Drug-induced agranulocytosis: impact of different fcgamma receptor polymorphisms?

Drug-induced agranulocytosis is a rare but life-threatening side effect which is possibly based on immunogenetic mechanisms. Some studies regarding agranulocytosis induced by the atypical antipsychotic clozapine dealing with HLA subtyping and enzyme polymorphisms have been performed to elucidate its genetic background. To further screen possibly genetically based pathways of developing agranulocytosis, we assessed clinically relevant polymorphisms of immunoglobulin G or Fcgamma receptors in patients with clozapine-induced (n = 48), ticlopidine-induced (n = 11), thyroid inhibitors-induced agranulocytosis (n = 8), and controls (n = 75). We found significant age-related effects in each of the drug-induced agranulocytoses but no further associations that underline an effect of polymorphisms in FcgammaRIIa, FcgammaRIIIa, and FcgammaRIIIb genes on drug-induced agranulocytosis. Thus, Fcgamma receptors may not serve as a genetic marker to identify patients at risk for this life-threatening side effect.     

Influence of molecular properties on oral bioavailability of lipophilic drugs – Mapping of bulkiness and different measures of polarity

The biopharmaceutical assessment of new drug candidates based on their chemical structure is important in drug discovery and development. The scope of this study is to focus on lipophilic drugs and to clarify the role of their chemical predictors on oral bioavailability in humans. First their chemical properties were calculated from molecular modeling and the bioavailability data was obtained from the literature. The data was then analyzed by a partial least square method including non-linear terms. Significant coefficients were identified from a group of polarity- and solubility-related properties. Contour plots were constructed mapping molecular weight together with different polarity factors. Depending on the molecular weight a maximal bioavailability was found at solubility parameters of about 31–35 (J/cm³)^1/2 and HLB values of roughly 4–12. The mapping of lipophilic drugs also revealed that a solubility parameter of less than 20 (J/cm³)^1/2 or a HLB of smaller than unity is critical for the drug-likeness of new compounds.     

Evaluation of cytotoxicity of a new hemostatic agent Ankaferd Blood Stopper® using different assays

The aim of this study is to investigate the effects of the Ankaferd Blood Stopper? (ABS), on cell viability, cytotoxicity, and erythrocyte numbers in in vitro cultured human blood cells. We studied the cytotoxic effects of the ABS using lactate dehydrogenase (LDH) assay, cell proliferation (WST-1) assay and hemolytic assay. The cytotoxicity increased when cells were treated with ABS dilutions of 5%, 12.5%, 25%, and 50% (p < 0.05). Moreover, treatment of the cells with the same concentrations significantly elevated the cell number at 24 and 48 h (p < 0.05). ABS causes a significant increase (p < 0.05) in the hemolytic activity on human erythrocytes and hemolytic activity increases with increase in ABS concentrations. The red blood cell aggregation and cell membrane disruption during the coagulation process lead to induction of hemolytic activity and increase of LDH level in cell culture medium. In addition, ABS has proliferative effects on human leukocytes. Based on these results, ABS can be used as an alternative blood stopping agent safely.     

Do different mechanisms underlie two anxiogenic effects of systemic nicotine?

Alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) and 5-hydroxytryptamine 1A (5-HT1A) receptors have been implicated in the anxiogenic effects of centrally administered nicotine, but the receptors that mediate the anxiogenic effects of systemic nicotine are not known. This study explored whether competitive nAChR antagonists [dihydro-beta-erythroidine (DHbetaE), 4 mg/kg, and methyllycaconitine (MLA), 5 mg/kg], and a 5-HT1A receptor antagonist (WAY 100635, 0.5 and 1 mg/kg) could block the effects of two anxiogenic doses of nicotine in the social interaction test of anxiety. The anxiogenic effect of 0.1 mg/kg nicotine, given 5 min before the test, was blocked by DHbetaE and WAY 100635, establishing roles for alpha4beta2 nAChRs and 5-HT1A receptors. None of the antagonists could block the effect of 0.45 mg/kg nicotine, given 30 min before the test, precluding firm conclusions about the mechanisms underlying this anxiogenic effect. However, there was evidence for a role of alpha7 nAChRs in mediating an endogenous anxiogenic tone, since MLA itself had an anxiolytic effect that was blocked by both doses of nicotine. Thus, both alpha7 and alpha4beta2 nAChRs might have a role in mediating the anxiogenic effects of nicotine.     

