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New Drugs (new + drug)
Kinds of New Drugs Terms modified by New Drugs Selected AbstractsAccelerating drug development: methodology to support first-in-man pharmacokinetic studies by the use of drug candidate microdosingDRUG DEVELOPMENT RESEARCH, Issue 1 2007Matthew A. McLean Abstract Microdosing of experimental therapeutics in humans offers a number of benefits to the drug development process. Microdosing, conducted under an exploratory Investigational New Drug (IND) application, entails administration of a sub-pharmacological dose of a new chemical entity (NCE) that allows for early evaluation of human pharmacokinetics. Such information can be pivotal for: (1) selecting a compound for full drug development from a small group of candidates; (2) defining the amount of material needed for early development; and (3) setting the initial Phase I dose regimen in humans. Appropriate safety studies must be conducted to support microdosing in humans, but the requirements are generally less extensive than those needed to support a traditional IND. To date, microdosing has not been broadly applied by the pharmaceutical industry due to concerns about analytical sensitivity and the possibility of non-linear pharmacokinetics at extremely low doses. The primary method for detecting analytes following microdosing until now has been accelerator mass spectrometry, which is expensive, not generally available, and requires test agents to be radiolabeled. Presented in this report is an example of pharmacokinetics analysis using LC/MS/MS following microdosing of an experimental agent in cynomolgus monkeys. The results show good linearity in plasma pharmacokinetics for oral doses of 10,mg/kg (therapeutic dose) and 0.0005,mg/kg (microdose) of the test agent. The results also demonstrate the feasibility of applying standard laboratory analytics to support microdosing in humans and raise the possibility of establishing an animal model to screen for compounds having non-linear pharmacokinetics at low dose levels. Drug Dev. Res. 68:14,22, 2007. © 2007 Wiley-Liss, Inc. [source] Latest news and product developmentsPRESCRIBER, Issue 7 2007Article first published online: 11 JUL 200 Poor asthma control with off-licence prescribing Children who are prescribed off-licence medications are more likely to have poor asthma control, according to an analysis from Dundee (Br J Gen Practice 2007;57:220-2). The review of 17 163 consultations identified 1050 (6.1 per cent) who received a prescription for an unlicensed use (defined as not licensed for children or the particular age group, or dose not licensed). High doses (4.5 per cent) were more frequent than unlicensed indications (1.9 per cent). Children who received off-label prescriptions reported statistically significantly more symptoms in the day or night, symptoms during activity, and increased use of daily short-acting beta2-agonists. The authors note that off-label prescribing appears to be increasing. Atkins diet most effective over one year? The ultra low-carbohydrate, high-protein Atkins diet achieved greater weight loss than other popular diets in overweight women over one year, say US investigators (J Am Med Assoc 2007;297:969-77). The study compared the Atkins diet with three diets designed as low- or very high-carbohydrate, or based on USA nutritional guidance, in 311 women with body mass index 27-40. After one year, mean weight loss was 4.7kg with the Atkins diet , significantly greater than with the low- carbohydrate diet (1.6kg) but not compared with very high-carbohydrate (2.2kg) or the nutrition-based diet (2.6kg). Metabolic endpoints were comparable or more favourable in women using the Atkins diet. Androgen therapy linked to gum disease The majority of men treated with androgen deprivation therapy for prostate cancer are more likely to have periodontal disease (J Urol 2007;177:921-4). After controlling for risk factors, the prevalence of periodontal disease was 80.5 per cent among treated men compared with 3.7 per cent in matched controls not receiving treatment. There was no difference in bone mineral density between the groups but plaque scores were significantly higher among treated men. Food Commission rebuts MHRA on additives An independent watchdog has not accepted the MHRA's justification for including certain additives in medicines for children. The Food Commission (www.foodcomm.org.uk) found that most medicines for children contained additives, some of which , including azo dyes and benzoates , are not permitted in food. The Commission called on the pharmaceutical industry to stop using ,questionable additives'. The MHRA stated that the licensing process takes into account the likely exposure to excipients that are considered essential to make medicines palatable to children. Colouring helps children to identify the correct medicine, and preservatives ensure a reasonable shelf-life. A list of additives is included in the product's summary of product characteristics and patient information leaflet. In response, the Commission states: , , it is quite possible to flavour medicines with natural oils or extracts, and natural colourings such as beetroot and beta-carotene can be used instead of azo dyes. If parents were advised to give these medicinal products at mealtimes the manufacturers could also add a little sugar to sweeten their products, rather than relying on artificial sweeteners.' All triptans the same? There is no economic case for choosing one triptan over another and no evidence for preferring a particular triptan for adults, a systematic review has concluded. The Canadian Agency for Drugs and Technologies in Health (www.cadth.ca) found that published trials had compared most triptans with sumatriptan but not with one another, and most economic evaluations were flawed. New drug for HIV Janssen-Cilag has introduced darunavir (Prezista), a new protease inhibitor for the treatment of HIV infection. Licensed for highly pre- treated patients in whom more than one other pro- tease inhibitor regimen has failed, darunavir must be co-administered with ritonavir (Norvir). A month's treatment at the recommended dose of 600mg twice daily costs £446.70. Variation in liquid captopril