Home About us Contact
|
Home About us Contact | ||
|
|
||
US Food (us + food)
Selected AbstractsPopulation-based case,control study of oral ketoconazole treatment for birth outcomesCONGENITAL ANOMALIES, Issue 1 2005Zoltán Kazy ABSTRACT The objective of the study presented here was to check the effect of oral ketoconazole treatment on fetal development. Ketoconazole has been given a teratogenic classification of C by the US Food and Drug Administration, but human controlled epidemiological studies of the treatment's effects have not been reported. The occurrence of ketoconazole use in the second to third months of gestation was compared between cases with congenital abnormalities and their matched controls in the large population-based data set of the Hungarian Case,Control Surveillance of Congenital Abnormalities, 1980,1996. Birth weight and gestational age were evaluated in control newborn infants born to mothers with or without ketoconazole treatment. The case group comprised 22 843 cases with congenital abnormalities, while the control group contained 38 151 newborn infants without any defects. Six infants (0.03%) and 12 controls (0.03%) had mothers who had received oral ketoconazole treatment (prevalence odds ratio: with 95% confidence interval: 0.8, 0.3,2.2). No group of infants with congenital abnormalities had mothers with a higher incidence of use of the drug. The mean gestational age was somewhat longer while birth weight was somewhat larger in controls with ketoconazole treated mothers. Our study failed to demonstrate a higher rate of congenital abnormalities in infants with mothers who had received oral ketoconazole treatment during pregnancy. [source] A Comparison of Two Botulinum Type A Toxin Preparations for the Treatment of Glabellar Lines: Double-Blind, Randomized, Pilot StudyDERMATOLOGIC SURGERY, Issue 12 2005Philippa L. Lowe MB ChB Background. Botulinum toxins have been proven effective for reducing facial lines. There are two commercial types of botulinum toxin type A available in many countries but no published comparison studies. Objective. To compare the efficacy and tolerability of Botox Cosmetic and Dysport 50 U in the treatment of glabellar lines (using 20 U of Botox Cosmetic, which is the dose approved by the US Food and Drug Administration for the treatment of glabellar lines, and 50 U of Dysport, which has been reported to be the optimal dose for this formulation). Study Design. Parallel-group double-blind pilot study. Evaluation by observing physician, photographic, and patient evaluations. Conclusion. Botox 20 U provided better and more prolonged efficacy than Dysport 50 U in the treatment of glabellar lines. NICHOLAS LOWE, MD, FRCP, AND RICKIE PATNAIK, MD, HAVE RECEIVED RESEARCH GRANTS FROM ALLERGAN INC. NICHOLAS LOWE OWNS STOCK IN ALLERGAN INC AND HAS RECEIVED CONSULTING PAYMENTS AND EDUCATIONAL GRANTS FROM ALLERGAN INC. THIS STUDY WAS FUNDED BY A GRANT FROM ALLERGAN INC. [source] REVIEW: Developing human laboratory models of smoking lapse behavior for medication screeningADDICTION BIOLOGY, Issue 1 2009Sherry A. McKee ABSTRACT Use of human laboratory analogues of smoking behavior can provide an efficient, cost-effective mechanistic evaluation of a medication signal on smoking behavior, with the result of facilitating translational work in medications development. Although a number of human laboratory models exist to investigate various aspects of smoking behavior and nicotine dependence phenomena, none have yet modeled smoking lapse behavior. The first instance of smoking during a quit attempt (i.e. smoking lapse) is highly predictive of relapse and represents an important target for medications development. Focusing on an abstinence outcome is critical for medication screening as the US Food and Drug Administration approval for cessation medications is contingent on demonstrating effects on smoking abstinence. This paper outlines a three-stage process for the development of a smoking lapse model for the purpose of medication screening. The smoking lapse paradigm models two critical features of lapse behavior: the ability to resist the first cigarette and subsequent ad libitum smoking. Within the context of the model, smokers are first exposed to known precipitants of smoking relapse (e.g. nicotine deprivation, alcohol, stress), and then presented their preferred brand of cigarettes. Their ability to resist smoking is then modeled and once smokers ,give in' and decide to smoke, they participate in a tobacco self-administration session. Ongoing and completed work developing and validating these models