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Many Drugs (many + drug)
Selected AbstractsRandomized trial of trigger point injection for renal colicINTERNATIONAL JOURNAL OF UROLOGY, Issue 9 2002MASANORI IGUCHI Abstract Background: Many drugs have been utilized for the treatment of renal colic, but to date no drugs that relieve pain quickly and completely have been developed. Thus, we conducted a prospective trial to evaluate the effects of trigger point injection on renal colic. In this study, we used a local injection of lidocaine to the trigger point of patients experiencing renal colic, and evaluated the efficacy in patients using the visual analog scale. Methods: Sixty patients with renal colic were enrolled in this study and divided into two groups by a simple randomization: (i) the butylscopolamine group (n = 30, intravenous injection of butylscopolamine bromide and sulpyrine); and (ii) the lidocaine group (n = 30, local anesthesia to the trigger point with lidocaine). Results: Renal colic had disappeared completely at the end of the trigger point injection in 15/30 patients and the average time required to produce a 50% improvement in symptoms was 9 min in all patients in the group. In the lidocaine group, only one patient needed an additional anodyne treatment after 60 min and none of the 29 patients whose pain disappeared within 60 min needed further anodyne treatment within 24 h. These results were all significantly superior to those of the conventional treatment. No side-effects and complications were observed. Conclusion: Trigger point injection, in our experience, is an easy, safe and effective method for the amelioration of renal colic. It was significantly superior to the combination of intravenous butylscopolamine and sulpyrine. [source] The Effect of Antihistamine Cetirizine on Ventricular Repolarization in Congenital Long QT SyndromeJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 7 2007ANNA-MARI HEKKALA M.D. Introduction: Many drugs are known to block cardiac potassium channels, thus prolonging QT interval and predisposing to malignant arrhythmias. Patients with congenital long QT syndrome are particularly vulnerable, but usually electrophysiological effects of drugs have not been assessed in these patients at risk. Methods: Fifteen asymptomatic patients with type 1 (LQT1), 15 patients with type 2 (LQT2) long QT syndrome, and 15 healthy volunteers took a placebo and cetirizine 10 mg. In addition, healthy volunteers took cetirizine 50 mg. The study was single-blinded and randomized. Exercise tests were performed during stable plasma concentrations. The electrocardiogram was recorded with a body surface potential mapping system (BSPM). Data were analyzed with an automated analyze program. QT intervals to the T wave apex and T wave end and their difference (Tp-e) were determined at rest and at specified heart rates during and after exercise. Results: Cetirizine did not lengthen the QT intervals at rest or during exercise and recovery in any group. It shortened Tp-e at rest in LQT1 and LQT2 patients and during exercise test in LQT1 patients, thus slightly decreasing electrocardiographic transmural dispersion of repolarization. Conclusions: Cetirizine does not adversely modify ventricular repolarization in types 1 and 2 long QT syndrome, suggesting that it might be used safely in these long QT syndrome patients. [source] The effect of disorder on the chemical reactivity of an organic solid, tetraglycine methyl ester: Change of the reaction mechanismJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 2 2002Evgenyi Shalaev Abstract Many drugs undergo chemical changes in the solid state, and understanding chemical reactivity of organic crystals is a critical factor in the drug development process. In this report, the impact of milling on the thermal chemical reactivity of an organic solid, tetraglycine methyl ester, was studied using DSC, isothermal calorimetry, chemical analysis (HPLC and insoluble residue determination), and powder X-ray diffraction. Significant changes in both X-ray diffraction patterns and DSC curves were detected after very brief milling (5 s). The changes were interpreted as the formation of a disordered phase. The disordered phase was tentatively identified as a crystal mesophase that combines properties of both crystalline (i.e., long-range order) and amorphous (i.e., glass transition) states. In the disordered material, the reaction mechanism changed from the methyl transfer reaction, which was observed in the intact crystal, to a polycondensation reaction when the reaction was performed at 165°C. Such changes in the reaction mechanism occurred in materials milled for >,30 s. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:584,593, 2002 [source] Rosiglitazone Inhibits Cell Proliferation by Inducing G1 Cell Cycle Arrest and Apoptosis in ADPKD Cyst-Lining Epithelia CellsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 6 2010Yawei Liu Many drugs inhibiting cell proliferation have been proved to be effective in slowing the disease progression in ADPKD. Recent evidence has suggested that peroxisome proliferator-activated receptor , (PPAR,) ligands have anti-neoplasm effects through inhibiting cell growth and inducing cell apoptosis in various cancer cells. In the present study, we examined the expression of PPAR, in human ADPKD kidney tissues and cyst-lining epithelial cell line, and found that the expression of PPAR, was greater in ADPKD kidney tissues and cyst-lining epithelial cell line than in normal kidney tissues and human kidney cortex (HKC) cell line. Rosiglitazone inhibited significantly proliferation of cyst-lining epithelial cells in a concentration- and time-dependent manner. These effects were diminished by GW9662, a specific PPAR, antagonist. Cell cycle analysis showed a G0/G1 arrest in human ADPKD cyst-lining epithelial cells with rosiglitazone treatment. Analysis of cell cycle regulatory proteins revealed that rosiglitazone decreased the protein levels of proliferating cell nuclear antigen, pRb, cyclin D1, cyclin D2 and Cdk4 but increased the levels of p21 and p27 in a dose-dependent manner. Rosiglitazone also induced apoptosis in cyst-lining epithelial cells, which was correlated with increased bax expression and decreased bcl-2 expression. These results suggest PPAR, agonist might serve as a promising drug for the treatment of ADPKD. [source] Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiologyBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 1 2010Adam L. VanWert Abstract Our understanding of the mechanisms behind inter- and intra-patient variability in drug response is inadequate. Advances in the cytochrome P450 drug metabolizing enzyme field have been remarkable, but those in the drug transporter field have trailed behind. Currently, however, interest in carrier-mediated disposition of pharmacotherapeutics is on a substantial uprise. This is exemplified by the 2006 FDA guidance statement directed to the pharmaceutical industry. The guidance recommended that industry ascertain whether novel drug entities interact with transporters. This suggestion likely stems from the observation that several novel cloned transporters contribute significantly to the disposition of various approved drugs. Many drugs bear anionic functional groups, and thus interact with organic anion transporters (OATs). Collectively, these transporters are nearly ubiquitously expressed in barrier epithelia. Moreover, several reports indicate that OATs are subject to diverse forms of regulation, much like drug metabolizing enzymes and receptors. Thus, critical to furthering our understanding of patient- and condition-specific responses to pharmacotherapy is the complete characterization of OAT interactions with drugs and regulatory factors. This review provides the reader with a comprehensive account of the function and substrate profile of cloned OATs. In addition, a major focus of this review is on the regulation of OATs including the impact of transcriptional and epigenetic factors, phosphorylation, hormones and gender. Copyright © 2009 John Wiley & Sons, Ltd. [source] Generalized eruptive lentiginosis induced by chemotherapyCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 4 2010D. De Summary Lentigines are characterized by brown macules developing due to increased proliferation of melanocytes in the dermoepidermal junction. Many drugs, including immunosuppressants and immunomodulators, have been shown to cause generalized lentiginosis. We describe a case of lentiginosis induced by cancer chemotherapy, an extremely rare occurrence. [source] Introducing triage logic as a new strategy for the detection of signals in the WHO Drug Monitoring Database,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 6 2004M. Stĺhl Abstract Purpose An important role for the WHO Programme for International Drug Monitoring is to identify signals of international drug safety problems as early as possible. The signal detection strategy, operated at the Uppsala Monitoring Centre (UMC), gave too many drug,adverse drug reaction (ADR) combinations for individual review. Therefore additional selection strategies