for children The NHS uses a wide range of liquid formulations of captopril to treat children with heart failure , with no assurance of their bioequivalence (Arch Dis Child 2007; published online 15 March. doi: 10.1136/adc.2006.109389). Specialists in Leicester surveyed 13 tertiary paediatric cardiac centres and 13 hospitals that referred patients to them. Only three tertiary centres supplied the same liquid for-mulation of captopril as their referring hospitals. Four hospitals supplied tablets for crushing and dissolving in water; the other hospitals and centres used a total of nine different formulations. The authors say the formulations had widely varying shelf-lives, determined empirically in all but one case, and were used interchangeably despite a lack of quality control data to establish their bioequivalence. QOF CVD targets not good enough for GPs Two-thirds of GPs want Quality Outcome Framework (QOF) targets for cardiovascular disease brought into line with those of the Joint British Societies latest guidance (JBS2), according to a survey by doctor.net.uk. The survey of 1000 GPs showed that 88 per cent were aware of the JBS2 guidelines and most were already implementing the targets for lipids, blood pressure and blood glucose in some form; however, only 55 per cent were implementing the JBS2 obesity target and 14 per cent were implementing screening for the over-40s. The JBS2 target for lipids in at-risk patients is <4mmol per litre total cholesterol and <2 mmol per litre LDL-cholesterol, compared with <5 and <3mmol per litre respectively in QOF and the NSF. The survey was commissioned by Merck Sharp & Dohme and Schering- Plough. Fracture warning Following warnings in the US that rosiglitazone (Avandia) is associated with an increased risk of fractures in women, Takeda has advised prescribers that pioglitazone (Actos) carries a similar risk. An analysis of the company's clinical trials database has revealed an excess risk of fractures of bones below the elbow and knee. The incidence was similar to the excess risk associated with rosiglitazone and also confined to women. Scottish approvals The Scottish Medicines Consortium (www.scottish medicines.org.uk) has approved for use within NHS Scotland the sublingual tablet formulation buprenorphine/naloxone (Suboxone) for the treatment of opioid dependence. It has also approved the combined formulation of valsartan and amlodipine (Exforge) and the restricted use of the If inhibitor ivabradine (Procoralan). [source] Population pharmacokinetics of sirolimus in de novo Chinese adult renal transplant patientsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2009Zheng Jiao WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT? , Sirolimus is an immunosuppressive agent used for the prophylaxis of renal allograft rejection. , Several conventional pharmacokinetic and population pharmacokinetic studies have been conducted to assess the pharmacokinetic characteristics of sirolimus in White or African-American recipients. WHAT THIS STUDY ADDS? , The population pharmacokinetics of sirolimus in Chinese adult renal transplant recipients was characterized for the first time. , New drug,drug interactions between herbal medicines and sirolimus were identified as the covariates on sirolimus clearance. AIMS This study was aimed at determining the population pharmacokinetics of sirolimus and identifying factors that explain pharmacokinetic variability in de novo Chinese adult renal transplant patients. METHODS Data were retrospectively extracted from a formal multicentre clinical trial, which was originally designed to evaluate the safety and efficacy of ciclosporin dose reduction and ciclosporin elimination in patients receiving sirolimus. All patients received 12-month treatment, i.e. induction therapy with ciclosporin, sirolimus and corticosteroids during the first 3 months followed by either ciclosporin dose reduction or ciclosporin discontinuation thereafter. Eight-hundred and four sirolimus trough blood concentrations (C0) from 112 patients were used to develop a population pharmacokinetic model using the nonmem program. A one-compartment model with first-order absorption and elimination was selected as the base model. The influence of demographic characteristics, biochemical and haematological indices, ciclosporin daily dose, ciclosporin C0 as well as other commonly used co-medications were explored. RESULTS The typical values with interindividual variability for apparent clearance (CL/F) and apparent volume of distribution (V/F) were 10.1 l h,1 (23.8%) and 3670 l (56.7%), respectively. The residual variability was 29.9%. CL/F decreased significantly with silymarin or glycyrrhizin co-therapy in hepatically impaired patients, and with increasing total cholesterol levels or ciclosporin C0. Moreover, CL/F increased nonlinearly with increasing sirolimus daily dose. The median parameter estimates from a nonparametric bootstrap procedure were comparable and within 5% of the estimates from nonmem. CONCLUSIONS These results provide important information for clinicians to optimize sirolimus regimens in Chinese renal transplant patients. [source] New drugs: Kids come first; Con: First adults, then childrenINFLAMMATORY BOWEL DISEASES, Issue 9 2007M. Stephen Murphy MD First page of article [source] Hepatitis B and hepatitis C in 2009LIVER INTERNATIONAL, Issue 2009Patrick Marcellin Abstract Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are among the most frequent viral infections in humans, and represent a major global public health problem. HBV- and HCV-related chronic hepatitis are the main causes of cirrhosis and hepatocellular carcinoma (HCC) that are responsible for a high rate of morbidity and mortality. End-stage HBV- and HCV-related liver disease and HCC are the main causes of liver transplantation. In the last few years, knowledge of the epidemiology and the natural history of HBV and HCV infection has markedly improved. Furthermore, considerable progress has been made in the efficacy of therapy. New drugs and new therapeutic strategies that are currently under evaluation could further improve the efficacy of therapy in the near future. [source] New drugs for the treatment of hepatocellular carcinomaLIVER INTERNATIONAL, Issue 