for the purpose of medication screening is discussed. [source] Use of ristocetin cofactor activity in the management of von Willebrand diseaseHAEMOPHILIA, Issue 2001B.M. Ewenstein von Willebrand disease (vWD), the most common of the hereditary bleeding disorders, arises from quantitative or qualitative defects in von Willebrand factor (vWF). vWF is a multimeric plasma protein that plays a key role in primary and secondary haemostasis. In the current classification scheme, vWD is divided into six subtypes that are based on the nature of the vWF defect. Therapeutic strategies depend on the accurate identification of these subtypes. In most clinical situations, desmopressin is effective treatment for the great majority of patients with mild (type 1) disease, while replacement therapy with factor VIII/vWF concentrates that contain high levels of vWF activity is required for most type 2 and nearly all type 3 vWD patients. Several factor VIII/vWF replacement products are available, one of which (Humate P) has been approved for the treatment of vWD by the US Food and Drug Administration. Preliminary results of recent studies support the hypothesis that treatment with factor VIII/vWF concentrates based upon the content of vWF activity as reflected in the ristocetin cofactor assay is practicable, safe and efficacious. The establishment of optimal treatment regimens with respect to dose intensity and duration will require further study. [source] Neuromodulators for Migraine PreventionHEADACHE, Issue 4 2008Robert Kaniecki MD Migraine is a debilitating condition characterized by a cycle of painful headaches and headache-related symptoms interspersed with periods of worry, distress, and apprehension. The negative impact of migraine on patient functioning, workplace productivity, and other daily activities has been demonstrated through the use of a variety of clinician- and patient-reported assessment tools, including the Migraine-Specific Questionnaire and the Migraine Disability Assessment questionnaire. In addition to considering the frequency and severity of migraine, clinicians need to encourage more open dialogue with their patients about the impact of this disorder on daily activities and productivity. Only then can the most appropriate course of treatment be determined. Appropriately prescribed acute and preventive therapies should break the cycle of migraine and improve the daily activities of patients with this chronic condition. Divalproex sodium and topiramate are neuromodulators that are approved by the US Food and Drug Administration (FDA) for the prophylaxis (prevention) of migraine headache in adults. Non-FDA-approved neuromodulators sometimes used in the management of migraine headache include gabapentin, lamotrigine, levetiracetam, and zonisamide. All medications need to be titrated, and treatment-related adverse events need to be managed appropriately. Preventive medications should be taken for at least 2-3 months to ascertain their therapeutic effect. [source] Cutting through the statistical fog: understanding and evaluating non-inferiority trialsINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 10 2010W. S. Weintraub Summary Every year, results from many important randomised, controlled trials are published. Knowing the elements of trial design and having the skills to critically read and incorporate results are important to medical practitioners. The goal of this article is to help physicians determine the validity of trial conclusions to improve patient care through more informed medical decision making. This article includes a review of 162 randomised, controlled non-inferiority (n = 116) and equivalence (n = 46) hypothesis studies as well as the larger Stroke Prevention using Oral Thrombin Inhibitor in atrial Fibrillation V study and the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial. Evaluation of data from small and large trials uncovers significant flaws in design and models employed and uncertainty about calculations of statistical measures. As one example of questionable study design, discussion includes a large (n = 3922), double-blind, randomised, multicentre trial comparing the efficacy of ximelagatran with warfarin for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and additional stroke risk factors. Investigators concluded that ximelagatran was effective compared with well-controlled warfarin for prevention of thromboembolism. However, deficiencies in design, as well as concerns about liver toxicity, resulted in the rejection of the drug by the US Food and Drug Administration. Many trials