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Drugs Used (drug + used)
Selected AbstractsDrugs Used to Treat Osteoporosis: The Critical Need for a Uniform Nomenclature Based on Their Action on Bone Remodeling,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2005B Lawrence Riggs MD Abstract There continues to be uncertainty about the classification of available drugs for treating osteoporosis. We find that grouping them into anti-catabolic and anabolic classes based on the mechanisms of their action on bone remodeling and fracture reduction removes ambiguities and provides a relatively straightforward classification. The recent introduction of teriparatide into clinical practice initiated the era of anabolic therapy for osteoporosis, but it is still unclear how to define an anabolic drug. All drugs that increase bone mass do so by affecting bone remodeling. When their mechanisms of action on bone remodeling and on fracture reduction are considered, we find that anti-osteoporotic drugs fall naturally into either anti-catabolic or anabolic classes. Anti-catabolic drugs increase bone strength and reduce fractures mainly by decreasing the number of bone multicellular units (BMUs). This reduces perforative resorption and preserves skeletal microarchitecture (by preventing further structural damage to trabecular bone and increased porosity in cortical bone induced by high bone remodeling). Reduction in bone remodeling by anti-catabolic drugs may increase bone mass moderately during the interval in which previously initiated BMUs are completing mineralization. Some anti-catabolic drugs may also enhance the formation phase of the remodeling cycle, but their major action is to reduce overall bone turnover (i.e., the number of BMUs in bone). In contrast, anabolic drugs increase bone strength and reduce fractures by substantially increasing bone mass as a result of an overall increase in the number of BMUs combined with a positive BMU balance (the magnitude of the formation phase is greater than that of the resorption phase). Some anabolic drugs also induce renewed modeling, increase periosteal apposition and repair of trabecular microstructure. We hope that this classification will serve as a starting point for continued discussion on the important issue of nomenclature. [source] Environmental temperature stress on drugs in prehospital emergency medical serviceACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 4 2003M. Helm Background: Drugs used in prehospital emergency medical service (EMS) in principle are subject to the same storage restrictions as hospital-based medications. The prehospital emergency environment however, often exceeds these storage recommendations. Main stress factors are sunlight, vibration and extreme temperature, which may lead to alteration in chemical and physical stability of stored pharmaceuticals, as well as microbiological contamination and concentration enhancement of pharmacological inserts. Methods: The purpose of this study was to determine the environmental temperature stress upon drugs used in the prehospital EMS under real mission conditions within different types of rescue vehicles (rescue helicopter [HEMS], ambulance [AMB] and emergency physician transport vehicle [EPTV]) during a ,summer' and ,winter' monitoring period (2 months duration each/location: southern Germany). Results: Recorded temperatures varied from ,13.2°C to +50.6°C. The recommended maximum storage temperature (+25°C) was exceeded in all rescue vehicles (33,45% of total exposure time), whereas the recommended minimum storage temperature (0°C) only fell short in the EPTV (19% of total exposure time). The daily maximum temperature variations ranged from 19.0°C (winter) to 32.9°C (summer). Conclusions: These results show that even in a moderate climatic zone, drugs used in prehospital EMS are significantly influenced by temperature stress; furthermore, these results recommend the usage of temperature-controlled drug boxes. [source] Postural induced-tremor in psychiatryPSYCHIATRY AND CLINICAL NEUROSCIENCES, Issue 6 2008Beatriz Arbaizar md Postural tremor is the most common movement disorder in psychiatry, and often a difficult problem for clinicians. It can be classified as physiological, essential, drug-induced, and postural tremor in Parkinson's disease. Drugs used in psychiatry that can produce postural tremor, include lithium, valproic acid, lamotrigine, antidepressants, and neuroleptics. Clinical characteristics of postural tremor induced by each of these drugs are described. Pharmacological strategies for therapy in disabling drug-induced tremor include beta-blockers, primidone, gabapentin, topiramate, and benzodiazepines; their utility, doses and side-effects are also discussed. [source] Influence of promethazine on cardiac repolarisation: a double-blind, midazolam-controlled studyANAESTHESIA, Issue 6 2009R. Owczuk Summary Drugs used in anaesthesia may provoke torsadogenic changes in cardiac repolarisation. The aim of this study was to assess the effect of promethazine on the parameters of ventricular repolarisation: QTc interval and transmural dispersion of repolarisation. Forty patients were randomly allocated to receive promethazine (25 mg) or midazolam (2.5 mg). Changes in the ECG and arterial blood pressure were recorded. Correction of QT interval was calculated using Bazett's formula and Fridericia's correction; transmural dispersion of repolarisation was determined as Tpeak,Tend time. Significant prolongation of QT interval, corrected with both formulae, was detected in patients receiving promethazine, while no change in the QTc value was observed in the midazolam group. There were no significant differences in Tpeak,Tend time either between or within the groups. In conclusion, promethazine induces significant QTc prolongation but the lack of influence on transmural dispersion of repolarisation makes the risk of its torsadogenic action very low. [source] Influence of 1 and 25 Hz, 1.5 mT magnetic fields on antitumor drug potency in a human adenocarcinoma cell line,BIOELECTROMAGNETICS, Issue 8 2002M.J. Ruiz-Gómez Abstract The resistance of tumor cells to antineoplastic agents is a major obstacle during cancer chemotherapy. Many authors have observed that some exposure protocols to pulsed electromagnetic fields (PEMF) can alter the efficacy of anticancer drugs; nevertheless, the observations are not clear. We have evaluated whether a group of PEMF pulses (1.5 mT peak, repeated at 1 and 25 Hz) produces alterations of drug potency on a multidrug resistant human colon adenocarcinoma (HCA) cell line, HCA-2/1cch. The