2009Eveline Boucher Abstract Treatment of hepatocellular carcinoma has dramatically changed in the last years. The better knowledge of the molecular mechanisms responsible of tumor initiation and progression has allowed the development of molecular targeted therapies that specifically block the disrupted pathways. Among all these new agents, Sorafenib is the only one that has shown efficacy in terms of survival in advanced stage in two randomized, double-blind, controlled trials. The positive result of these two trials are the proof of the efficacy of molecular targeted therapies in hepatocellular carcinoma and opens the door to multipathway blockade and the use of these targeted therapies in the adjuvant setting. Other agents have shown promising results in phase 1-2 trials but further studies are needed to demonstrate their efficacy. In the next years, efforts should be directed to identifying genomic and proteomic profiling that will help us to assess the prognosis and to define what treatment benefits whom, ultimately giving way to personalized medicine. [source] Tagatose, a new antidiabetic and obesity control drugDIABETES OBESITY & METABOLISM, Issue 2 2008Y. Lu A potentially important new drug for treating type 2 diabetes, tagatose, is now in phase 3 clinical trial. The history, development, additional health benefits, mechanisms of action and the potential for the drug are presented in context with a review of the rapidly growing epidemic of type 2 diabetes and treatments for it. An epimer of fructose, the natural hexose tagatose was originally developed by Spherix Incorporated (formerly Biospherics Inc.) as a low-calorie sugar substitute. Only 20% of orally ingested tagatose is fully metabolized, principally in the liver, following a metabolic pathway identical to that of fructose. Following a decade of studies, tagatose became generally recognized as safe for use in foods and beverages under US FDA regulation. The simple sugar is commercially produced by isomerization of galactose, which is prepared from lactose. Early human studies suggested tagatose as a potential antidiabetic drug through its beneficial effects on postprandial hyperglycaemia and hyperinsulinaemia. A subsequent 14-month trial confirmed its potential for treating type 2 diabetes, and tagatose showed promise for inducing weight loss and raising high-density lipoprotein cholesterol, both important to the control of diabetes and constituting benefits independent of the disease. Furthermore, tagatose was shown to be an antioxidant and a prebiotic, both properties cited in the maintenance and promotion of health. No current therapies for type 2 diabetes provide these multiple health benefits. The predominant side effects of tagatose are gastrointestinal disturbances associated with excessive consumption, generally accommodated within 1- to 2-week period. The health and use potentials for tagatose (branded Naturlose® for this use) are given with respect to current type 2 diabetes drugs and markets. Under an FDA-affirmed protocol, Spherix is currently conducting a phase 3 trial to evaluate a placebo-subtracted treatment effect based on a decrease in HbA1c levels. Side effects, contraindications and possibly beneficial new findings will be carefully monitored. It is hoped that early results of the trial may become available by mid-2008. If a subsequent NDA is successful, tagatose may fill a major health need. [source] Pregabalin, tiapride and lorazepam in alcohol withdrawal syndrome: a multi-centre, randomized, single-blind comparison trialADDICTION, Issue 2 2010Giovanni Martinotti ABSTRACT Introduction The aim of this trial was to compare lorazepam with non-benzodiazepine medications such as pregabalin and tiapride in the treatment of alcohol withdrawal syndrome (AWS). These drugs were chosen for their inhibitorial effects on the hypersecretion of neurotransmitters usually observed in AWS. Craving reduction and improvement of psychiatric symptoms were the secondary end-points. Methods One hundred and ninety subjects affected by current alcohol dependence were considered consecutively: 111 were enrolled and divided into three groups of 37 subjects each. Within a treatment duration of 14 days, medication was given up to the following maximum doses (pregabalin 450 mg/day; tiapride 800 mg/day; lorazepam 10 mg/day). Withdrawal (CIWA-Ar), craving [visual analogue scale (VAS); Obsessive and Compulsive Drinking Scale (OCDS)], psychiatric symptoms [Symptom Check List 90 Revised (SCL-90-R)] and quality of life (QL-index) rating scales were applied. Results On the CIWA-Ar score, all the groups showed a significant reduction between times (P < 0.001) with a higher reduction for the pregabalin group (P < 0.01) on items regarding headache and orientation. Retention in treatment was lower in the tiapride group (P < 0.05), while the number of subjects remaining alcohol free was higher in the pregabalin group (P < 0.05). Significant reduction between baseline and the end of the treatment was found in all the groups at the OCDS and the VAS for craving, at the SCL-90-R and QL-index (P < 0.001). Discussion All the medications in the trial showed evidence of safety and efficacy in the treatment of uncomplicated forms of AWS, with some particular differences. The efficacy of pregabalin was superior to that of tiapride, used largely in research trials and, for some measures, to that of the ,gold standard', lorazepam. Accordingly, pregabalin may be considered as a potentially useful new drug for treatment of AWS, deserving further investigation. [source] New onsets of substance use disorders in borderline personality disorder over 7 years of follow-ups: findings from the Collaborative Longitudinal Personality Disorders StudyADDICTION, Issue 1 2009Marc Walter ABSTRACT Aims The purpose of this study was to examine whether patients with borderline personality disorder (BPD) have a higher rate of new onsets of substance use disorders (SUD) than do patients with other personality disorders (OPD). Design This study uses data from the Collaborative Longitudinal Personality Disorder Study (CLPS), a prospective naturalistic study with reliable repeated measures over 7 years of follow-up. Setting Multiple clinical sites in four northeastern