were needed to improve the likely signal-to-noise ratio and for the UMC to complement the efforts of national centres in an efficient way. Methods The combinations database of the first quarter of 2001 was analysed using algorithms representing different strategies for finding relevant signals using triage logic. Results The strategies that together gave a manageable number of combinations, i.e. around 600, for further consideration in a single quarter were the algorithms for ,Rapid reporting increase', ,Serious reaction and new drug' and ,Special interests'. These filters began to be used routinely on the combinations database in late 2001. Conclusions While stressing that human review is essential, triage strategies are useful when attempting analysis of large amounts of data. By definition, the use of triage strategies may exclude some potential signals from consideration, although the intention is to improve the chances of detection by focussing on areas of greatest importance. Copyright © 2004 John Wiley & Sons, Ltd. [source] Are we becoming more alike?DRUG AND ALCOHOL REVIEW, Issue 5 20082004 national household surveys, Comparison of substance use in Australia, the United States as seen in the 199 Abstract Introduction. This paper reports the results of the 1995, 1998, 2001 and 2004 Australian and US household surveys, with emphasis on changes since 2001. Design and Methods. The US survey data were recalculated to match age groups in the Australian data. Statistically significant changes are reported. Differences in prevalence of use by gender within age group were tested for significance. Results. The past-year use of ,any illicit drug', cannabis, cocaine, tranquillisers and injecting drugs decreased between 2001 and 2004 in Australia, but remained stable for all these drugs except ecstasy between 2002 and 2004 in the United States. The use of hallucinogens decreased in both countries. Alcohol and use of many illicit drugs by teenage girls in both countries increased to rates similar to or higher than boys, and teens in both countries reported binge and heavy drinking in the past month. Australians in their 20s had the highest rates of use, but in the United States, past-year use of many drugs was highest among teenagers. Discussion. More treatment services are needed, particularly for people dependent upon non-opiate drugs. The changes in acceptability of use of different drugs and their perceived availability are related to changes in prevalence rates. Even with the similarities in levels of use, there are differences in patterns of use and preferences for certain drugs in each country, and geographic proximity to drug sources is a factor. [source] Pharmacogenomics in Cardiovascular MedicineDRUG DEVELOPMENT RESEARCH, Issue 3 2004John F. Carlquist Abstract The completion of the Human Genome Project (HGP) holds promise for further insight into how genetic differences contribute to an individual's response to a medicine(s). Even before the completion of the HGP, cardiovascular medicine was thrust into the arena of pharmacogenomics by the observation that many drugs, cardiovascular and noncardiovascular, promote cardiac arrhythmias. It is now recognized that these adverse responses as well as beneficial responses to cardiovascular medicines can be influenced by alterations in the genes for metabolizing enzymes, drug transporters, and drug targets. To the present, much basic information regarding gene,drug interactions has accumulated, but translation to clinical care has been slow. It is anticipated that the pace of clinical cardiovascular pharmacogenomics will increase as the result of better-designed studies and technological advances. The final adoption of this area of investigation into clinical practice will also be influenced by financial, psychosocial, and legal factors. Drug Dev. Res. 62:180,190, 2004. © 2004 Wiley-Liss, Inc. [source] Organic anion-transporting polypeptide (OATP) transporter family and drug dispositionEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2003R. B. Kim Abstract Drug transporters are increasingly recognized as a key determinant of drug disposition. Recent studies have revealed that targeted expression of drug uptake and efflux transporters to specific cell membrane domains allows for the efficient directional movement of many drugs in clinical use. While the role of certain efflux transporters such as MDR1 (P-glycoprotein) in drug disposition has been extensively studied, emerging evidence suggests that uptake transporters may also be important to the intestinal absorption and renal