experiments were performed including (a) exposures to drug and PEMF exposure for 1 h at the same time, (b) drug exposure for 1 h, and then exposure to PEMF for the next 2 days (2 h/day). Drugs used were vincristine (VCR), mitomycin C (MMC), and cisplatin. Cell viability was measured by the neutral red stain cytotoxicity test. The results obtained were: (a) The 1 Hz PEMF increased VCR cytotoxicity (P,<,0.01), exhibiting 6.1% of survival at 47.5 ,g/ml, the highest dose for which sham exposed groups showed a 19.8% of survival. For MMC at 47.5 ,g/ml, the % of survival changed significantly from 19.2% in sham exposed groups to 5.3% using 25 Hz (P,<,0.001). Cisplatin showed a significant reduction in the % of survival (44.2,39.1%, P,<,0.05) at 25 Hz and 47.5 ,g/ml, and (b) Minor significant alterations were observed after nonsimultaneous exposure of cells to PEMF and drug. The data indicate that PEMF can induce modulation of cytostatic agents in HCA-2/1cch, with an increased effect when PEMF was applied at the same time as the drug. The type of drug, dose, frequency, and duration of PEMF exposure could influence this modulation. Bioelectromagnetics 23:578,585, 2002. © 2002 Wiley-Liss, Inc. [source] Comedication related to comorbidities: a study in 1203 hospitalized patients with severe psoriasisBRITISH JOURNAL OF DERMATOLOGY, Issue 5 2008S. Gerdes Summary Background, Psoriasis is a common dermatological disorder characterized by an immune-mediated chronic inflammation which is associated with a variety of other diseases commonly referred to as comorbidities. The treatments for these diseases may interfere with the course and the treatment of psoriasis. Little is known on the general drug intake of patients with psoriasis. Objectives, To gain more insight into the general drug intake of patients with severe psoriasis. A correlation of comedication to respective diseases could lead to a better knowledge of comorbidities. Methods, Data on demographics, comedication and comorbidities from 1203 patients with severe psoriasis in Germany were analysed. As a control group data from 7099 subjects from the German National Health Survey 1998 were used. Results, Patients with severe psoriasis are receiving significantly more different systemic drugs on average than the general population, with the most prominent difference in multidrug treatment. Drugs used in the treatment of arterial hypertension, diabetes mellitus and other diseases of the metabolic syndrome as well as oral anticoagulants and anticonvulsant agents showed the greatest differences. Special characteristics of antihypertensive drug treatments could be determined. Conclusions, The data obtained in this study provide the basis for an improved management of patients with psoriasis. Knowledge of existing comedication and comorbidities may lead to the ability to treat psoriasis and comorbidities at the same time more safely and to use possible synergistic effects. [source] Drugs used in paediatric allergy: should we conduct studies in children or extrapolate from adults?CLINICAL & EXPERIMENTAL ALLERGY REVIEWS, Issue 1 2006A. Custovic First page of article [source] Differentiating members of the thiazolidinedione class: a focus on efficacy,DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue S2 2002Barry J. Goldstein Abstract The thiazolidinediones (TZDs) or ,glitazones' are a new class of drug used for the treatment of type 2 diabetes. Although their precise mechanism of action is not known, TZDs target insulin resistance directly and thus tackle an underlying cause of the disease. Two TZDs are indicated for use in type 2 diabetes in the USA, pioglitazone and rosiglitazone. A third, troglitazone, has been associated with significant hepatotoxicity and has been withdrawn from use. In clinical trials, all three TZDs effectively lower blood glucose levels as monotherapy and in combination therapy with sulfonylureas, metformin and insulin. To date, head-to-head comparative studies with these agents have not been performed. It is difficult, therefore, to make direct comparisons of their efficacy since other variables, including baseline glucose levels and study design, can have a significant impact on treatment outcome. Despite this and in light of unique safety issues characterized with certain TZDs, it is useful to look closely at the efficacy data for these agents. It is not sufficient to assume that ,all glitazones are the same' because the studies have not yet been done to support this statement. This article will review what is known about the relative efficacy of the TZDs. Copyright © 2002 John Wiley & Sons, Ltd. [source] Simultaneous determination of metronidazole and spiramycin in bulk powder and in tablets using different spectrophotometric techniquesDRUG TESTING AND ANALYSIS, Issue 1 2010Fatma I. Khattab Abstract Metronidazole (MZ) is an anti-infective drug used in the treatment of anaerobic bacterial and protozoa infections in humans. It is also used as a vetinary antiparasitic drug. Spiramycin (SP) is a medium-spectrum antibiotic with high effectiveness against Gram-positive bacteria. Three simple, sensitive, selective and precise spectrophotometric methods were developed and validated for the simultaneous determination of MZ and SP in their pure form and in pharmaceutical formulations. In methods A and B, MZ was determined by the application of direct spectrophotometry and by measuring its zero-order (D0) absorption spectra at its ,max = 311 nm. In method A, SP was determined by the application of first derivative spectrophotometry (D1) and by measuring the amplitude at 218.3 nm. In method B, the first derivative of the ratio spectra (DD1) was applied, and SP was determined by measuring the peak amplitude at 245.6 nm. Method C entailed mean centring of the ratio spectra (MCR), which allows the determination of both MZ and SP. The methods developed were used for the determination of MZ and SP over a concentration range of 5,25 µg ml,1. The proposed methods were used to determine both drugs in their pure, powdered forms with mean percentage recoveries of 100.16 ± 0.73 for MZ in methods A and B, 101.10 ± 0.90 in method C, 100.09 ± 0.70, 100.02 ± 0.88 and 100.49 ± 1.26 for SP in methods A, B and C, respectively. The proposed methods were proved using laboratory-prepared mixtures of the two drugs and were successfully applied to the analysis of MZ and SP in tablet formulation without any interference from each other or from the excipients. The results obtained by applying the proposed methods were compared statistically with a reported HPLC method and no significant difference