US cities. Participants A total of 175 patients with BPD and 396 patients with OPD (mean age 32.5 years) were assessed at baseline and at 6, 12, 24, 36, 48, 60, 72 and 84 months. Measurements The Structured Clinical Interview for DSM-IV Axis I Disorders and the Diagnostic Interview for DSM-IV Personality Disorders were used at baseline, the Follow-Along version of the DIPD-IV and the Longitudinal Interval Follow-up Evaluation at the follow-up evaluations. Kaplan,Meier analyses were calculated to generate the time to new onsets. Findings BPD patients showed a shorter time to new onsets of SUD. Thirteen per cent of BPD patients developed a new alcohol use disorder and 11% developed a new drug use disorder, compared to rates of 6% and 4%, respectively, for OPD. Non-remitted BPD and remitted BPD patients did not differ significantly in rates of new onsets of SUD. Conclusions BPD patients have a high vulnerability for new onsets of SUDs even when their psychopathology improves. These findings indicate some shared etiological factors between BPD and SUD and underscore the clinical significance of treating SUD when it co-occurs in BPD patients. [source] Treatment satisfaction with insulin glargine in patients with diabetes mellitus in a university hospital clinic in SwedenEUROPEAN DIABETES NURSING, Issue 1 2009M Annersten Gershater RN, MNSc Research Nurse Abstract Background: Few studies evaluate patients' perspectives when a new drug is intro-duced to treat chronic diseases such as diabetes mellitus. The clinical role of a new insulin treatment, in terms of the relationship between higher cost and better treat-ment outcomes (as defined from the patient perspective) has been discussed. We sought to explore patient satisfaction with a new insulin treatment (insulin glargine). At its launch in 2002/3 it was purported to provide constant, peakless insulin release following once- or twice-daily administration, thus leading to fewer hypoglycaemic episodes while providing metabolic control equivalent to that achieved with NPH human basal insulin. Aims: To investigate the indications used for prescription of a new drug and its clinical effects on glycosylated haemoglobin (HbA1c) levels, perceived hypoglycaemic events and patient satisfaction. Methods: The Diabetes Treatment Satisfaction Questionnaire (Status Version, DTSQ-s), which measures satisfaction with treatment regimen, and perceived frequency of hyperglycaemia and hypoglycemia, was circulated to all living patients who had ever started treatment with insulin glargine at the Department of Endocrinology at Malmö University Hospital. Medical records of 913 patients were assessed for HbA1c levels at 0 and 12 months after starting insulin glargine therapy. Results: Completed questionnaires were returned by 615 of 960 patients (64%) who had ever started insulin glargine. The main indications for starting treatment were physicians' or nurses' initiatives, desire for fewer fluctuations and improved metabolic control. HbA1c levels fell by 0.41% for patients with type 1 diabetes and by 0.68% for those with type 2 diabetes. The mean DTSQ-s score was 28.45 for satisfaction, whereas the mean perceived hypoglycaemic/hyperglycaemic events score was 3. Conclusion: Treatment satisfaction was very high and perceived frequency of hypoglycaemia/hyperglycaemia was very low. The indications for treatment of insulin glargine are being followed in accordance with national recommendations. Copyright © 2009 FEND [source] Why use a new drug for an old disease?,Z-HE' for treatment of erysipeloid cutaneous leishmaniasisFOCUS ON ALTERNATIVE AND COMPLEMENTARY THERAPIES AN EVIDENCE-BASED APPROACH, Issue 1 2001F Zerehsaz [source] Optimal drug pricing, limited use conditions and stratified net benefits for Markov models of disease progressionHEALTH ECONOMICS, Issue 11 2008Gregory S. Zaric Abstract Limited use conditions (LUCs) are a method of directing treatment with new drugs to those populations where they will be most cost effective. In this paper we investigate how a drug manufacturer could determine pricing and LUCs to maximize profits. We assume that the payer makes formulary decisions on the basis of net monetary benefits, that the disease can be modeled using a Markov model of disease progression, and that the drug reduces the probability of progression between states of the Markov model. LUCs are expressed as a range of probabilities of disease progression over which patients would have access to the new drug. We assume that the manufacturer determines the price and LUCs in order to maximize profits. We show that an explicit trade-off exists between the drug's price and the use conditions, that there is an upper bound on the drug price, that the proportion of the population targeted by the LUC does not depend on quality of life or costs in each health state or the payer's willingness to pay, and that high drug prices do not always correspond with high profits. Copyright © 2008 John Wiley & Sons, Ltd. [source] Patient perceptions of the risks and benefits of infliximab for the treatment of inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 1 2008Corey A. Siegel MD Abstract Background: For a patient to make informed, preference based decisions, they must be able to balance the risks and benefits of treatment. The aim of this study was to determine patients' and parents' perceptions of the risks and benefits of infliximab for the treatment of inflammatory bowel disease (IBD). Methods: Adult patients with IBD and parents of patients attending IBD patient education symposiums were asked to complete a questionnaire regarding the risks and benefits of infliximab. Results: One hundred and sixty-five questionnaires were completed. A majority (59%) of respondents expected a remission rate greater than 50% at 1 year and 18% expected a remission rate greater than 70% at 1 year. More than one-third (37%) of respondents answered that infliximab is not associated with a risk of lymphoma and 67% responded that the lymphoma risk is no higher than twice that of the general population. When presented a scenario of a hypothetical new drug for IBD with risks mirroring those estimated for infliximab, 64% of respondents indicated that they would not take the