fail to follow good design principles, resulting in conclusions of questionable validity. Well-designed non-inferiority trials can provide valuable data and demonstrate efficacy for beneficial new therapies. Objectives and primary end-points must be clearly stated and rigorous standards met for sample size, establishing the margin, patient characteristics and adherence to protocol. [source] Update in the pharmaceutical therapy of the irritable bowel syndromeINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 4 2004F. Thielecke Summary The therapeutic management of the irritable bowel syndrome (IBS) is ineffective and not satisfying either patients or practitioners. Research in functions of the enteric nervous system and its interaction with the central nervous system is the basis for the development of emerging pharmaceuticals in therapy of the IBS. These pharmaceuticals include agents such as opioid agonists, psychotropic agents and particularly serotonin receptor modulators. These novel pharmaceuticals aim to provide a more comprehensive approach in the therapy of the IBS and will serve both patients and practitioners. So far, the US Food and Drug Administration has approved two agents specifically for the treatment of the IBS, both belonging to the group of serotonin receptor modulators. However, questions remain whether a single therapy is sufficient in the management of IBS because this disease is influenced by biological and psychological as well as cultural and social factors. [source] Ticlopidine quantification in human plasma by high-performance liquid chromatography coupled to electrospray tandem mass spectrometry.JOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 12 2004Application to bioequivalence study Abstract A rapid, sensitive and specific method to quantify ticlopidine in human plasma using clopidogrel as the internal standard (IS) is described. The analyte and the IS were extracted from acidified plasma by liquid,liquid extraction using diethyl ether,hexane (80 : 20, v/v). The extracts were analyzed by high-performance liquid chromatography coupled to electrospray tandem mass spectrometry (HPLC/MS/MS). Chromatography was performed isocratically on a Jones Genesis C8 4 µm analytical column (150 × 4.1 mm i.d.). The method had a chromatographic run time of 3.0 min and a linear calibration curve over the range 1.0,1000 ng ml,1 (r2 > 0.999427). The limit of quantification was 1.0 ng ml,1. This HPLC/MS/MS procedure was used to assess the bioequivalence of two ticlopidine 250 mg tablet formulations (ticlopidine test formulation from Apotex do Brasil, Brazil, and Ticlid from Sanofi-Synthelabo, standard reference formulation). A single 250 mg dose of each formulation was administered to healthy volunteers. The study was conducted using an open, randomized, two-period crossover design with a 2 week washout interval. Since the 90% confidence interval for Cmax and area under the curve ratios were all inside the 80,125% interval proposed by the US Food and Drug Administration, it was concluded that ticlopidine formulation from Apotex do Brasil is bioequivalent to Ticlid formulation with respect to both the rate and the extent of absorption. Copyright © 2004 John Wiley & Sons, Ltd. [source] The pharmacology and epidemiology of post-market surveillance for suicide: the case of gabapentinJOURNAL OF PHARMACEUTICAL HEALTH SERVICES RESEARCH, Issue 2 2010Jill E. Lavigne Abstract Objectives, To describe the challenges in measurement of suicidal thoughts and behaviours and any causal relationship to prescription drug exposures. Recent US Food and Drug Administration (FDA) investigations of potential provocation of suicidal ideation and behaviour have led to black-box warnings of suicidal thoughts and behaviour on drugs ranging from smoking cessation to urinary incontinence agents. We describe the challenges faced in studying the effects of specific drug exposures on suicidal thoughts and behaviours using gabapentin (Neurontin) as an example because it has been implicated by the FDA as a drug that may induce suicidal thoughts or behaviours, offers more than 20 diverse indications including several known to be associated with an increase in suicide risk, and derives its clinical effect from 2 divergent mechanisms. Key findings, Gabapentin has two primary mechanisms: GABAergic neurotransmission and interruption of sodium and calcium channels. An increase in GABAergic neurotransmission is expected to improve anxiety and essential tremor, but to have no effect on pain, specifically migraine and neuropathic pain. Improvements