or hepatic elimination of drugs. Members of the organic anion-transporting polypeptide (OATP) family of drug uptake transporters have been found capable of transporting a large array of structurally divergent drugs. Moreover, expression of OATP isoforms in the gastrointestinal tract, liver and kidney, as well as at the level of the blood,brain barrier, has important implications for our understanding of the factors governing drug absorption, elimination and tissue penetration. [source] Effects of nicotine in the dopaminergic system of mice lacking the alpha4 subunit of neuronal nicotinic acetylcholine receptorsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2003L. M. Marubio Abstract The mesostriatal dopaminergic system influences locomotor activity and the reinforcing properties of many drugs of abuse including nicotine. Here we investigate the role of the ,4 nicotinic acetylcholine receptor (nAChR) subunit in mediating the effects of nicotine in the mesolimbic dopamine system in mice lacking the ,4 subunit. We show that there are two distinct populations of receptors in the substantia nigra and striatum by using autoradiographic labelling with 125I ,-conotoxin MII. These receptors are comprised of the ,4, ,2 and ,6 nAChR subunits and non-,4, ,2, and ,6 nAChR subunits. Non-,4 subunit-containing nAChRs are located on dopaminergic neurons, are functional and respond to nicotine as demonstrated by patch clamp recordings. In vivo microdialysis performed in awake, freely moving mice reveal that mutant mice have basal striatal dopamine levels which are twice as high as those observed in wild-type mice. Despite the fact that both wild-type and ,4 null mutant mice show a similar increase in dopamine release in response to intrastriatal KCl perfusion, a nicotine-elicited increase in dopamine levels is not observed in mutant mice. Locomotor activity experiments show that there is no difference between wild-type and mutant mice in basal activity in both habituated and non-habituated environments. Interestingly, mutant mice sustain an increase in cocaine-elicited locomotor activity longer than wild-type mice. In addition, mutant mice recover from depressant locomotor activity in response to nicotine at a faster rate. Our results indicate that ,4-containing nAChRs exert a tonic control on striatal basal dopamine release, which is mediated by a heterogeneous population of nAChRs. [source] Fish venom: pharmacological features and biological significanceFISH AND FISHERIES, Issue 2 2009Gisha Sivan Abstract Nearly 1200 species of marine fish are venomous and they account for two-third of the population of venomous vertebrates. Fish venoms are focused as a potential source of pharmacological agents and physiological tools that have evolved to target vital processes in the human body that appear to have more electivity than many drugs. Fish venoms possess cardiovascular, neuromuscular, oedematic and cytolytic activity. Lethal toxins have been isolated and purified, with some having LD50 values comparable to that of snake venoms. Cardiovascular activity seems to be the dominant effect of fish venoms in experimental models. Piscine venom acts both pre- and post-junctionally to produce depolarization of cell membranes. Studies on cytolytic activity of fish venom found that it produces lysis by forming hydrophilic pores in cell membranes which then result in cell lysis. Almost all fish venoms with neuromuscular activity also possesses cytolytic activity, and it is very likely that the two activities are related. Fish venom is known to induce intense and sustained edematogenic response. As piscine venoms have evolved for the same purpose, they show a number of similarities pharmacologically and it seems likely that most of the biological activities of any given toxin can be traced back to its cytolytic activity. A variety of toxins have been isolated from piscine venom. Although there is a complex balance between the components present in the venom of different fish, all of them seem to share similar activity , functionally and pharmacologically as well as structurally. [source] Methylenedioxymethamphetamine (MDMA, ,Ecstasy'): a stressor on the immune systemIMMUNOLOGY, Issue 4 2004Thomas J. Connor Summary Drug abuse is a global problem of considerable concern to health. One such health concern stems from the fact that many drugs of abuse have immunosuppressive actions and consequently have the potential to increase susceptibility to infectious disease. This article is focused on the impact of the amphetamine derivative, methylenedioxymethamphetamine (MDMA; ,Ecstasy') on immunity. Research conducted over the last 5 years, in both laboratory animals and humans, has demonstrated that MDMA has immunosuppressive actions. Specifically, MDMA suppresses neutrophil phagocytosis, suppresses production of the pro-inflammatory cytokines tumour necrosis factor-, (TNF-,) and interleukin (IL)-1,, and increases production of the endogenous immunosuppressive cytokine (IL-10), thereby promoting an immunosuppressive cytokine phenotype. MDMA also suppresses circulating lymphocyte numbers, with CD4+ T cells being particularly affected, and alters T-cell function as indicated by reduced mitogen-stimulated T-cell proliferation, and a skewing of T-cell cytokine production in a T helper 2 (Th2) direction. For the most part, the aforementioned effects of MDMA are not the result of a direct action of the drug on immune cells, but rather caused by the release of endogenous immunomodulatory substances. Consequently, the physiological mechanisms that are thought to underlie the immunosuppressive effects of MDMA will be discussed. As many of the physiological changes elicited by MDMA closely resemble those induced by acute stress, it is suggested that exposure to MDMA could be regarded as a ,chemical stressor' on the immune system. Finally, the potential of MDMA-induced immunosuppression to translate into significant health risks for abusers of the drug will be discussed. [source] The extraordinary ligand binding properties of human serum albuminIUBMB LIFE, Issue 12 2005Mauro Fasano Abstract Human serum albumin (HSA), the most prominent protein in plasma, binds different classes of ligands at multiple sites. HSA provides a depot for many compounds, affects pharmacokinetics of many drugs, holds some ligands in a strained orientation providing their metabolic modification, renders potential toxins harmless transporting them to disposal sites, accounts for most of the antioxidant capacity of human serum, and acts as a NO-carrier. The globular domain structural organization of monomeric HSA is at the root of its allosteric properties which are reminiscent of those of multimeric proteins. Here, structural, functional, biotechnological, and biomedical aspects of ligand binding to HSA are summarized. [source] Malaysian Indians are genetically similar to Caucasians: CYP2C9 polymorphismJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 2 2006Z. Zainuddin MSc Summary Background:,CYP2C9 is one of the major drug metabolizing enzymes for many drugs including warfarin, NSAIDs and losartan. It is polymorphic in many populations. Data on the distribution of CYP2C9 and the implication of CYP2C9 polymorphism in the Malaysian population is lacking. Our objectives were therefore to investigate the prevalence of CYP2C9 variants among unrelated healthy volunteers of Malays, Chinese and Indians in Malaysia. Method:, Deoxyribonucleic acid was extracted using standard lysis methods. Allele specific polymerase chain reaction was performed for determination of CYP2C9*1, *2, *3, *4 and *5 variants according to Z. Zainuddin, L.K. Teh, A.W.M. Suhaimi, M.Z. Salleh, R. Ismail (2003, Clinica Chimica Acta, 336, 97). Result:, The Chinese had the highest frequency of CYP2C9*1 (321/330, 97·27%), followed by the Malays and the Indians (402 of 420, 95·71% and 291 of 330, 88·18%, respectively). CYP2C9*2 was not found in the Chinese. CYP2C9*3 were detected in all the three races with the Indians having the highest frequency of CYP2C9*3 (9·7%). The Indians had a frequency of CYP2C9*2 and *3 similar to Tamilians and Caucasians. Two of the Indians had *2/*3 and one had *3/*3 genotypes and are likely to be slow metabolizers. No subject with CYP2C9*4 and *5 were detected in our populations. Conclusion:,CYP2C9*2 and *3 were identified in our population. Indians are similar to Caucasians in terms of CYP2C9 genotypes and thus may respond to CYP2C9 substrates differently when compared with the Malays and Chinese in Malaysia. [source] Hyperosmotic stress induces Axl activation and cleavage in cerebral endothelial cellsJOURNAL OF NEUROCHEMISTRY, Issue 1 2008Imola Wilhelm Abstract Because of the relative impermeability of the blood-brain barrier (BBB), many drugs are unable to reach the CNS in therapeutically relevant concentration. One method to deliver drugs to the CNS is the osmotic opening of the BBB using mannitol. Hyperosmotic mannitol induces a strong phosphorylation on tyrosine residues in a broad spectrum of proteins in cerebral endothelial cells, the principal components of the BBB. Previously, we have shown that among targets of tyrosine