medication, despite its described benefits. Thirty percent of these patients were either currently taking or had previously taken infliximab. Patients actively taking infliximab predicted the highest remission rates for the infliximab (P = 0.05), and parents of patients predicted the lowest (P = 0.01). Parents estimated a higher risk of lymphoma than patients (P = 0.003). Risk and benefit perception was independent of gender and age of patient respondents. Conclusions: Compared to published literature, patients and parents of patients overestimate the benefit of infliximab and underestimate its risks. We conclude that effective methods for communicating risks and benefits to patients need to be developed. (Inflamm Bowel Dis 2007) [source] When, in the context of drug design, can a fluorine atom successfully substitute a hydroxyl group?INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 4 2002Marcin Hoffmann Abstract In this article, we deal with the question of whether a fluorine atom can substitute a hydroxyl group in such a way that will lead to a compound showing a desired biologic activity, that is, a potential new drug. It is obvious that a fluorine atom differs from a hydroxyl group, as it cannot donate hydrogen bonds. However, it can accept them. Moreover, both fluorine and oxygen are of similar size and are the most electronegative elements. Therefore, a fluorine atom is thought to be a good substitute for a hydroxyl group. However, it was shown that for conformationally labile aliphatic compounds a replacement of a hydroxyl by a fluorine increases conformational diversity, so the fluorine-containing aliphatic molecules are present in equilibrium at room temperature as a mixture of several different conformers. In contrast, for cyclic compounds the substitution of an OH group by an F atom does not much change shape and electrostatic potential around corresponding conformers. Moreover, these compounds are present in equilibrium at room temperature in aqueous solution as a mixture of the same most favored structures. © 2002 Wiley Periodicals, Inc. Int J Quantum Chem, 2002 [source] Current therapy of HIVJOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, Issue 1 2010Anja Verena Potthoff Summary Antiretroviral therapy has improved continuously. Almost every year a new drug has been approved. Nucleoside analogs still build the backbone of antiretroviral therapy. They inhibit reverse transcriptase and thus the transcription of RNA to DNA. They are combined with non-nucleoside reverse transcriptase inhibitors or protease inhibitors. New therapeutic approaches are attachment or entry inhibitors, integrase inhibitors and maturation inhibitors. Multiple prospective multicenter studies have proven the life prolonging effect of antiretroviral therapy. With the optimal therapy life expectancy of HIV patients is only slightly reduced, similar to that of those with chronic diseases such as diabetes mellitus. One result of the higher age of HIV patients is an increase in concomitant diseases and medications. Drug interactions have to be considered and avoided. There has been a long discussion about the best time point to start antiretroviral therapy. In the late 1990s, every infected patient was treated hoping to eliminate the virus, ignoring the CD4+ cell count and viral load. This caused multiple (long-term) side effects and a rising resistance problem. The guidelines now recommend starting therapy at about 350/,l CD4 lymphocytes. Due to its complexity antiretroviral therapy should be initiated and monitored in specialized centers. [source] The endocannabinoid system and rimonabant: a new drug with a novel mechanism of action involving cannabinoid CB1 receptor antagonism , or inverse agonism , as potential obesity treatment and other therapeutic useJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2007S. Xie Pharm D student Summary There is considerable evidence that the endocannabinoid (endogenous cannabinoid) system plays a significant role in appetitive drive and associated behaviours. It is therefore reasonable to hypothesize that the attenuation of the activity of this system would have therapeutic benefit in treating disorders that might have a component of excess appetitive drive or over-activity of the endocannabinoid system, such as obesity, ethanol and other drug abuse, and a variety of central nervous system and other disorders. Towards this end, antagonists of cannabinoid receptors have been designed through rational drug discovery efforts. Devoid of the abuse concerns that confound and impede the use of cannabinoid receptor agonists for legitimate medical purposes, investigation of the use of cannabinoid receptor antagonists as possible pharmacotherapeutic agents is currently being actively investigated. The compound furthest along this pathway is rimonabant, a selective CB1 (cannabinoid receptor subtype 1) antagonist, or inverse agonist, approved in the European Union and under regulatory review in the United States for the treatment of obesity. This article summarizes the basic science of the endocannabinoid system and the therapeutic potential of cannabinoid receptor antagonists, with emphasis on the treatment of obesity. [source] Synthesis of pyrazolo[1,5- a]-, 1,2,4-triazolo[1,5- a]- and imidazo[1,2- a]pyrimidines related to zaleplon, a new drug for the treatment of insomniaJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 5 2001Carlo Mustazza This paper describes the preparation of some pyrazolo[1,5- a]-, 1,2,4-triazolo[1,5- a]- and imidazo[1,2- a]-pyrimidines substituted on the pyrimidine moiety by a 4-[(N -acetyl- N -ethyl)amino]phenyl group. A new synthesis of related benzo[h]pyrazolo[1,5- a]-, benzo[h]pyrazolo[5,1- b]- and benzo[h]1,2,4-triazolo[1,5- a]-quinazolines is also reported. [source] Novel synthesis of [1- 11C], -vinyl- , -aminobutyric acid ([1,11C]GVG) for pharmacokinetic studies of addiction treatmentJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 3 2002Zongren Zhang Abstract , -Vinyl- , -aminobutyric acid (GVG, Vigabatrin®), a suicide inhibitor of GABA-transaminase (GABA-T), has been suggested as a new drug for the treatment of substance abuse. In order to better understand its pharmacokinetics and potential side effects, we have developed a radiosynthesis of carbon-11 (t1/2=20 min) labeled GVG for positron emission tomographic (PET) studies. We report here a novel synthetic strategy to prepare the precursor and to efficiently label GVG with C-11. 