in pain after gabapentin exposure are likely the result of the interruption of calcium and sodium channels. Neither mechanism is expected to affect bipolar disorder or schizophrenia, serious mental illnesses associated with a risk of suicide. Conclusions, These two independent mechanisms are expected to have mutually exclusive effects on a wide range of indications, only some of which are associated with increased risk of suicide. This very complexity and heterogeneity may present fertile ground for research aimed at not only improving our understanding of drug action, but also at expanding our knowledge of suicidal thoughts and behaviours. [source] In situ chemical analysis of modern organic tattooing inks and pigments by micro-Raman spectroscopyJOURNAL OF RAMAN SPECTROSCOPY, Issue 9 2008Kelvin W. C. Poon Abstract The chemical composition of tattooing pigments has varied greatly over time according to available technologies and materials. Beginning with naturally derived plant and animal extracts, to coloured inorganic oxides and salts, through to the modern industrial organic pigments favoured in today's tattooing studios. The demand for tattooing is steadily growing as it gains cultural popularity and acceptance in today's society, but ironically, increasing numbers of individuals are seeking laser removal of their tattoos for a variety of reasons. Organic pigments are favoured for tattooing because of their high tinting strength, light fastness, enzymatic resistance, dispersion and relatively inexpensive production costs. Adverse reactions have been reported for some organic inks, as well as potential complications, during laser removal procedures stemming from the unintentional creation of toxic by-products. Currently, regulatory bodies such as the US Food and Drug Administration have not approved any coloured inks to be injected into the skin, and tattoo ink manufacturers often do not disclose the ingredients in their products to maintain proprietary knowledge of their creations. A methodology was established using micro-Raman spectroscopy on an animal model to correctly identify the constituents of a selection of modern, organic tattoo inks in situ or post procedure, within the skin. This may serve as a preliminary tool prior to engaging in Q-switched laser removals to assess the risks of producing potentially hazardous compounds. Likewise, the pigments responsible for causing adverse reactions in some patients may be quickly identified to hasten any corresponding treatment. Copyright © 2008 John Wiley & Sons, Ltd. [source] Automated determination of venlafaxine in human plasma by on-line SPE-LC-MS/MS.JOURNAL OF SEPARATION SCIENCE, JSS, Issue 4 2009Application to a bioequivalence study Abstract A new automated SPE-LC-ESI-MS/MS method was developed and validated to quantify venlafaxine in human plasma using fluoxetine as an internal standard. The analytes were automatically extracted from plasma by C18 SPE cartridges, separated on a C8 RP column and analyzed by MS in the multiple reaction-monitoring (MRM) mode. The method has a chromatographic run time of 4.0 min and a linear calibration curve over the range of 0.25,200 ng/mL (r >0.997). The between-run precisions, based on the percent RSD for replicate quality controls (0.75; 80, and 200 ng/mL), were < 8.5% for all concentrations. The between-run accuracies, based on the percent relative error, were < 4.0%. This method was successfully employed in a bioequivalence study of two venlafaxine capsule formulations (test formulation from Eurofarma (Brazil) and Efexor XR, reference formulation, from Wyeth-Whitehall, Brazil) in 48 healthy volunteers of both sexes who received a single 150 mg dose of each formulation. More than 3000 samples were analyzed eliminating the analyst's exposure to hazardous organic solvents normally employed in off-line liquid,liquid extractions. The 90% confidence interval (CI) of the individual ratio geometric mean for Test/Reference was 91.6,103.4% for AUC0,48 h and 102.2,112.6% for Cmax. Since both 90% CI for AUC0,48 h and Cmax were included in the 80,125% interval proposed by the US Food and Drug Administration (FDA) and the Brazilian National Health Surveillance Agency (ANVISA), the test formulation was considered bioequivalent to Efexor XR according to both the rate and extent of absorption. [source] Enantioselective HPLC resolution of synthetic intermediates of armodafinil and related substancesJOURNAL OF SEPARATION SCIENCE, JSS, Issue 6-7 2008Ramisetti Nageswara Rao Abstract Armodafinil is a unique psychostimulant recently approved by the US Food