imprinting effects of testosterone, but not those of dihydrotestosterone. Thus, testosterone is oxidized to estradiol prior to imprinting, while dihydrotestosterone imprints as the parent compound. The latter may reflect a pharmacologic occupancy of the estrogen receptor by dihydrotestosterone.     

Comparative trial of an antihistamine,mequitazine, and placebo

Summary

Forty patients suffering from a dermatological condition suitable for treatment with an antihistamine were studied in a double-blind randomized trial to compare the effectiveness and tolerance of mequitazine and placebo. Over a period of 2 weeks, patients received either 5?mg mequitazine twice daily or placebo. Where justified, patients were also given concomitant topical treatment but only with a hydrating cream or ichthyol paste. Patientsl overall response to treatment was significantly better in the mequitazine group, whether the results were analyzed for all patients or those receiving just the trial drugs without topical treatment. Few side-effects were reported and there was no significant difference between the levels of drowsiness experienced with mequitazine compared with placebo.     

Zearalenone,an Estrogenic Mycotoxin,Is an Immunotoxic Compound

The aim of this study was to assess the toxic effects of zearalenone (ZEA) on the immune function. Ovariectomised rats were treated daily by gavage with 3.0 mg/kg of ZEA for 28 days. Body weight gain, food consumption, haemotological parameters, lymphoid organs, and their cellularities were evaluated. Moreover, acquired immune responses and macrophage activity were also assessed. ZEA promoted reduction in body weight gain, which is not fully explained by diminished food consumption. Despite no effect on haematological parameters, ZEA caused thymic atrophy with histological and thymocyte phenotype changes and decrease in the B cell percentage in the spleen. With respect to acquired and innate immune responses, no statistically significant differences in delayed-type hypersensitivity were noticed; however, in the ZEA-treated rats, antibody production and peroxide release by macrophages were impaired. The observed results could be related to ZEA activity on ERs; thus, ZEA is an immunotoxic compound similar to estrogen and some endocrine disruptors.     

Characterization, selection, and development of an orally dosed drug polymorph from an enantiotropically related system

Solid-state characterization methods are used to study a dimorphic pharmaceutical compound and select a form for development. Polymorph screening found that [4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl] acetic acid can crystallize into two non-solvated polymorphs designated Forms 1 and 2. Physical methods including vibrational spectroscopy, X-ray powder diffraction, solid-state NMR (SSNMR), thermal analysis, and gravimetric water vapor sorption are used to fully characterize the two polymorphs. Temperature-dependent competitive ripening experiments and solubility measurements indicated that the polymorphs in this system exhibit enantiotropy with a thermodynamic transition temperature of 35+/-3 degrees C. This complicates the selection of a polymorph to progress in drug development. Both forms had undesirable qualities; however, a particular drawback of Form 1 was found in its tendency to convert to Form 2 upon milling. Combining this effect and the desired formulation approach with physical property results led to a rationale for the choice of Form 2 for further development. Because this form is thermodynamically metastable at room temperature, analytical approaches were developed to ensure its exclusive presence, including a quantitative infrared spectroscopic method for drug substance and (13)C and (19)F solid-state NMR limit tests for the undesired form in drug product at drug loads of 8.3% (w/w).     

Comparative trial of an antihistamine, mequitazine, and placebo.

Forty patients suffering from a dermatological condition suitable for treatment with an antihistamine were studied in a double-blind randomized trial to compare the effectiveness and tolerance of mequitazine and placebo. Over a period of 2 weeks, patients received either 5 mg mequitazine twice daily or placebo. Where justified, patients were also given concomitant topical treatment but only with a hydrating cream or ichthyol paste. Patients' overall response to treatment was significantly better in the mequitazine group, whether the results were analyzed for all patients or those receiving just the trial drugs without topical treatment. Few side-effects were reported and there was no significant difference between the levels of drowsiness experienced with mequitazine compared with placebo.     

Organophosphate poisoning and management, an update

Organophosphate poisoning is characterised for the most part, by acute incidents. Management is by way of first aid (in mild poisoning) and use of atropine with or without the oximes, (in moderate to severe poisoning). Of late, it has become apparent that subchronic and chronic organophosphate poisoning are a common manifestation. This review paper summarises this triphasic nature of organophosphate poisoning. Possible future diagnostic and management techniques are also discussed.     

Alzheimer's, angiotensin IV and an aminopeptidase

The angiotensin AT(4) receptor was originally defined as the specific, high affinity binding site for the hexapeptide angiotensin IV (Ang IV). Subsequently, the peptide LVV-hemorphin 7 was also demonstrated to be a bioactive ligand of the AT(4) receptor. Central administration of Ang IV or LVV-hemorphin 7 (LVV-H7) markedly enhances learning and memory in normal rodents and reverse memory deficits observed in animal models of amnesia. The high affinity binding site has a broad distribution in the brain including areas such as the hippocampus that are involved in memory processing. The high affinity Ang IV binding site (AT(4) receptor) has been identified as the transmembrane enzyme, insulin-regulated membrane aminopeptidase (IRAP). Insulin-regulated aminopeptidase is a type II integral membrane spanning protein belonging to the M1 family of aminopeptidases and in insulin-responsive cells colocalizes with GLUT4 in specific intra-cellular vesicles. Both Ang IV and LVV-H7 are competitive inhibitors of IRAP catalytic activity and are not substrates of the enzyme.     