5-Bromo-3-(carbobenzyloxy)amino-1-pentene was synthesized in five steps from homoserine lactone, including reduction and methylenation. This was used in a one-pot, two-step radiosynthesis. Displacement of bromide with no-carrier-added [11C]cyanide followed by acid hydrolysis afforded [1- 11C]GVG with decay corrected radiochemical yields of 27±9% (n=6, not optimized) with respect to [11C]cyanide in a synthesis time of 45 min. Copyright © 2002 John Wiley & Sons, Ltd. [source] Successful treatment of an entecavir-resistant hepatitis B virus variantJOURNAL OF MEDICAL VIROLOGY, Issue 12 2007Hiromi Yatsuji Abstract Emergence of a lamivudine (LAM)-resistant hepatitis B virus (HBV) with amino acid substitutions in the YMDD motif is a well-documented problem during long-term LAM therapy. Entecavir (ETV) is a new drug approved for treatment of HBV infection with or without LAM-resistant mutants. This report describes an ETV-resistant strain of HBV, which emerged after prolonged ETV therapy in a patient who did not respond to LAM therapy. Direct sequence analysis of the ETV-resistant strain showed appearance of amino acid substitution rtS202G in the reverse transcriptase (RT) domain, together with rtL180M,+,M204V substitution that had developed at the emergence of LAM-resistant mutant. In vitro analysis demonstrated that the rtL180M,+,M204V,+,S202G mutant strain displayed a 200-fold and a 5-fold reduction in susceptibility to ETV compared with the wild- type and the rtL180M,+,M204V mutant strain, respectively. Adefovir was effective against the ETV-resistant strain both in vitro and during the clinical course. In conclusion, this study showed that virological and biochemical breakthrough due to ETV could occur in patients infected with LAM-resistant HBV and confirmed that the addition of rtS202G substitution to the rtL180M,+,M204V mutant strain is responsible for ETV resistance and we could treat the resistant mutant successfully. J. Med. Virol. 79:1811,1817, 2007. © 2007 Wiley-Liss, Inc. [source] Selective inhibition of Porphyromonas gingivalis growth by a factor Xa inhibitor, DX-9065aJOURNAL OF PERIODONTAL RESEARCH, Issue 3 2006Kenji Matsushita Background:,Porphyromonas gingivalis is a causative bacterium of adult periodontitis. However, there is no drug specific for P. gingivalis and for its virulence factor. Objectives:, The objective of this study was to examine the effects of a new selective inhibitor of activated factor X, DX-9065a, on growth of Porphyromonas gingivalis and other periodontopathic bacteria. Methods:, We incubated P. gingivalis and other periodontopathic bacteria in the presence or absence of DX-9065a and examined the effect of DX-9065a on bacterial growth and trypsin-like activity in its cultures. We also examined the effects of DX9065a on amidolytic activity of purified trypsin-like proteinases (gingipains RgpA and RgpB), from P. gingivalis and on trypsin-like activity in gingival crevicular fluids from patients with adult periodontitis. Results:, DX-9065a selectively inhibited the growth of P. gingivalis and Prevotella intermedia, and its effect on P. gingivalis was bactericidal. Trypsin-like proteinase activity was detected in P. gingivalis, and the activity was strongly inhibited by DX-9065a. DX-9065a even inhibited amidolytic activity of RgpA and RgpB from P. gingivalis. Furthermore, trypsin-like proteinase activity in gingival crevicular fluids was strongly inhibited by DX-9065a. Conclusions:, DX-9065a inhibits P. gingivalis growth in part through to its ability to inhibit the trypsin-like proteinase activity in P. gingivalis and may be useful for a new drug for treatment of adult periodontitis. [source] Biomarkers in drug development: friend or foe?PHARMACEUTICAL STATISTICS: THE JOURNAL OF APPLIED STATISTICS IN THE PHARMACEUTICAL INDUSTRY, Issue 4 2007A personal reflection gained working within oncology Abstract Hopes and expectations for the use and utility of new, emerging biomarkers in drug development have probably never been higher, especially in oncology. Biomarkers are exalted as vital patient selection tools in an effort to target those most likely to benefit from a new drug, and so to reduce development costs, lessen risk and expedite developments times. It is further hoped that biomarkers can be used as surrogate endpoints for clinical outcomes, to demonstrate effectiveness and, ultimately, to support drug approval. However, I perceive that all is not straightforward, and, particularly in terms of the promise of accelerated drug development, biomarker strategies may not in all cases deliver the advances and advantages hoped for. Copyright © 2007 John Wiley & Sons, Ltd. [source] Short-term reactogenicity and gender effect of anthrax vaccine: analysis of a 1967,1972 study and review of the 1955,2005 medical literature,,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 3 2007Michael M. McNeil MD Abstract Purpose In the 1960s, the Centers for Disease Control and Prevention (CDC) held the investigational new drug (IND) application for the anthrax vaccine and collected short-term safety data from approximately 16,000 doses administered to almost 7000 individuals. While some recent anthrax vaccine safety studies have suggested that women experience more injection site reactions (ISRs), to our knowledge the IND safety data were not previously examined for a gender-specific difference. Methods We identified and analyzed a subset of the IND study data representing a total of 1749 persons who received 3592 doses from 1967 to 1972. Original data collection forms were located and information extracted, including: vaccine recipient's name, age at vaccination, gender, dose number, date of vaccination, lot number, grading of ISR, presence and type of systemic reactions. Overall and gender-specific rates for adverse reactions to anthrax vaccine were calculated and we performed a multivariable analysis. Results We found an ISR was associated with 28% of anthrax vaccine doses; however, 87% of these were considered mild. Systemic