Biphasic stimulant and sedative effects of ethanol: are children of alcoholics really different?

Children of alcoholics (COAs) have an increased risk of developing alcoholism themselves. The mechanisms responsible are not yet known. One compelling theory postulates that COAs may have an increased sensitivity to the stimulant effects of alcohol during the ascending limb of the blood alcohol curve combined with a decreased sensitivity to the putatively undesirable sedative effects of the drug during the descending limb, providing a particularly strong motivation to drink. Consistent with this theory, we hypothesized that compared to children of nonalcoholics (CONAs), COAs would display higher levels of ascending limb stimulation and lower levels of descending limb sedation. In the present study, 100 college students, who were either COAs (n=18) or CONAs (n=82), completed the Biphasic Alcohol Effects Scale (a self-report measure of stimulation and sedation): (1) before consuming 0.85n ml/kg ethanol; (2) during the ascending limb of their BAC, and; (3) during the descending limb of their BAC. Although findings indicated that COAs and CONAs had comparable levels of sedation at each time point, a significant GroupxTime interaction (P<.02) indicated that COAs had greater increases in stimulation from baseline than CONAs, providing partial support for our hypothesis. Interestingly, simple effects analyses revealed that COAs had lower baseline levels of stimulation but almost identical levels of ascending and descending limb stimulation as CONAs, suggesting that increased sensitivity to alcohol among COAs may be the result of baseline understimulation. Overall, findings suggest that theorized differences between COAs and CONAs may be due in part to broader trait differences or other nonpharmacological factors.     

What is the long‐term outcome of the different subgroups of functional dyspepsia?

BACKGROUND: Functional dyspepsia is often a long-lasting disorder that accounts for substantial healthcare costs. It has been classified into subgroups assuming that it can guide management of dyspepsia. AIM: To evaluate the clinical significance of subgrouping functional dyspepsia in a long-term perspective study. METHODS: Consecutive patients with dyspepsia identified by general practitioners were investigated. Those patients with functional dyspepsia (n=201) were enrolled in this study. Initially, patients were divided into five subgroups (ulcer-like, dysmotility-like, reflux-like, unspecified, and irritable bowel syndrome-like). Patients' medical histories were reviewed after 6-7 years, and the number and outcome of repeated investigations were analysed. At the end of follow-up, patients filled in a questionnaire similar to that at baseline, and were invited for gastroscopy. RESULTS: Only 2% of patients developed peptic ulcer during follow-up, none of them were in the ulcer-like subgroup. When referrals to hospital and examinations during follow-up were registered, no statistically significant differences existed between subgroups. Patients with reflux-like dyspepsia made fewer revisits than others (P=0.02), but had used antidyspepsia drugs during the previous year more often (P=0.036). Stability of the subgroups over time was poor. CONCLUSIONS: Functional dyspepsia is a long-lasting disorder with a very good prognosis. Subgroups of functional dyspepsia play only a minor role in prediction of the long-term outcome, and their usefulness in clinical practice is also hampered by subgroup instability over time.     

Does the relative silicone content of different syringes affect the stability of foam in sclerotherapy?