phosphorylation are ,-catenin, extracellular signal-regulated kinase 1/2 and the non-receptor tyrosine kinase Src. The aim of this study was to identify new signalling pathways activated by hypertonicity in cerebral endothelial cells. Using an antibody array and immunoprecipitation we identified the receptor tyrosine kinase Axl to become tyrosine phosphorylated in response to hyperosmotic mannitol. Besides activation, Axl was also cleaved in response to osmotic stress. Degradation of Axl proved to be metalloproteinase- and proteasome-dependent and resulted in 50,55 kDa C-terminal products which remained phosphorylated even after degradation. Specific knockdown of Axl increased the rate of apoptosis in hyperosmotic mannitol-treated cells; therefore, we assume that activation of Axl may be a protective mechanism against hypertonicity-induced apoptosis. Our results identify Axl as an important element of osmotic stress-induced signalling. [source] The norepinephrine transporter and its regulationJOURNAL OF NEUROCHEMISTRY, Issue 2 2006Prashant Mandela Abstract For many years, the norepinephrine transporter (NET) was considered a ,static' protein that contributed to the termination of the action of norepinephrine in the synapse of noradrenergic neurons. The concept that the NET is dynamically regulated, adjusting noradrenergic transmission by changing its function and/or expression, was considered initially in the mid 1980s. Since that time, a plethora of studies demonstrate that the NET is regulated by several intracellular and extracellular signaling molecules, and that phosphorylation of the NET is a major pathway regulating its cell surface expression and thereby its function. The NET is a target of action of a number of drugs that are used long-term therapeutically or abused chronically. This has driven numerous investigations of how the NET and its function are regulated by long-term exposure to drugs. While repeated exposure to many drugs has been shown to affect NET function and expression, the intracellular mechanisms for these effects remains elusive. [source] Distribution of saquinavir, methadone, and buprenorphine in maternal brain, placenta, and fetus during two different gestational stages of pregnancy in miceJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 8 2009Lisa D. Coles Abstract Efflux transporters such as P-glycoprotein (P-gp) play a critical role in the maternal-to-fetal and blood-to-brain transfer of many drugs. Using a mouse model, the effects of gestational age on P-gp and MRP expression in the placenta and brain were evaluated. P-gp protein levels in the placenta and brain were greater at mid-gestation (gd 13) than late-gestation (gd 18). Likewise, brain MRP1 levels were greater at mid-gestation, whereas, placental levels were greater at late-gestation. To evaluate these effects on drug disposition, concentrations of [3H]saquinavir, [3H]methadone, [3H]buprenorphine, and the paracellular marker, [14C]mannitol were measured in plasma, brain, placenta, and fetal samples after i.v. administrations to nonpregnant and pregnant mice. Following i.v. administration, [3H]saquinavir placenta-to-plasma and fetal-to-plasma ratios were significantly greater in late-gestation mice versus mid-gestation. Furthermore, late-gestation mice experienced significant increases in the [3H]saquinavir and [3H]methadone brain-to-plasma ratios 60 min after dosing relative to mid-gestation (p,<,0.05). No significant differences were observed in these tissue-to-plasma ratios for buprenorphine or mannitol. Repeated dosing (three doses, once daily) decreased the differential uptake of [3H]saquinavir in brain but potentiated it in the fetus. These results suggest that differential expression of P-gp and possibly MRP1 contributes to the gestational-induced changes in brain and fetal uptake of saquinavir. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2832,2846, 2009 [source] Stereospecific reduction of the original anticancer drug oracin in rat extrahepatic tissuesJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2003Barbora Szotáková ABSTRACT The liver is the major site of drug metabolism in the body. However, many drugs undergo metabolism in extrahepatic sites and in the gut wall and lumen. In this study, the distribution and activity of reductases in rat that reduced potential cytostatic oracin to its principal metabolite 11-dihydrooracin (DHO) were investigated. The extension and stereospecificity of oracin reduction to DHO were tested in microsomal and cytosolic fractions from the liver, kidney, heart, lung and wall