and Drug Administration for the treatment of narcolepsy. The chromatographic resolution of its chiral intermediates including related substances in the total synthesis of armodafinil was studied on polysaccharide-based stationary phases, viz. cellulose tris-(3,5-dimethylphenylcarbamate) (Chiralcel OD-H) and amylose tris-(3,5-dimethylphenylcarbamate) (Chiralpak AD-H) by HPLC. The effects of 1-propanol, 2-propanol, ethanol, and trifluoroacetic acid added to the mobile phase and of column temperature on resolution were studied. A good separation was achieved on cellulose-based Chiralcel OD-H column compared to amylose-based Chiralpak AD-H. The effects of structural features of the solutes and solvents on discrimination between the enantiomers were examined. Baseline separation with Rs >1.38 was obtained using a mobile phase containing n -hexane,ethanol,TFA (75:25:0.15 v/v/v). Detection was carried out at 225 nm with photodiode array detector while identification of enantiomers was accomplished by a polarimetric detector connected in series. The method was found to be suitable not only for process development of armodafinil but also for determination of the enantiomeric purity of bulk drugs and pharmaceuticals. [source] Skin bleaching: highlighting the misuse of cutaneous depigmenting agentsJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 7 2009OE Dadzie Abstract Hydroquinone and other cutaneous depigmenting agents are widely used by dermatologists to treat pigmentary disorders. On 29 August 2006, the US Food and Drug Administration (FDA) published a monograph in the US Federal Register proposing to ban all hydroquinone products that have not been approved via a New Drug Application process. Reports in the scientific literature on the occurrence of exogenous ochronosis, in relation to the use of hydroquinone, was one of the concerns expressed by the FDA in relation to this agent. However, a review of the English-language scientific literature reveals that most of the reported cases of hydroquinone-induced exogenous ochronosis occurs in Africa, where the cultural practice of skin bleaching is highly prevalent. Skin bleaching is the practice of applying hydroquinone and/or other depigmenting agents to specific or widespread areas of the body, the primary function being to lighten normally dark skin. This practice typically occurs in men and women with Fitzpatrick skin phototypes IV to VI. It is a dangerous practice associated with a diverse range of side-effects, including mercury poisoning. Thus, this current discussion within the dermatological community on the safety of hydroquinone provides a unique opportunity to raise awareness about skin bleaching. [source] Comparative thrombotic event incidence after infusion of recombinant factor VIIa versus factor VIII inhibitor bypass activityJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2004L. M. Aledort Summary. Thrombosis is a rare but well-recognized potential complication of Factor VIII Inhibitor Bypass Activity (FEIBA) infusion. Recombinant factor VIIa (rFVIIa) is increasingly used as an alternative to FEIBA; however, the thrombotic safety profile of rFVIIa remains incompletely characterized. To determine the incidence rates of thrombotic adverse events (AEs) after infusion of rFVIIa and FEIBA. Data from the MedWatch pharmacovigilance program of the US Food and Drug Administration, as supplemented by published case reports, were used in conjunction with estimated numbers of infusions available from manufacturers to assess comparative incidence of thrombotic AEs in patients receiving rFVIIa or FEIBA in the period from April 1999 through June 2002. Reported thrombotic AEs were rare, with incidence rates of 24.6 per 105 infusions (CI, 19.1,31.2 per 105 infusions) for rFVIIa and 8.24 per 105 infusions (CI, 4.71,13.4 per 105 infusions) for FEIBA. Thrombotic AEs were significantly more frequent in rFVIIa than FEIBA recipients (incidence rate ratio, 2.98; CI, 1.71,5.52). The most commonly documented single type of thrombotic AE after rFVIIa infusion was cerebrovascular thrombosis, while myocardial infarction was the most frequent type in patients receiving FEIBA. Contrasting AE reporting patterns between rFVIIa and FEIBA may have contributed to the observed difference in thrombotic event incidence. Nevertheless, this comprehensive pharmacovigilance assessment does not support superior thrombotic safety of rFVIIa and suggests that thrombotic AE risk may be higher in rFVIIa than FEIBA recipients. [source] Bone morphogenetic proteins in tissue engineering: the road from laboratory