BACKGROUND: Sclerotherapy has become the gold standard in the treatment of varicose veins. Foam sclerosing solution with sodium tetradecyl sulfate (STS) is one of the most popular agents used. This study examined the possibility that relative silicone content of different syringes may affect the overall foam stability. MATERIALS AND METHODS: A double-syringe system (DSS) technique to make sclerosing foam (STS 0.5% and air) was applied. Four different brands of syringes were tested. The time required for half of the original volume of sclerosing solution to settle was recorded. RESULTS: The time for the sclerosing solution to settle to half of its initial volume varied with each brand of syringes. CONCLUSION: The type of syringe used in the DSS technique to produce foam for sclerotherapy is a determinant of foam stability. Whether this will affect the result of sclerotherapy requires further investigation.     

β-Adrenoceptor and post-receptor components show different rates of desensitization to desipramine

Both 3-day and 15-day desipramine treatments (10 mg/kg, once daily) significantly reduced β₁- but not β₂-adrenoceptor and isoproterenol-stimulated adenylyl cyclase activities in rat cortical, hippocampal and amygdaloid membrane preparations. In contrast, 15-day but not 3-day desipramine treatment resulted in a significant reduction in NaF-, GppNHp- and forskolin-stimulated adenylyl cyclase activity. The results suggest that post-β-adrenoceptor component desensitization occurs more slowly than receptor downregulation in response to desipramine.     

The water binding behavior of κ-Carrageenan determined by three different methods

κ-Carrageenan is a biopolymer extracted from red seaweeds which has been in the focus of pharmaceutical development for many years. Most applications make use of the large water binding capacity of κ-carrageenan. The primary limitation of κ-carrageenan is the variation in the substance quality. Therefore, the water binding capacity of different κ-carrageenan products was investigated by dynamic vapor adsorption, freezing and non-freezing bound water and water retention value. The κ-carrageenans were observed to have a higher water binding capacity than microcrystalline cellulose (MCC) in all three methods. The amount of adsorbed water is similar for all carrageenans. Differences between the carrageenan types (κ, ι, and λ) were remarkable for the freezing bound water and centrifugation bound water as well as between the κ-carrageenans of different suppliers.     

Intracerebral injection of different antibodies against endogenous opioids suggest α-neoendorphin participation in control of feeding behaviour

Summary The mechanism of feeding behaviour of rats was examined. We used antibodies to different opioid peptides in order to reduce the tonic activity of various endogenous opioid peptide systems that may underly appetite. Unilateral microinjection of anti--neoendorphin antibodies into various areas of the ventromedial hypothalamus (VMH) inhibited food and water intake up to 45% in deprived animals. Injections outside this area failed to affect feeding. Administration of anti--endorphin antibodies into the VMH moderately attenuated appetite. A considerable decrease of food and water intake was observed only upon injection of this antibody into the nucleus periventricularis hypothalami, a region generally believed to be involved with feeding. A marginal reduction of appetite was observed with anti-dynorphin antibodies injected into the VMH. These data may suggest that -neoendorphin is involved in the control of food and water intake in the VMH.     

Effects of the administration of miconazole by different routes on the biomarkers of the “steroidal module” of the Athlete Biological Passport

This article reports the results obtained from the investigation of the influence of miconazole administration on the physiological fluctuation of the markers of the steroid profile included in the “steroidal module” of the Athlete Biological Passport. Urines collected from male Caucasian subjects before, during, and after either systemic (i.e., oral and buccal) or topical (i.e., dermal) treatment with miconazole were analyzed according to validated procedures based on gas chromatography coupled to tandem mass spectrometry (GC–MS/MS) (to determine the markers of the steroid profile) or liquid chromatography coupled to MS/MS (LC–MS/MS) (to determine miconazole urinary levels). The results indicate that only after systemic administration, the markers of the steroid profile were significantly altered. After oral and buccal administration, we have registered (i) a significant increase of the 5α-androstane-3α,17β-diol/5β-androstane-3α,17β-diol ratio and (ii) a significant decrease of the concentration of androsterone, etiocholanolone, 5β-androstane-3α,17β-diol, and 5α-androstane-3α,17β-diol and of the androsterone/etiocholanolone, androsterone/testosterone, and 5α-androstane-3α,17β-diol/epitestosterone ratios. Limited effects were instead measured after dermal intake. Indeed, the levels of miconazole after systemic administration were in the range of 0.1–12.5 μg/ml, whereas after dermal administration were below the limit of quantification (50 ng/ml). Significant alteration started to be registered at concentrations of miconazole higher than 0.5 μg/ml. These findings were primarily explained by the ability of miconazole in altering the kinetic/efficacy of deglucuronidation of the endogenous steroids by the enzyme β-glucuronidase during the sample preparation process. The increase of both incubation time and amount of β-glucuronidase was demonstrated to be effective countermeasures in the presence of miconazole to reduce the risk of uncorrected interpretation of the results.     