reactions were uncommon (<1%) and most (70%) accompanied an ISR. Our dose-specific analysis by gender found women had at least twice the risk of having a vaccine reaction compared to men. Our age-adjusted relative risk for ISR in women compared to men was 2.78 (95%CI: 2.29, 3.38). Conclusions Our results for both overall and gender-specific reactogenicity are consistent with other anthrax safety studies. To date, possible implications of these gender differences observed for anthrax and other vaccines are unknown and deserve further study. Copyright © 2007 John Wiley & Sons, Ltd. [source] A glimpse into the clinical proteome of human malaria parasites Plasmodium falciparum and Plasmodium vivaxPROTEOMICS - CLINICAL APPLICATIONS, Issue 11 2009Pragyan Acharya Abstract Malaria causes a worldwide annual mortality of about a million people. Rapidly evolving drug-resistant species of the parasite have created a pressing need for the identification of new drug targets and vaccine candidates. By developing fractionation protocols to enrich parasites from low-parasitemia patient samples, we have carried out the first ever proteomics analysis of clinical isolates of early stages of Plasmodium falciparum (Pf) and P. vivax. Patient-derived malarial parasites were directly processed and analyzed using shotgun proteomics approach using high-sensitivity MS for protein identification. Our study revealed about 100 parasite-coded gene products that included many known drug targets such as Pf hypoxanthine guanine phosphoribosyl transferase, Pf L -lactate dehydrogenase, and Plasmepsins. In addition, our study reports the expression of several parasite proteins in clinical ring stages that have never been reported in the ring stages of the laboratory-cultivated parasite strain. This proof-of-principle study represents a noteworthy step forward in our understanding of pathways elaborated by the parasite within the malaria patient and will pave the way towards identification of new drug and vaccine targets that can aid malaria therapy. [source] Hereditary inclusion body myopathy: single patient response to GNE gene Lipoplex therapyTHE JOURNAL OF GENE MEDICINE, Issue 5 2010Gregory Nemunaitis Abstract Background Hereditary inclusion body myopathy (HIBM) is an autosomal recessive adult onset myopathy. It is characterized by mutations of the GNE (UDP- N -acetylglucosamine 2-epimerase/N -acetylmannosamine kinase) gene. Afflicted patients have no therapeutic options. In preclinical testing, we have previously demonstrated the ability to correct GNE gene function and the safety of delivery of wild type GNE gene using a liposomal delivery vehicle. Methods A single patient (subject #001) with severe HIBM treated by compassionate investigational new drug received four doses of GNE gene Lipoplex via intramuscular injection. GNE transgene expression, downstream induction of sialic acid, safety and muscle function were evaluated. Results Significant durable improvement in locoregional skeletal muscle function was observed in the injected left extensor carpi radialis longus of #001 in correlation with GNE transgene upregulation and local induction of sialic acid. Other than transient low grade fever and pain at the injection site, no significant toxicity was observed. Conclusions Proof of principle for manufacturing of ,clinical grade' GNE gene Lipoplex, clinical safety and activity are demonstrated with GNE gene Lipoplex. Further assessment will involve intravenous administration and subsequent phase I trial involving additional but less severely afflicted HIBM patients. Copyright © 2010 John Wiley & Sons, Ltd. [source] Cyclodextrins and the emergence of sugammadexANAESTHESIA, Issue 2009L. H. D. J. Booij Summary Residual paralysis, with its subsequent postoperative pulmonary sequelae, is one of the major complications of anaesthesia, and was recognised shortly after the introduction of neuromuscular blocking drugs into routine clinical practice. Although its incidence decreased with the introduction of intermediate duration drugs, and further diminished with routine neuromuscular monitoring and reversal with cholinesterase inhibitors, residual paralysis still remained a problem. In the search for alternatives to stop the effect of neuromuscular blocking drugs and to match their duration of action to clinical need, chelation of the non-depolarising neuromuscular blocking drugs was considered. It was recognised that cyclodextrins could encapsulate steroidal molecules and thereby inactivate the aminosteroidal neuromuscular blocking drugs. In order to improve the binding of rocuronium to the cyclodextrin and to increase the compound's water solubility, the molecule was modified. This led to the development of sugammadex (Org 25969), a modified ,-cyclodextrin. The modification of the molecule and the initial in vitro studies that led to in vivo and later human studies of this conceptually new drug for anaesthesia are described. [source] Antimicrotubular and cytotoxic activity of geiparvarin analogues, alone and in combination with paclitaxelCELL BIOCHEMISTRY AND FUNCTION, Issue 3 2001Antonella Miglietta Abstract Geiparvarin is an antiproliferative compound isolated from the leaves of Geijera parviflora, and may represent a new drug which targets tubulin. To better explore the potential use of this agent, we investigated the antimicrotubular and cytotoxic effects of new synthetic aromatic derivatives of geiparvarin. These drugs inhibited polymerization of microtubular protein, particularly when the assembly was induced by paclitaxel. The microtubular network organization of fibroblasts was altered more effectively by some drugs. Normal microtubule architecture completely disappeared when the cells were treated simultaneously with drugs and paclitaxel: microtubules depolymerized or were reorganized into bundles, in a similar but more disarrayed fashion than that observed after treatment with paclitaxel alone. Cytotoxicity studies showed a dose-dependent effect, whereas combined administration of drugs and paclitaxel increased cytotoxicity, more effectively in paclitaxel versus derivatives administration alone. Copyright © 2001 John Wiley & Sons, Ltd. [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. Ståhl 