of small intestine, caecum and large intestine. Intestinal bacterial reduction of oracin was studied as well. The amount of DHO enantiomers was measured by HPLC with Chiralcel OD-R as chiral column. Reductive biotransformation of oracin was mostly stereospecific for (+)-DHO, but the enantiomeric ratio differed significantly among individual tissues and subcellular fractions (from 56% (+)-DHO in heart microsomes to 92% (+)-DHO in liver cytosol). Stereospecificity for (-)-DHO (60%) was observed in bacterial oracin reduction in the lumen of small intestine, caecum and large intestine. Shift of the (+)-DHO/(-)-DHO enantiomeric ratio from 90:10 (in liver subcellular fractions) to 60:40 (in-vivo) clearly demonstrated the importance of the contribution of extrahepatic metabolism to the total biotransformation of oracin to DHO. [source] Checkpoints and pitfalls in the experimental neuropathology of circulatory disturbanceNEUROPATHOLOGY, Issue 1 2003Toshihiko Kuroiwa In neural tissue injury many pathological processes are common to different neurological disorders, including cerebral ischemia. Because ischemia has a fundamentally simple impact on neural tissue, good laboratory modeling can help improve the general understanding of the neuropathological processes involved. Summarized here are some basic principles that should be followed to ensure that cerebral ischemia studies are reproducible and informative: (i) selection of an appropriate model of cerebral ischemia in an appropriate species (although rodents are widely used for genomic studies, the use of larger animals, with brain structures macroscopically similar to those of humans, is appropriate for many studies, e.g. of white matter lesions or the pathophysiology of cerebral edema); (ii) correct maintenance of physiological parameters, including body temperature, systemic blood pressure, and blood gas tensions, under appropriate general anesthesia; (iii) selection of an appropriate method of cerebral blood flow (CBF) monitoring (decisions include whether or not the experiment requires real-time monitoring, in vivo measurement, and CBF mapping); (iv) appropriate timing of drug application in therapeutic studies (many drugs that are effective when given immediately after a short period of ischemi are ineffective in clinical trials, probably because of longer periods of ischemia and delayed drug delivery in clinical settings); and (v) multiparametric evaluation of therapeutic effect (with the recent increase in diagnosis of cases of mild stroke, measurement of mortality and infarct size have proven to be insufficient for the evaluation of therapeutic effect). Use of mild ischemia models and batteries of neurological tests for individual neurological functions, such as motor, somatosensory, and visual function, are becoming important in experimental ischemia research. In histological evaluation, assessment of the extent of both selective neuronal loss and the infarct will become mandatory. Regional analysis of each brain structure and coordination of the results with the apparent neurological dysfunction is a promising approach. [source] The science of aerosol delivery in cystic fibrosisPEDIATRIC PULMONOLOGY, Issue S9 2008David E. Geller MD Abstract Aerosolized drugs are universally used for treatment of cystic fibrosis airway disease. Inhalation can increase topical efficacy and reduce systemic exposure and toxicity of many drugs. A wide variety of inhaled drugs already exist with many more in the therapeutic pipeline. Understanding the principles of aerosol delivery and how aerosol devices function is important in designing the best therapeutic regimens for CF patients. The variables that determine where an aerosol deposits are numerous and complex. Important aerosol-related variables include particle-size distribution, hygroscopic properties, viscosity and surface tension of the drug. Patient-related variables include inspired flow rate, tidal volume, respiratory rate, breath-holding, upper airway anatomy, lower airways obstruction, and the cognitive and physical ability to use the device. These factors vary widely between patients of different age groups and disease severities, and cause the high variability in drug delivery seen with aerosol drugs. Classic aerosol delivery devices like metered dose inhalers and dry-powder inhalers are small, portable, and have short treatment times. However, they are limited by small drug payloads and user technique problems. Jet nebulizers are commonly used for CF drugs, are easy to operate, require no special breathing pattern, and can deliver very large quantities of drug. However, they require a power or air source, cleaning and sanitizing, and are relatively time consuming. Recently, novel aerosol delivery systems and formulations have been developed to improve delivery efficiency and reduce variability and delivery time. These new systems can ease the treatment burden and improve adherence and outcomes in cystic fibrosis. Pediatr Pulmonol. 