Kinetics of α-glucosidase inhibition by different fractions of three species of Labiatae extracts: a new diabetes treatment model

Context: Glucosidases are a group of enzymes playing crucial roles in digestion of carbohydrates. Glucosidase inhibitors can reduce carbohydrate digestion rate and have the potential to prevent development of type 2 diabetes. The Labiatae is one of the largest plant families grown globally and many studies that have isolated new pharmaceutical compounds. In folk medicine, some of Labiatae plants such as Zataria multiflora Boiss, Salvia mirzayanii Rech. F. &; Esfand, and Otostegia persica Boiss are consumed for the treatment of diabetes.

Objectives: This study investigates the inhibitory effects of different fractions of three mentioned species extracts on α-glucosidase.

Materials and methods: Ethanol extracts of these plants leaves were fractionated using petroleum ether, chloroform, ethyl acetate, and n-butanol solutions. The duration of this study was 12?months. To measure enzyme inhibition, 5?μL of the enzyme, 20?μL of substrate and samples were used and for evaluation mode of inhibition, constant amounts of α-glucosidase were incubated with rising concentrations of substrate (PNPG).

Results: The results revealed that the ethyl acetate fraction of Zataria multiflora (IC₅₀ =?0.35?±?0.01?mg/mL) and petroleum ether fraction of Salvia mirzayanii (IC₅₀ =?0.4?±?0.11?mg/mL) were the most potent inhibitors of α-glucosidase in comparison with the other samples and acarbose as the standard (IC₅₀ =?7?±?0.19?mg/mL). All of the samples exhibited noncompetitive-uncompetitive inhibition.

Discussion and conclusion: It can be inferred from this study that α-glucosidase inhibitory potential of the studied extracts may be a marker of antidiabetic potential of these extracts.     

Modulation of ammonium perfluorooctanoate-induced hepatic damage by genetically different PPARα in mice

Perfluorooctanoic acid is a ligand for peroxisome proliferator-activated receptor (PPAR??). Ammonium perfluorooctanoate (APFO) at 0.1 and 0.3?mg/kg doses activated mouse PPAR??, but not human PPAR??. This study aimed to clarify whether milligram-order APFO can activate human PPAR??, and the receptor is involved in APFO-induced chronic hepatic damage. Male Sv/129 wild-type (mPPAR??), Ppar??-null, and humanized PPAR?? (hPPAR??) mice (8 weeks old) were divided into three groups. The first was treated with water and the other two with 1.0 and 5.0?mg/kg APFO for 6?weeks, orally, respectively. Both doses activated mouse and human PPAR?? to a similar or lower degree in the latter. APFO dose dependently increased hepatic triglyceride levels in Ppar??-null and hPPAR?? mice, but conversely decreased those in mPPAR?? ones. APFO-induced hepatic damage differed markedly among the three genotyped groups: single-cell necrosis was observed in all genotyped mice; inflammatory cells and macrovesicular steatosis only in Ppar??-null mice; and microvesicular steatosis and hydropic degenerations in hPPAR?? and Ppar??-null mice. The molecular mechanism underlying these differences may be attributable to those of gene expressions involved in lipid homeostasis (PPAR??, ??- and ??-oxidation enzymes, and diacylglycerol acyltransferases) and uncoupling protein 2. Thus, milligram-order APFO activated both mouse and human PPAR?? in a different manner, which may reflect histopathologically different types of hepatic damage.     