was observed between these methods regarding both accuracy and precision. Copyright © 2010 John Wiley & Sons, Ltd. [source] Persistence of drug use during imprisonment: relationship of drug type, recency of use and severity of dependence to use of heroin, cocaine and amphetamine in prisonADDICTION, Issue 8 2006John Strang ABSTRACT Aim To investigate the persistence of use of heroin, cocaine and amphetamine drugs during imprisonment, and to identify factors associated with increased levels of persistence. Design The use of heroin, cocaine and amphetamine by current prison inmates has been examined and, in particular, the relationship between drug use within prison and the type of drug used prior to imprisonment, recency of use and severity of dependence., Setting and participants A randomly selected sample of 1009 adult male prisoners in 13 prisons in England and Wales during 1994/95; structured confidential interviews conducted by independent research staff. Enquiry about prior use of heroin, cocaine or amphetamine focused on three time-periods (ever, last year and last month pre-prison) and the use of these drugs during the first month of imprisonment. Findings A total of 557 (55%) of the 1009 prisoners had used previously one of the three drugs selected for study: 58% had used heroin, 69% cocaine and 75% amphetamine. More than half (59%; 327/557) had used these drugs in the month before the current imprisonment. Drug use in prisons was most likely to occur among those who had used in the month prior to imprisonment. The persistence of heroin use in prison occurred more frequently (70%) than use of cocaine (20%) or amphetamine (15%). Of those using heroin pre-imprisonment, 67% considered they were dependent, compared to 15% and 22%, respectively, for cocaine and amphetamine users. Conclusions Changes in the drug-taking behaviour of drug users after imprisonment vary according to the type of drug being taken. Prisoners were much more likely to continue to use heroin than either cocaine or amphetamines while in prison. Heroin was most likely to be used by those who had been using heroin during the immediate pre-imprisonment period, and particularly by the two-thirds of heroin users who considered themselves dependent. In view of the high prevalence of prior use of these drugs by individuals currently imprisoned, continuing attention is required to study of their behaviour and of the impact of interventions that may be introduced during or following their incarceration. [source] The acute anti-craving effect of acamprosate in alcohol-preferring rats is associated with modulation of the mesolimbic dopamine systemADDICTION BIOLOGY, Issue 3 2005Michael Cowen Acamprosate (Campral ?) is a drug used clinically for the treatment of alcoholism. In order to examine further the time-course and mechanism of action of acamprosate, the effect of acute and repeated acamprosate administration was examined on (i) operant ethanol self-administration and (ii) voluntary home cage ethanol consumption by alcohol-preferring Fawn-Hooded, iP and Alko Alcohol (AA) rats. Acutely, acamprosate was shown to cause a significant decrease in operant ethanol self-administration by Fawn-Hooded and alcohol-preferring iP rats in part by decreasing the motivational relevance of a specific ethanol cue; however, repeated injection of acamprosate led to tolerance to this effect. Voluntary alcohol consumption in the home cage in Fawn-Hooded and AA rats was also reduced by an acute acamprosate injection; however, again tolerance developed to repeated injections. In a separate experiment, the effect of acamprosate on markers of the dopaminergic system was examined. Interestingly, acute acamprosate was also shown to cause increased dopamine transporter density and decreased dopamine D2-like receptor density within the nucleus accumbens but not in the caudate-putamen, suggesting a link between the decreased motivational salience of the ethanol cue and altered dopaminergic signalling within the nucleus accumbens. With repeated injections of acamprosate, markers of the dopaminergic system returned to steady state levels with a similar temporal profile to the development of tolerance in the behavioural studies. Along with previous studies, our findings indicate that acamprosate modulates the mesolimbic dopaminergic system and may thereby decrease ethanol reinforcement processes; however, these effects undergo tolerance in alcohol-preferring rats and may in part explain the fact why some subjects are non-responders to chronic acamprosate treatment. [source] Comparison of Routes of Flumazenil Administration to Reverse Midazolam-induced Respiratory Depression in a Canine ModelACADEMIC EMERGENCY MEDICINE, Issue 5 2000Melanie S. Heniff MD ABSTRACT Objective: To determine whether flumazenil, a drug used to reverse benzodiazepine-induced respiratory depression and approved only for IV use, is effective by alternative routes. Methods: A randomized, controlled, nonblinded, crossover canine trial was performed to evaluate reversal of midazolam-induced respiratory depression by flumazenil when administered by alternative routes. Mongrel dogs were sedated with thiopental 19 mg/kg IV, then tracheally intubated. With the dogs spontaneously breathing, tidal volume, end-tidal CO2, and O2 saturation were observed until a stable baseline was achieved. Incremental doses of midazolam were administered until respiratory depression (30% decline in tidal volume, 10% decrease in O2 saturation, and 15% increase in end-tidal CO2) occurred. Flumazenil was administered by a randomly selected route [0.2 mg followed 1 minute later by 0.3 mg IV, sublingual (SL) or intramuscular (IM); or 1 mg followed 1 minute later by 1.5 mg per rectum (PR)]. Time to return to baseline respiratory functions was recorded ("time to reversal"). Each of 10 dogs was studied using all 4 routes of flumazenil administration with a washout period of at least 7 days. An additional dog served as a control (no flumazenil). Results: The control time to reversal was 1,620 seconds. The IV route was significantly faster (mean 120 ± 24.5 sec) than the other 3 routes (p < 0.005). The SL route was the second fastest (mean 262 ± 94.5 sec), the IM route was the third fastest (mean 310 ± 133.7 sec), and the PR route was the slowest (mean 342 ± 84.4 sec). The SL, IM, and PR routes did not differ significantly from one another. Conclusions: Flumazenil administered by all 4 routes reversed midazolam-induced respiratory depression in a dog model. For the selected dosages used, the IV route was significantly faster than all 3 other routes, and SL was