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] Investigational New Drug-Directed Toxicology and Pharmacokinetic Study of 4-[3-(2-Nitro-1-Imidazolyl)-Propylamino]-7-Chloroquinoline Hydrochloride (NLCQ-1, NSC 709257) in Beagle DogsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 6 2010Maria V. Papadopoulou The present study is one of several pre-clinical toxicology studies conducted in support of an ,investigational new drug' (IND) application to test this agent as an adjuvant to radio/chemotherapy for the treatment of cancer in humans. Twenty-four dogs were each assigned to one vehicle control group or to one of three test article-treated groups (three dogs/sex/treatment group). Intravenous (i.v.) doses of 0, 2.74, 5.48 and 10.95 mg/kg/day (54.8, 109.6 or 219 mg/m2/day) were administered on a per day × 5 days (qd × 5) schedule. NLCQ-1 was formulated as a solution in sterile saline at 1.5 mg/ml. None of the dogs died during this 33-day study. With few exceptions, most of the clinical signs of toxicity were noted within 2 hr following dosing in the 10.95 mg/kg/day dose group. These observations included aggressive behaviour, ataxia, tachypnea, emesis, hypoactivity, excessive salivation, tremors, and involuntary urination and defecation. Aggressive behaviour was judged to be dose-limiting. No clinical signs of toxicity were noted during the 28-day observation period that followed the 5-day dose period. Findings in a functional observation battery examination were consistent with the clinical observations. No drug-related effects were noted on the body weight or food consumption values, and no drug-related changes were noted during ocular examinations made on these animals prior to scheduled necropsy or during examination of electrocardiogram recordings made at 15 min. and 2 hr after dosing on days 1 and 5. No definitive changes in haematology, clinical chemistry or coagulation values were noted in dogs treated with NLCQ-1. NLCQ-1 was detected in the plasma of treated dogs on days 1 and 5, up to 60 min. after dosing (2.74 and 5.48 mg/kg/day) and up to 8 hr after dosing (10.95 mg/kg/day). There was a dose-related increase in maximum plasma concentration of NLCQ-1 at 5 min. after dosing; comparable concentrations were noted on days 1 and 5. No definitive test article-related lesions were noted during microscopic evaluation of tissues from dogs in this study, although lesions noted at the injection site and in the vascular tissue, lungs, thymus, prostate gland, muscle, adrenal cortex and tongue may have resulted from treatment with this drug. Any drug-related toxicity noted was readily reversible and not cumulative. No sex difference was detected in the susceptibility to NLCQ-1-induced toxicity. [source] Double-stranded RNA-mediated gene silencing of cysteine proteases (falcipain-1 and -2) of Plasmodium falciparumMOLECULAR MICROBIOLOGY, Issue 5 2002Pawan Malhotra Summary Malaria remains a public health problem of enormous magnitude, affecting over 500 million people every year. Lack of success in the past in the development of new drug/vaccines has mainly been attributed to poor understanding of the functions of different parasite proteins. Recently, RNA interference (RNAi) has emerged as a simple and incisive technique to study gene functions in a variety of organisms. In this study, we report the results of RNAi by double-stranded RNA of cysteine protease genes (falcipain -1 and -2) in the malaria parasite, Plasmodium falciparum. Using RNAi directed towards falcipain genes, we demonstrate that blocking the expression of these genes results in severe morphological abnormalities in parasites, inhibition of parasite growth in vitro and substantial accumulation of haemoglobin in the parasite. The inhibitory effects produced by falcipain double-stranded (ds)RNAs are reminiscent of the effects observed upon administering E-64, a cysteine protease inhibitor. The parasites treated with falcipain's dsRNAs also show marked reduction in the levels of corresponding endogenous falcipain mRNAs. We also demonstrate that dsRNAs of falcipains are broken into short interference RNAs , 25 nucleotides in size, a characteristic of RNAi, which in turn activates sequence-specific nuclease activity in the malaria parasites. These results thus provide more evidence for the existence of RNAi in P. falciparum and also suggest possibilities for using RNAi as an effective tool to determine the functions of the genes identified from the P. falciparum genome sequencing project. [source] Follow-Up of 1 mg Finasteride Treatment of Male Pattern Baldness,Difference between Clinical Trials and Private Office Follow-Up: Influences on Prescribing Habits EvaluatedDERMATOLOGIC SURGERY, Issue 5 2004Marvin J. Rapaport MD Background. Finasteride (Propecia) was approved by the FDA in 1998 for treating men with androgenetic alopecia. The published clinical trials demonstrated statistical differences between drug and placebo. Rarely do new drugs undergo further non-drug-company-sponsored studies of efficacy. Concerns about clinical studies and marketing of drugs prompted this evaluation of a large group of patients taking this medication. Objective. Finasteride usage offered an opportunity not only to understand the acceptance of a cosmetically oriented medication, but also to evaluate subjective comments and compliance after a long period of time. Methods. A total of 1261 patients were monitored with phone calls every 3 months after finasteride was initially prescribed. After 12 months, a detailed questionnaire was sent to all patients with an additional letter and two telephone calls if no response was received. Statistical analysis of the patients' data was made. Results. Thirty-two percent or 414 men continued to take finasteride daily for 1 to 3 years. Twenty-four percent or 297 men discontinued the drug between 3 and 15 months owing to poor results. The remaining 44% or 549 men were lost to follow-up despite numerous attempts to contact them. Conclusion. A total of 414 men continued to take the medication, but only 211 returned detailed questionnaires. A small percentage of this group felt that they grew hair. The remaining patients noted poor results. [source] | |||||||||||||||||||||||||||||||||||||||||||