Compaction and measurement of tablets in liquids with different dielectric constants for determination of bonding mechanisms—Evaluation of the concept

In order to study bonding mechanisms in tablets, liquids with increasing dielectric constants have been used to filter out weak long range distance forces. The aim of this study was to further critically evaluate this concept.Tablets of sodium chloride, sodium bicarbonate, Avicel®, Emcompress®, lactose and sucrose were compacted in media with dielectric constants from 1 to 24 and the remaining tensile strength of tablets compacted in liquid was calculated. With increasing dielectric constant a continuos decrease in tensile strength was obtained and at a dielectric constant above approximately 10–15, a plateau level was reached for all materials except for Avicel®. This level was assumed to reflect the proportion of solid bridges in the compact and the values were consistent with previous data reported from our laboratory.The results also showed that by compacting particles suspended in a liquid a more effective reduction of long range distance forces was obtained, than if tablets were compacted in air followed by a soaking process in liquid.Compaction in liquids may be unsuitable for some materials due to swelling or changes in volume reduction behaviour. Nevertheless, the method appears to be favourable for studying bonding mechanisms, especially for tablets with a low porosity.     

Effect of different durations and formulations of diltiazem on the single-dose pharmacokinetics of midazolam: how long do we go?

Understanding how inhibition of cytochrome P4503A (CYP3A) affects the metabolism of a new drug is critical in determining if a clinically relevant drug interaction will occur. Diltiazem interaction studies assess a given compound's sensitivity to moderate CYP3A inhibition. The present study compared the effect different durations and formulations of diltiazem (extended release [XR] and conventional release [CR]) had on the single-dose pharmacokinetics of midazolam. The geometric mean ratio (GMR; midazolam + diltiazem(XR × 5 days)/midazolam + diltiazem(XR × 2 days)) for midazolam AUC(0-∞) was 0.98 (90% confidence interval [CI], 0.87, 1.10). The GMR (midazolam + diltiazem(XR × 2 days)/midazolam + diltiazem(CR × 2 days)) for midazolam AUC(0-∞) was 0.82 (90% CI, 0.73, 0.92). Simcyp simulations accurately predicted the observed clinical results only when a hepatic CYP3A degradation rate (k(deg)) different from that provided by the software was used. The data suggest that dosing diltiazem XR for 2 days predicts the change in midazolam AUC as reliably as 5 days of XR dosing and 2 days of CR dosing. In addition, the authors believe that a hepatic CYP3A kdeg of 0.03 h(-1) should be considered for future Simcyp studies.     

Determination of nucleosides and nucleobases in different species of Cordyceps by capillary electrophoresis–mass spectrometry

In present study, a capillary electrophoresis–mass spectrometry (CE–MS) method was developed for the simultaneous analysis of 12 nucleosides and nucleobases including cytosine, adenine, guanine, cytidine, cordycepin, adenosine, hypoxanthine, guanosine, inosine, 2′-deoxyuridine, uridine and thymidine in natural and cultured Cordyceps using 5-chlorocytosine arabinoside as an internal standard (IS). The CE separation conditions and MS parameters were optimized systematically for achieving good CE resolution and MS response of the investigated compounds. The optimum CE electrolyte was 100 mM formic acid containing 10% (v/v) methanol. The optimum MS parameters were as follows: 75% (v/v) methanol containing 0.3% formic acid with a flow rate of 3 μL/min was selected as the sheath liquid; the flow rate and temperature of drying gas were 6 L/min and 350 °C, respectively. The optimized CE–MS method was successfully applied for the simultaneous determination of 12 nucleosides and nucleobases in natural and cultured Cordyceps. On the basis of quantitative results, the total content of nucleosides is much higher in cultured Cordyceps (9138 ± 4823 μg/g for cultured C. sinensis; 3722 ± 1446 μg/g for C. militaris) than in natural ones (2167 ± 412 μg/g). However, the hypoxanthine (131 ± 47 μg/g) and inosine (335 ± 90 μg/g) are much higher in natural C. sinensis. Cordycepin, which is abundant in cultured C. militaris (2276.5 ± 842.6 μg/g), is only found in natural C. sinensis with very low content and cannot be detected in the cultured ones.     