the second fastest. [source] Hyperactivity, startle reactivity and cell-proliferation deficits are resistant to chronic lithium treatment in adult Nr2e1frc/frc miceGENES, BRAIN AND BEHAVIOR, Issue 7 2010B. K. Y. Wong The NR2E1 region on Chromosome 6q21-22 has been repeatedly linked to bipolar disorder (BP) and NR2E1 has been associated with BP, and more specifically bipolar I disorder (BPI). In addition, patient sequencing has shown an enrichment of rare candidate-regulatory variants. Interestingly, mice carrying either spontaneous (Nr2e1frc) or targeted (Tlx,) deletions of Nr2e1 (here collectively known as Nr2e1 -null) show similar neurological and behavioral anomalies, including hypoplasia of the cerebrum, reduced neural stem cell proliferation, extreme aggression and deficits in fear conditioning; these are the traits that have been observed in some patients with BP. Thus, NR2E1 is a positional and functional candidate for a role in BP. However, no Nr2e1 -null mice have been fully evaluated for behaviors used to model BP in rodents or pharmacological responses to drugs effective in treating BP symptoms. In this study we examine Nr2e1frc/frc mice, homozygous for the spontaneous deletion, for abnormalities in activity, learning and information processing, and cell proliferation; these are the phenotypes that are either affected in patients with BP or commonly assessed in rodent models of BP. The effect of lithium, a drug used to treat BP, was also evaluated for its ability to attenuate Nr2e1frc/frc behavioral and neural stem cell-proliferation phenotypes. We show for the first time that Nr2e1 -null mice exhibit extreme hyperactivity in the open field as early as postnatal day 18 and in the home cage, deficits in open-field habituation and passive avoidance, and surprisingly, an absence of acoustic startle. We observed a reduction in neural stem/progenitor cell proliferation in Nr2e1frc/frc mice, similar to that seen in other Nr2e1 -null strains. These behavioral and cell-proliferation phenotypes were resistant to chronic-adult-lithium treatment. Thus, Nr2e1frc/frc mice exhibit behavioral traits used to model BP in rodents, but our results do not support Nr2e1frc/frc mice as pharmacological models for BP. [source] Nuclear factor-kappaB as a molecular target for migraine therapy.HEADACHE, Issue 4 2003U Reuter Ann Neurol. 2002;51:507-516. Nitric oxide (NO) generated from inducible NO synthase (iNOS) participates in immune and inflammatory responses in many tissues. The NO donor glyceryl trinitrate (GTN) provokes delayed migraine attacks when infused into migraineurs and also causes iNOS expression and delayed inflammation within rodent dura mater. Sodium nitroprusside, an NO donor as well, also increases iNOS expression. Because inflammation and iNOS are potential therapeutic targets, we examined transcriptional regulation of iNOS following GTN infusion and the consequences of its inhibition within dura mater. We show that intravenous GTN increases NO production within macrophages. L-N(6)-(1-iminoethyl)lysine, a selective iNOS inhibitor, attenuates the NO signal, emphasizing the importance of enzymatic activity to delayed NO production. iNOS expression is preceded by significant nuclear factor kappa B (NF-kappaB) activity, as reflected by a reduction in the inhibitory protein-kappa-Balpha (IkappaBalpha) and activation of NF-kappaB after GTN infusion. IkappaBalpha degradation, NF-kappaB activation, and iNOS expression were attenuated by parthenolide (3mg/kg), the active constituent of feverfew, an anti-inflammatory drug used for migraine treatment. These findings suggest that GTN promotes NF-kappaB activity and inflammation with a time course consistent with migraine attacks in susceptible individuals. We conclude, based on results with this animal model, that blockade of NF-kappaB activity provides a novel transcriptional target for the development of anti-migraine drugs. Comment: This paper suggesting the localization of NO production in dural macrophages as part of delayed inflammation may indicate proliferation and or recruitment of these cells in migraine. Could this also be a target for drug treatment? Specifically, is the genetic transcription that leads to nitric oxide generation such a target? To amend slightly the old advertising slogan, "when Michael Moskowitz talks, we all listen." DSM and SJT [source] Fenofibrate differentially regulates plasminogen activator inhibitor-1 gene expression via adenosine monophosphate,activated protein kinase,dependent induction of orphan nuclear receptor small heterodimer partner,HEPATOLOGY, Issue 3 2009Dipanjan Chanda Plasminogen activator inhibitor type I (PAI-1) is a marker of the fibrinolytic system and serves as a possible predictor for hepatic metabolic syndromes. Fenofibrate, a peroxisome proliferator-activated receptor , (PPAR,) agonist, is a drug used for treatment of hyperlipidemia. Orphan nuclear receptor small heterodimer partner (SHP) plays a key role in transcriptional repression of crucial genes involved in various metabolic pathways. In this study, we show that fenofibrate increased SHP gene expression in cultured liver cells and in the normal and diabetic mouse liver by activating the adenosine monophosphate,activated protein kinase (AMPK) signaling pathway in a PPAR,-independent manner. Administration of transforming growth factor beta (TGF-,) or a methionine-deficient and choline-deficient (MCD) diet to induce the progressive fibrosing steatohepatitis model in C57BL/6 mice was significantly reversed by fenofibrate via AMPK-mediated induction of SHP gene expression with a dramatic decrease in PAI-1 messenger RNA (mRNA) and protein expression along with other fibrotic marker genes. No reversal was observed in SHP null mice treated with fenofibrate. Treatment with another PPAR, agonist, WY14643, showed contrasting effects on these marker gene expressions in wild-type and SHP null mice, demonstrating the specificity of fenofibrate in activating AMPK signaling. Fenofibrate exhibited a differential inhibitory pattern on PAI-1 gene expression depending on the transcription factors inhibited by SHP. Conclusion: By demonstrating that a PPAR,-independent fenofibrate-AMPK-SHP regulatory cascade can play a key role in PAI-1 gene down-regulation and reversal of fibrosis, our study suggests that various AMPK activators regulating SHP might provide a novel pharmacologic option in ameliorating hepatic metabolic syndromes. (HEPATOLOGY 2009.) [source] Relationships between partner's support during labour and maternal outcomesJOURNAL OF CLINICAL NURSING, Issue 2 2000MPhil, Wan Yim Ip BN ,,The objective of this study was to measure the relationship between women's ratings of partners' participation during labour and maternal outcomes as measured by anxiety level, pain perception, dosage of pain-relieving drug used and length of labour. ,,A convenience sample of 45 primigravid women was selected from the postpartum unit of a public hospital in Hong Kong. They were all first-time Chinese mothers, aged 18 or over, who had attended antenatal classes and had their partners present during labour. ,,The State Scale of the State-Trait Anxiety Inventory was used to measure maternal anxiety during labour. Labour pain was measured by the Visual Analogue Scale. A series of scales were developed to measure partners' participation during labour. ,,Women's ratings of partners' practical support were significantly lower than their ratings of partners' emotional support. There were no significant associations between level of emotional support and maternal outcome measures. However, perceived practical support was positively related to the dosage of pain-relieving drug used and total length of labour. Positive relationships between the duration of partners' presence and women's ratings of perceived support provided by partners during labour were also found. [source] Harm minimization strategies: opinions of health professionals in rural and remote AustraliaJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 5 2007G. M. Peterson BPharm (Hons) PhD MBA Summary Background and objective: There is some evidence that the problem of illicit drug use (IDU) is increasing in rural areas of Australia. Lack of access to harm minimization (HM) strategies is potentially exacerbated by a shortage of health care facilities and health care professionals in rural areas. This study was conducted to determine barriers to implementation, access to, and success of HM strategies, as seen by health professionals presently working in rural Australia. Methods: Four hundred rural pharmacists Australia-wide and 425 doctors in rural Victoria and Tasmania were sent postal surveys to assess their opinions on the level of IDU in their area, the types of drugs commonly used, the adequacy of HM strategies and facilities, and the barriers faced by doctors, pharmacists and clients. Results: The overall response rate was almost 50%. Slightly less than half of surveyed health professionals felt that IDU was increasing in their area, with heroin perceived to be the most prevalent drug used in all States except Tasmania and the Northern Territory. Both methadone prescribers and dispensers believed the methadone maintenance programmes were highly valuable to the community, but not without problems (e.g. risk of overdose). A lack of time or staff was the greatest influence on doctors not participating in the methadone programmes, whereas safety concerns were prominent with pharmacists. The majority of doctors felt HM facilities were inadequate, with needle-syringe exchange being the most frequently nominated HM strategy lacking. Conclusion: Despite best intentions, there are still problems with HM strategies in these areas. Improving the number and expertise of health professionals in rural areas, and providing adequate support for them, would address some of these problems. [source] Synthesis of the stable isotope labeled antiviral nucleoside analog [8- 13C,7,9- 15N2]-ganciclovirJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 13 2006Naiyu Zheng Abstract Ganciclovir, a nucleoside analog of 2,-deoxyguanosine, is a drug used in suicide gene therapy for the treatment of mesothelioma. We required a stable isotope analog of ganciclovir for use in pharmacokinetic studies in order to monitor the systemic exposure of patients to the drug. Therefore, a facile and efficient synthesis of [8- 13C,7,9- 15N2]-ganciclovir, was devised. The synthesis was achieved in 4 steps with 25% total yield using commercially-available [8- 13C,7,9- 15N2]-guanine, without the need for purification of intermediates. The key step of the synthesis involved the coupling of [8- 13C,7,9- 15N2]-guanine with 3-propionyloxy-2-propionyloxy-methoxypropyl propionate. The latter was synthesized from a commercially available dichlorohydrin. Each step of the reaction could be easily monitored by liquid chromatography,mass spectrometry. The structure of the labeled ganciclovir was confirmed using 1H, 13C, and 15N nuclear magnetic resonance spectroscopy. Copyright © 2006 John Wiley & Sons, Ltd. [source] The emerging role of epigenetic modifications and chromatin remodeling in spinal muscular atrophyJOURNAL OF NEUROCHEMISTRY, Issue 6 2009Sebastian Lunke Abstract As the leading genetic cause for infantile death, Spinal Muscular Atrophy (SMA) has been extensively studied since its first description in the early 1890s. Though today much is known about the cause of the disease, a cure or effective treatment is not currently available. Recently the short chain fatty acid valproic acid, a drug used for decades in the management of epilepsy and migraine therapy, has been shown to elevate the levels of the essential survival motor neuron protein in cultured cells. In SMA mice, valproic acid diminished the severity of the disease phenotype. This effect was linked to the ability of the short chain fatty acid to suppress histone deacetylase activity and activate gene transcription. Since then, the study of different histone deacetylase inhibitors and their epigenetic modifying capabilities has been of high interest in an attempt to find potential candidates for effective treatment of SMA. In this review, we summarize the current knowledge about use of histone deacetylase inhibitors in SMA as well as their proposed effects on chromatin structure and discuss further implications for possible treatments of SMA arising from research examining epigenetic change. [source] Zidovudine-loaded PLA and PLA,PEG blend nanoparticles: Influence of polymer type on phagocytic uptake by polymorphonuclear cellsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2009Rubiana Mara Mainardes Abstract Mononuclear (macrophages) and polymorphonuclear leucocytes cells play an important role in the immunopathogenesis of acquired immunodeficiency syndrome. Zidovudine is a broad-spectrum drug used in current antiretroviral therapy. The development of controlled drug delivery systems for the treatment of chronic diseases is of great interest since these systems can act as vectors, carrying the drug only to the target, and the adverse effects can be reduced. In this study, PLA and PLA/PEG blend nanoparticles containing zidovudine were developed and their uptake by polymorphonuclear leucocytes were studied in vitro. The influence of polymer type on particle size, Zeta potential and particle uptake by polymorphonuclear leucocytes was investigated. The cells were isolated from rat peritoneal exudate and their activation by nanoparticles was measured by luminol-dependent chemiluminescence and microscopical analysis. The PEG in the blend modified the Zeta potential suggested the formation of a PEG coat on the particle surface. The phagocytosis depended on the PEG and its ratio in the blend, the results showed that the PLA nanoparticles were more efficiently phagocytosed than PLA/PEG blends. The blend with the highest PEG proportion did not prevent phagocytosis, indicating that the steric effect of PEG was concentration dependent. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:257,267, 2009 [source] An extract of Apium graveolens var. dulce leaves: structure of the major constituent, apiin, and its anti-inflammatory propertiesJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2007T. Mencherini Flavonoids, natural compounds widely distributed in the plant kingdom, are reported to affect the inflammatory process and to possess anti-inflammatory as well as immunomodulatory activity in-vitro and in-vivo. Since nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) is one of the inflammatory mediators, the effects of the ethanol/water (1:1) extract of the leaves of Apium graveolens var. dulce (celery) on iNOS expression and NO production in the J774.A1 macrophage cell line stimulated for 24 h with Escherichia coli lipopolysaccharide (LPS) were evaluated. The extract of A. graveolens var. dulce contained apiin as the major constituent (1.12%, w/w, of the extract). The extract and apiin showed significant inhibitory activity on nitrite (NO) production in-vitro (IC50 0.073 and 0.08 mg mL,1 for the extract and apiin, respectively) and iNOS expression (IC50 0.095 and 0.049 mg mL,1 for the extract and apiin, respectively) in LPS-activated J774.A1 cells. The croton-oil ear test on mice showed that the extract exerted anti-inflammatory activity in-vivo (ID50 730 ,g cm,2), with a potency seven-times lower than that of indometacin (ID50 93 ,g cm,2), the non-steroidal anti-inflammatory drug used as reference. Our results clearly indicated the inhibitory activity of the extract and apiin in-vitro on iNOS expression and nitrite production when added before LPS stimulation in the medium of J774.A1 cells. The anti-inflammatory properties of the extract demonstrated in-vivo might have been due to reduction of iNOS enzyme expression. [source] An extract of Lannea microcarpa: composition, activity and evaluation of cutaneous irritation in cell cultures and reconstituted human epidermisJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2006P. Picerno Lannea microcarpa (Anacardiaceae) is a tropical tree used in African folk medicine and commercial dermopharmaceutical formulations. Fractionation and analysis of its polar extract allowed the identification of 4,-methoxy-myricetin 3- O -,- l -rhamnopyranoside, myricetin 3- O -,- l -rhamnopyranoside, myricetin 3- O -,- d -glucopyranoside, vitexin, isovitexin, gallic acid and epi-catechin, as the major constituents. In-vivo assay (the croton oil ear test in mice) showed that the extract had significant anti-inflammatory effect (ID50 = 900 ,g cm2) but ten times lower than that of indometacin (ID50 = 93 ,g cm2), the non-steroidal anti-inflammatory drug used as reference. Cytotoxicity and cutaneous irritation of the extract and its constituents were investigated. The crude extract and its major components did not affect cell viability in-vitro either in three different cultures (J774.A1, WEHI-164 and HEK-293) of cells grown in monolayers or in the reconstituted human epidermis (RHE, 3D model), nor did they cause release of pro-inflammatory mediators (IL-1,) or histomorphological modification of RHE. [source] Complexation of aminoglutethimide with native and modified cyclodextrinsJOURNAL OF PHYSICAL ORGANIC CHEMISTRY, Issue 10 2009Michal Nowakowski Abstract Complexations of R(+) and RS(+/,)aminoglutethimide (AGT), the drug used in a treatment of breast and prostate cancer with native and modified cyclodextrins (, -CD, , -CD, , -CD, 2,6-di- O -methyl- , -CD (DM- , -CD), 2,3,6-tri- O -methyl- , -CD (TM- , -CD) and carboxymethyl- , -CD (CM- , -CD)) were studied. The stability constants were determined with UV,Vis spectrophotometric method at pH 9.0. The NMR data obtained for TM- , -CD suggest that the complexation of AGT is possible from both sides of CD molecule. This was confirmed by molecular dynamic simulations. Copyright © 2009 John Wiley & Sons, Ltd. [source] Glycine Receptors Involved in Acamprosate's Modulation of Accumbal Dopamine Levels: An In Vivo Microdialysis StudyALCOHOLISM, Issue 1 2010PeiPei Chau Background:, Glycine receptors (GlyRs) in the nucleus accumbens (nAc) and nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area (VTA) have been suggested to be involved in the positive reinforcing and dopamine elevating effects of ethanol. Recent studies have also shown that ethanol high-preferring rats substantially decrease their ethanol intake when treated with a glycine transporter 1 inhibitor (ORG 25935). Acamprosate, a drug used for relapse prevention in treatment of alcohol dependence, has also been demonstrated to elevate extracellular dopamine levels in the nAc. However, the underlying mechanism of action of acamprosate is not fully understood. Here we investigated whether acamprosate interferes with a neuronal circuitry that previously has been demonstrated to be involved in the dopamine elevating effects of ethanol and taurine. Methods:, In vivo microdialysis in freely moving rats was used to assess accumbal dopamine levels before and during local (nAc) or systemic administration of acamprosate. Results:, Perfusion of 0.5 mM acamprosate in the nAc significantly increased dopamine levels. Pretreatment either with 10 ,M strychnine in the nAc or 100 ,M mecamylamine in the VTA, completely antagonized the acamprosate-induced elevation of accumbal dopamine levels. Also, systemic acamprosate administration elevated accumbal dopamine output, an effect that was abolished by local (nAc) pretreatment with 10 ,M strychnine. Conclusions:, These results suggest that both systemic and local application of acamprosate elevate extracellular dopamine levels in the nAc by activating accumbal GlyRs, and, secondarily, tegmental nAChRs. [source] Effects of SZ1677, a new non-depolarizing steroidal neuromuscular blocking drug, and rocuronium on two