Antitumor and antimetastatic activity of an antibiotic, ascofuranone, and activation of phagocytes

Ascofuranone demonstrated antitumor activity against FM3A murine mammary carcinoma, implanted in the peritoneal cavity of syngeneic mice, C3H/He. It was more effective by treatment prior to implantation than by that after implantation. Treatment with ascofuranone also increased splenic cytotoxicity and phagocytic activity of host animal cells. Moreover, ascofuranone induced inflammatory cells in the peritoneal cavity which are mainly composed of polymorphonuclear leukocytes and macrophages. These cells are more potent in cytotoxicity against FM3A cells than with resident peritoneal cells. The antitumor activity of ascofuranone was suppressed by ip administration of silica, just prior to tumor implantation. These results suggest that the prophylactic antitumor activity of ascofuranone is expressed through the activation of phagocytes. Ascofuranone also suppressed pulmonary metastasis of B16 melanoma and Lewis lung carcinoma. Treatment after tumor implantation failed to suppress the metastasis. Single treatment of ascofuranone 4 days prior to implantation decreased the metastasis of Lewis lung carcinoma but not that of B16, whereas single treatment of ascofuranone 24 hours prior to the tumor implantation decreased the metastasis of B16 but not that of Lewis lung carcinoma.     

Absorption, distribution and excretion of cefsulodin, an antipseudomonal cephalosporin, in mice, rats and dogs

A single dose of 20 mg/kg of cefsulodin [3-(4-carbamoyl-1-pyridiniomethyl)-7 beta-(D-alpha-sulfophenylacetamido)-ceph-3-em-4-carboxylate monosodium salt] was administered subcutaneously to mice, and intramuscularly to rats and dogs. The plasma and tissue levels reached the peak 15 approximately 30 minutes after administration. In mice and rats, no plasma levels were measurable 2 and 4 hours after administration. In dogs, the plasma levels were measurable 6 hours after administration. The level in the kidney of mice was slightly lower than the plasma level, while in rats and dogs, the level in the kidney was higher than the plasma level. The cefsulodin levels in the lung of rats and dogs were relatively high, and the level in mice was relatively low. The hepatic levels were very low in all test animal species. Cefsulodin was mainly excreted into the urine, and the excretion of cefsulodin into the bile was very slight.     

Pharmacokinetics of amosulalol, an alpha, beta-adrenoceptor blocker, in rats, dogs and monkeys

The pharmacokinetics of an alpha, beta-adrenoceptor blocker, amosulalol hydrochloride, were studied after i.v. and oral administration to rats, dogs and monkeys. After an i.v. dose (1 mg/kg), the plasma concentration-time curve fitted a two-compartment open model with terminal half-lives of 2.5 h in rats, 2.1 h in dogs and 1.8 h in monkeys. The order of plasma clearances for amosulalol was: rats greater than dogs greater than monkeys. After oral administration, the maximum plasma concentration was obtained at 0.5-1 h in rats (10-100 mg/kg) and dogs (3-30 mg/kg), and at 1.7-2.7 h in monkeys (3-10 mg/kg). A linear relationship between the area under the plasma concentration-time curve and dose administered was obtained for all three species. The systemic availabilities of the drug in rats, dogs and monkeys were 22-31%, 51-59% and 57-66%, respectively. After repeated oral administration (10 mg/kg) to dogs for 15 days, the pharmacokinetic parameters did not differ significantly from those on the first day.     

一种红蜂胶提取物治银屑病、消炎及镇痛作用(英文)

AIM: To study the antipsoriatic, anti-inflammatory, and analgesic effects of ethanolic extract of red propolis. METHODS and RESULTS: This extract induced the formation of granular layer in the mouse tail test used as a model of psoriasis. Propolis 50 mg·kg-1 ig showed anti-inflammatory activity in the cotton-pellet granuloma assay in rats, in croton oil-induced edema in mice at a dose of 25 % (2.5μL), and in the peritoneal capillary permeability test in mice at a dose of 10 mg·kg-1. The extract (25 mg·kg-1 ig) showed analgesic effect in the model of acetic acid-induced writhings, whereas 40 mg·kg-1 was effective in the hot plate test in mice. CONCLUSION- Anti-inflammatory, analgesic, and antipsoriatic properties of Cuban red propolis were evident.     

Discovery,gene modification,and optimization of fermentation of an enduracidin-producing strain

Abstract

Enduracidin significantly inhibits Gram-positive bacteria and had been widely used in many fields. However, as the poor technology for production of enduracidin and its scarcity, identification of novel strategies for production of enduracidin is important. Our group developed two methods to improve the yield of the production of enduracidin. The yield of enduracidin was increased by three- to fivefold. The highest yields of enduracidin A and enduracidin B achieved were 63.7 and 82.13 mg/ml. Thus, our results might provide a new reference method for the industrial production of enduracidin.     

Danshen: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use

Danshen, the dried root of Salvia miltiorrhiza, has been widely used in China and, to a lesser extent, in Japan, the United States, and other European countries for the treatment of cardiovascular and cerebrovascular diseases. In China, the specific clinical use is angina pectoris, hyperlipidemia, and acute ischemic stroke. The current review covers its traditional uses, chemical constituents, pharmacological activities, pharmacokinetics, clinical applications, and potential herb-drug interactions based on information obtained in both the English and Chinese literature. Although numerous clinical trials have demonstrated that certain Danshen products in China are effective and safe for the treatment of cardiovascular diseases, most of these lack sufficient quality. Therefore, large randomized clinical trials and further scientific research to determine its mechanism of actions will be necessary to ensure the safety, effectiveness, and better understanding of its action.