Noradrenaline-induced contraction of human saphenous vein and human internal mammary artery: involvement of different α-adrenoceptor subtypes

Although saphenous veins and internal mammary arteries are commonly used for coronary artery bypass grafting, only a very few comparative studies are available on alpha-adrenoceptor-mediated vasoconstriction in these vessels. Thus, we determined, in isolated rings from human saphenous vein and human internal mammary artery, contractile responses to noradrenaline (10(-8)-10(-4) M) in the absence and presence of the alpha-adrenoceptor antagonists yohimbine (alpha(2)-adrenoceptor antagonist, 10(-8)-10(-6) M), prazosin (alpha(1)-adrenoceptor antagonist, 10(-9)-10(-7) M), 5-methyl-urapidil (5-MU, alpha(1A)-adrenoceptor antagonist, 10(-8)-10(-6) M), BMY 7378 (alpha(1D)-adrenoceptor antagonist, 10(-7)-10(-6) M), and chloroethylclonidine (CEC, irreversible alpha(1B)-adrenoceptor antagonist, 3x10(-5) M for 30 min). All experiments were carried out in the presence of 10(-7) M propranolol and 10(-5) M cocaine. In both vessel types noradrenaline evoked concentration-dependent contractions. In saphenous veins yohimbine was a potent antagonist (pA(2)-value 8.32) while prazosin, 5-MU and BMY exhibited only marginal antagonistic effects. CEC, however, significantly decreased noradrenaline-induced contractions. In contrast, in internal mammary arteries prazosin (pA(2)-value 9.65) and 5-MU (pK(B)-values 7.2-7.5) were potent antagonists, while yohimbine and BMY exhibited only weak antagonistic effects. CEC, however, significantly decreased noradrenaline-induced contractions. We conclude that in saphenous vein the contractile response to noradrenaline is mediated predominantly by alpha(2)-adrenoceptors, while in internal mammary artery it is mediated (to a major part) by alpha(1B)- and (to a minor part) by alpha(1A)-adrenoceptors.     

Production of cyclosporin C by Gliomastix luzulae isolated from different areas of the P.R.China

本文调查了１５株粘鞭菌属Ｇｌｉｏｍａｓｔｉｘｌｕｚｕｌａｅ菌种产生环孢菌素Ｃ的能力。分离自中国１１省１５个不同地区的菌种在葡萄糖－麦芽汁－蛋白胨液体培养基中于２４～２６℃发酵１０ｄ。代谢产物经ＨＰＬＣ分析，其中１１株菌株除能产生环孢菌素Ｃ外不产生任何已知的环孢菌素，另４株菌虽然不产生已知的环孢菌素，但全部都产生一未知的环孢菌素。对产生环孢菌素Ｃ的两株具有不同液体培养性状的菌株用Ｌ－丙氨酸、Ｄ－丙氨酸、Ｌ－缬氨酸、ＤＬ－α－氨基丁酸、ＤＬ－原缬氨酸和Ｌ－苏氨酸进行氨基酸前体掺入实验，发现所有氨基酸前体均只能调节菌株合成环孢菌素Ｃ的能力，而不能使其合成相应的其它环孢菌素，其中Ｌ－丙氨酸和Ｄ－丙氨酸具有相近但比其他氨基酸更强的提高菌株合成环孢菌素Ｃ的能力，提示该类菌的合成机制与已知环孢菌素Ａ产生菌的合成机制明显不同。