laryngeal muscles and the anterior tibial muscle in guinea pigsACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 4 2006A. Michalek-Sauberer Background:, SZ1677 is a new neuromuscular blocking drug structurally related to rocuronium. We compared the effect of an ED90 of SZ1677 (25 ,g/kg) with that of rocuronium (100 ,g/kg) in guinea pig laryngeal and peripheral muscles. Methods:, Electromyography was used to quantify neuromusc-ular blockade at the posterior cricoarytenoid muscle, the thyroarytenoid muscle and the anterior tibial muscle after SZ1677 (n = 10) and rocuronium (n = 9). Results:, Maximum neuromuscular blockade was similar after SZ1677 and rocuronium (83 ± 11% vs. 89 ± 11%; thyroarytenoid muscle: 91 ± 8% vs. 97 ± 3%; anterior tibial muscle: 91 ± 15% vs. 96 ± 3%, respectively). Onset time of neuromuscular blockade at the laryngeal muscles was similar for the two neuromuscular blocking drugs; it was shorter at the thyroarytenoid muscle (67 ± 32 s vs. 42 ± 40 s) than at the posterior cricoarytenoid muscle (101 ± 26 s vs. 102 ± 108 s). Onset time at the anterior tibial muscle was longer after SZ1677 (114 ± 34 s) than after rocuronium (68 ± 46 s); P < 0.05. Neuromuscular recovery was faster after SZ1677 (interval 25%,75%: posterior cricoarytenoid muscle: 222 ± 66 s; thyroarytenoid muscle: 192 ± 92 s; tibial muscle 149 ± 55 s) than after rocuronium (450 ± 148 and 464 ± 183 s, 292 ± 86 s, respectively); P < 0.05. Conclusions:, In guinea pigs, SZ1677 offers a rapid onset of neuromuscular blockade at a laryngeal adductor muscle with a shorter duration than rocuronium. Regardless of the drug used, the course of neuromuscular blockade differs not only between peripheral muscles and the larynx but also between antagonistic laryngeal muscles. The differences seem to be species specific. [source] Pharmacokinetics of gamithromycin in cattle with comparison of plasma and lung tissue concentrations and plasma antibacterial activityJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2010R. A. HUANG Huang, R. A., Letendre, L. T., Banav, N., Fischer, J., Somerville, B. Pharmacokinetics of gamithromycin in cattle with comparison of plasma and lung tissue concentrations and plasma antibacterial activity. J. vet. Pharmacol. Therap.33, 227,237. The pharmacokinetics (PK) and dose proportionality of gamithromycin (ZACTRAN®), a novel azalide, after a single intravenous (i.v.) dose of 3 mg/kg or subcutaneous (s.c.) injection at 3, 6 and 9 mg/kg body weight were studied in 13 male castrate and 13 female Angus cattle. Following i.v. administration, the mean area under the curve extrapolated to infinity (AUCinf) was 4.28 ± 0.536 ,g·h/mL, and mean elimination half-life (t1/2) was 44.9 ± 4.67 h, with a large volume of distribution (Vss) of 24.9 ± 2.99 L/kg and a high clearance rate (Clobs) of 712 ± 95.7 mL/h/kg. For cattle treated with s.c. injection of 3, 6 or 9 mg/kg, mean AUCinf values were 4.55 ± 0.690, 9.42 ± 1.11 and 12.2 ± 1.13 ,g·h/mL, respectively, and the mean elimination half-lives (t1/2) were 51.2 ± 6.10, 50.8 ± 3.80 and 58.5 ± 5.50 h. Gamithromycin was well absorbed and fully bioavailable (97.6,112%) after s.c. administration. No statistically significant (, = 0.05) gender differences in the AUCInf or elimination half-life values were observed. Dose proportionality was established based on AUCInf over the range of 0.5 to 1.5 times of the recommended dosage of 6 mg/kg of body weight. Further investigations were conducted to assess plasma PK, lung/plasma concentration ratios and plasma antibacterial activity using 36 cattle. The average maximum gamithromycin concentration measured in whole lung homogenate was 18 500 ng/g at first sampling time of 1 day (,24 h) after treatment. The ratios of lung to plasma concentration were 265, 410, 329 and 247 at 1, 5, 10 and 15 days postdose. The lung AUCinf was 194 times higher than the corresponding plasma AUCinf. The apparent elimination half-life for gamithromycin in lung was 90.4 h (,4 days). Antibacterial activity was observed with plasma collected at 6 h postdose with a corresponding average gamithromycin plasma concentration of 261 ng/mL. In vitro plasma protein binding in bovine plasma was determined to be 26.0 ± 0.60% bound over a range of 0.1,3.0 ,g/mL of gamithromycin. The dose proportionality of AUC, high bioavailability, rapid and extensive distribution to lung tissue and low level of plasma protein binding are beneficial PK parameters for an antimicrobial drug used for the treatment and prevention of bovine respiratory disease. [source] Metabolism of isometamidium in hepatocytes isolated from control and inducer-treated ratsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2006I. BOIBESSOT Little is known about the metabolism and mechanism of action of the trypanocide, isometamidium (ISM), the major drug used for prophylaxis of trypanosomiasis. We have investigated its metabolism and distribution in isolated rat hepatocytes using liquid chromatography-mass spectrometry and confocal laser scanning microscopy (CLSM). Two putative metabolites were formed, which were proposed to be a mono-acetyl derivative and an oxidized metabolite (SII). This is the first demonstration of the hepatic metabolism of ISM, as previous in vivo studies were hampered by dose-limiting toxicity and insensitive analytical methods. The intrinsic fluorescence of the drug enabled its intracellular uptake to be followed by CLSM. It is taken up rapidly into the nucleolus, nuclear membrane and endoplasmic reticulum within 5 min, and retained in the nucleus for at least 24 h. Persistent binding of ISM to cellular macromolecules may contribute to its prophylactic effect in vivo. Pretreatment of rats with 3-methylcholanthrene, phenobarbitone (PB) or the widely used pyrethroid pesticide, deltamethrin, resulted in an increase in metabolism of ISM to the proposed SII after 1 h incubation with hepatocytes. 