2008; 43:S5,S17. © 2008 Wiley-Liss, Inc. [source] High-level expression and purification of Cys-loop ligand-gated ion channels in a tetracycline-inducible stable mammalian cell line: GABAA and serotonin receptorsPROTEIN SCIENCE, Issue 9 2010Zuzana Dostalova Abstract The human neuronal Cys-loop ligand-gated ion channel superfamily of ion channels are important determinants of human behavior and the target of many drugs. It is essential for their structural characterization to achieve high-level expression in a functional state. The aim of this work was to establish stable mammalian cell lines that enable high-level heterologous production of pure receptors in a state that supports agonist-induced allosteric conformational changes. In a tetracycline-inducible stable human embryonic kidney cells (HEK293S) cell line, GABAA receptors containing ,1 and ,3 subunits could be expressed with specific activities of 29,34 pmol/mg corresponding to 140,170 pmol/plate, the highest expression level reported so far. Comparable figures for serotonin (5-HT3A) receptors were 49,63 pmol/mg and 245,315 pmol/plate. The expression of 10 nmol of either receptor in suspension in a bioreactor required 0.3,3.0 L. Both receptor constructs had a FLAG epitope inserted at the N-terminus and could be purified in one step after solubilization using ANTI-FLAG affinity chromatography with yields of 30,40%. Purified receptors were functional. Binding of the agonist [3H]muscimol to the purified GABAAR was enhanced allosterically by the general anesthetic etomidate, and purified 5-hydroxytryptamine-3A receptor supported serotonin-stimulated cation flux when reconstituted into lipid vesicles. [source] The ,apparent clearance' of free phenytoin in elderly vs. younger adultsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2010Daniel F. B. Wright WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The clearance of many drugs is reduced in the elderly, but the data regarding phenytoin are conflicting. Most studies have estimated phenytoin metabolic clearance using total drug concentrations (bound plus unbound), which may be confounded by protein binding effects. Free phenytoin concentrations are independent of protein binding and should more accurately reflect true metabolic clearance changes in elderly patients. WHAT THIS STUDY ADDS , The two studies reported in this paper suggest a trend towards reduced free phenytoin ,apparent clearance' in the elderly, although statistically significant results were not found. Other published studies have largely found similar trends, suggesting an age effect. AIMS To test the hypothesis that the ,apparent clearance' of free phenytoin is reduced in elderly patients. METHODS Two separate studies were conducted comparing free phenytoin ,apparent clearance' in elderly vs. younger adults. The first study was a retrospective analysis of free phenytoin concentrations measured at Christchurch Hospital from 1997 to 2006. In the second study free phenytoin concentrations were measured prospectively in ambulatory subjects who were taking phenytoin regularly. RESULTS In the retrospective study (n= 29), free phenytoin ,apparent clearance' was 0.27 ± 0.04 l kg,1 day,1 (95% CI 0.19, 0.34) in the elderly cohort vs. 0.37 ± 0.06 l kg,1 day,1 (95% CI 0.22, 0.52) in younger adults, but the difference was not statistically significant. In the prospective study, free phenytoin ,apparent clearance' showed a non-significant trend to being reduced in the elderly patients (0.12 ± 0.02 l kg,1 day,1, 95% CI 0.07, 0.17) compared with the younger cohort (0.18 ± 0.07 l kg,1 day,1, 95% CI 0.09, 0.26) in those not taking interacting drugs (n= 21). CONCLUSIONS This research does not prove the hypothesis that the ,apparent clearance' of free phenytoin is reduced in the elderly. However, the trends found in these two studies are supported by trends in the same direction in other published studies, suggesting an age effect. [source] The modern treatment of heart failure: How many drugs are enough?CLINICAL CARDIOLOGY, Issue 3 2000C. Richard Conti M.D., M.A.C.C Editor-in-Chief No abstract is available for this article. [source] | |||||||||||||||||||||||||||||||