3-methylcholanthrene was the most potent inducer, causing a maximal 19.5-fold induction of SII formation after exposure of hepatocytes to ISM for 1 h compared with formation by control hepatocytes. In comparison, at the 1 h timepoint deltamethrin pre-treatment caused a 10.2-fold induction, and PB only 8.2 fold. [source] Pharmacokinetics and pharmacokinetic/pharmacodynamic integration of marbofloxacin in calf serum, exudate and transudateJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2002F. SHOJAEE ALIABADI Aliabadi, F. S., Lees, P. Pharmacokinetics and pharmacokinetic/pharmacodynamic integration of marbofloxacin in calf serum, exudate and transudate. J. vet. Pharmacol. Therap.25, 161,174. Marbofloxacin is a fluoroquinolone antimicrobial drug used in cattle for the treatment of respiratory infections. In this investigation the pharmacokinetics (PK) of marbofloxacin were determined after intravenous and intramuscular dosing at a dosage of 2 mg/kg. In addition the ex vivo pharmacodynamics (PD) of the drug were determined in serum and three types of tissue cage fluid (transudate, inflammatory exudate generated by carrageenan and exudate generated by lipopolysaccharide). Marbofloxacin PK was characterized by a high volume of distribution after dosing by both routes (1.28 L/kg intravenous and 1.25 L/kg intramuscular). Corresponding area under the concentration,time curve (AUC) and elimination half-life (t½el) values were 9.99 and 10.11 ,g h/mL and 4.23 and 4.33 h, respectively. Values of AUC for carrageenan-induced exudate, lipopolysaccharide-induced exudate and transudate were, respectively, 8.28, 7.83 and 7.75 ,g h/mL after intravenous and 8.84, 8.53 and 8.52 ,g h/mL after intramuscular dosing. Maximum concentration (Cmax) values were similar for the three tissue cage fluids after intravenous and intramuscular dosing. For in vivo PK data values of AUC: minimum inhibitory concentration (MIC) (AUIC) ratio for serum were 250 and 253, respectively, after intravenous and intramuscular dosing of marbofloxacin against a pathogenic strain of Mannheimia haemolytica (MIC=0.04 ,g/mL). For all tissue cage fluids AUIC values were >194 and >213 after intravenous and intramuscular dosing, and Cmax/MIC ratios were 9 or greater, indicating a likely high level of effectiveness in clinical infections caused by M. haemolytica of MIC 0.04 ,g/mL or less. This was confirmed by both in vitro (serum) and ex vivo (serum, exudate and transudate) measurements, which demonstrated a concentration-dependent killing profile for marbofloxacin against M. haemolytica. Ex vivo, after 24-h incubation, virtually all bacteria were killed (<10 cfu/mL) in all samples collected up to 9 h (serum), 24 h (carrageenan-induced exudate and transudate) and 36 h (lipopolysaccharide-induced exudate). Application of the sigmoid Emax equation to the ex vivo antibacterial data provided, for serum, AUIC24 h values of 37.1 for bacteriostasis, 46.3 for bactericidal activity and 119.6 for elimination of bacteria. These data may be used as a rational basis for setting dosing schedules which optimize clinical efficacy and minimize the opportunities for emergence of resistant organisms. [source] EthR, a repressor of the TetR/CamR family implicated in ethionamide resistance in mycobacteria, octamerizes cooperatively on its operatorMOLECULAR MICROBIOLOGY, Issue 1 2004Jean Engohang-Ndong Summary Ethionamide (ETH) is an important second-line antitubercular drug used for the treatment of patients infected with multidrug-resistant Mycobacterium tuberculosis. Although ETH is a structural analogue of isoniazid, only little cross-resistance to these two drugs is observed among clinical isolates. Both isoniazid and ETH are pro-drugs that need to be activated by mycobacterial enzymes to exert their antimicrobial activity. We have recently identified two M. tuberculosis genes, Rv3854c (ethA) and Rv3855 (ethR), involved in resistance to ETH. ethA encodes a protein that belongs to the Flavin-containing monooxygenase family catalysing the activation of ETH. We show here that ethR, which encodes a repressor belonging to the TetR/CamR family of transcriptional regulators, negatively regulates the expression of ethA. By the insertion of the ethA promoter region upstream of the lacZ reporter gene, overexpression of ethR in trans was found to cause a strong inhibition of ethA expression, independently of the presence of ETH in the culture media. Electrophoretic mobility shift assays indicated that EthR interacts directly with the ethA promoter region. This interaction was confirmed by DNA footprinting analysis, which, in addition, identified the EthR-binding region. Unlike other TetR/CamR members, which typically bind 15 bp operators, EthR recognises an unusually long 55 bp region suggesting multimerization of the repressor on its operator. Identification by primer-extension of the ethA transcriptional start site indicated that it is located within the EthR-binding region. Taken together, bacterial two-hybrid experiments and gel filtration assays suggested a dimerization of EthR in the absence of its operator. In contrast, surface plasmon resonance analyses showed that eight EthR molecules bind cooperatively to the 55 bp operator, which represents a novel repression mechanism for a TetR/CamR member. [source] Renoprotective effect of Hemidesmus indicus, a herbal drug used in gentamicin-induced renal toxicityNEPHROLOGY, Issue 3 2004MANGALA S KOTNIS SUMMARY: Background and Aims: Owing to the global trend towards improved ,quality of life', there is considerable evidence of an increase in demand for medicinal plants. The WHO guidelines define basic criteria for the standardization of herbal medicines. The present work is an effort in this direction to prove the safety and efficacy of Hemidesmus indicus Linn. in the management of nephrotoxicity induced by aminoglycosides such as gentamicin. Methods and Results: Simple, quality control methods using high performance thin layer chromatographic (HPTLC) phytochemical fingerprint, proximate analysis, and the stability of the H. indicus root powder were developed. From the toxicity study using albino Swiss mice, it was observed that the drug (H. indicus) was relatively safe up to 7 g/kg bodyweight dose. Efficacy was evaluated against gentamicin-induced nephrotoxicity in albino Wister rats. The study examined animals from the following groups: no treatment, gentamicin treated, gentamicin treated recovery, and gentamicin and plant treated. Animals from all groups were killed on day 13 of the study; those from gentamicin treated group were killed on the seventh day. Assessment of the drug efficacy drug was conducted by using haematological and histological examination. Conclusion: The treatment with H. indicus helped in the management of renal impairment, which was induced by gentamicin in rats. This is evident from the results obtained for various kidney function tests for gentamicin, along with the results from the plant treated group, and is in comparison with the results found for the gentamicin recovery group. A histological examination of kidneys also supports the findings from haematological evaluations. The plant shows promise as an adjunct therapy along side aminoglycosides as it reduces nephrotoxicity caused by aminoglycosides. [source] | ||||||||||||||||||||||||||||||||||||||||