to clinic, part II (BMP delivery)JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, Issue 2-3 2008P. C. Bessa Abstract Bone morphogenetic proteins (BMPs) are cytokines with a strong effect on bone and cartilage growth and with important roles during embryonic patterning and early skeletal formation. BMPs have promising potential for clinical bone and cartilage repair, working as powerful bone-inducing components in diverse tissue-engineering products. Synthetic polymers, natural origin polymers, inorganic materials and composites may be used as carriers for the delivery of BMPs. Carriers range from nanoparticles to complex three-dimensional (3D) scaffolds, membranes for tissue-guided regeneration, biomimetic surfaces and smart thermosensitive hydrogels. Current clinical uses include spinal fusion, healing of long bone defects and craniofacial and periodontal applications, amongst others. BMP-2 and BMP-7 have recently received approval by the US Food and Drug Administration (FDA) for specific clinical cases, delivered in absorbable collagen sponges. Considering the expanding number of publications in the field of BMPs, there are prospects of a brilliant future in the field of regenerative medicine of bone and cartilage with the use of BMPs. Copyright © 2008 John Wiley & Sons, Ltd. [source] Clenbuterol in the horse: urinary concentrations determined by ELISA and GC/MS after clinical dosesJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2001J. D. Harkins Clenbuterol is a ,2 agonist/antagonist bronchodilator marketed as Ventipulmin® and is the only member of this group of drugs approved by the US Food and Drug Administration (FDA) for use in horses. Clenbuterol is a class 3 drug in the Association of Racing Commissioners International (ARCI) classification system; therefore, its identification in postrace samples may lead to sanctions. Recently, the sensitivity of postrace testing for clenbuterol has been substantially increased. The objective of this study was to determine the ,detection times' for clenbuterol after administration of an oral clinical dose (0.8 g/kg, b.i.d.) of Ventipulmin syrup. Five horses received oral clenbuterol (0.8 g/kg, b.i.d.) for 10 days, and urine concentrations of clenbuterol were determined by an enhanced enzyme-linked immunoabsorbent assay (ELISA) test and gas chromatography/mass spectrometric (GC/MS) analysis by two different methods for 30 days after administration. Twenty-four hours after the last administration, urine concentrations of apparent clenbuterol, as measured by ELISA, averaged about 500 ng/mL, dropping to about 1 ng/mL by day 5 posttreatment. However, there was a later transient increase in the mean concentrations of apparent clenbuterol in urine, peaking at 7 ng/mL on day 10 postadministration. The urine samples were also analysed using mass spectral quantification of both the trimethylsilyl (TMS) and methane boronic acid (MBA) derivatives of clenbuterol. Analysis using the TMS method showed that, at 24 h after the last administration, the mean concentration of recovered clenbuterol was about 22 ng/mL. Thereafter, clenbuterol concentrations fell below the limit of detection of the TMS-method by day 5 after administration but became transiently detectable again at day 10, with a mean concentration of about 1 ng/mL. Derivatization with MBA offers significant advantages over TMS for the mass spectral detection of clenbuterol, primarily because MBA derivatization yields a high molecular weight base peak of 243 m/z, which is ideal for quantitative purposes. Therefore, mass spectral analyses of selected urine samples, including the transient peak on day 10, were repeated using MBA derivatization, and comparable results were obtained. The results show that clenbuterol was undetectable in horse urine by day 5 after administration. However, an unexpected secondary peak of clenbuterol was observed at day 10 after administration that averaged ,1 ng/mL. Because of this secondary peak, the detection time for clenbuterol (0.8 g/kg, b.i.d. × 10 days) is at least 11 days if the threshold for detection is set at 1 ng/mL. [source] Intratracheal clenbuterol in the horse: its pharmacological efficacy and analytical detectionJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2000J. D. HARKINS Clenbuterol, a ,2 agonist/antagonist, is the only bronchodilator approved by the US Food and Drug Administration for use in horses. The Association of Racing Commissioners International classifies clenbuterol as a class 3 agent, and, as such, its identification in post-race samples may lead to sanctions. Anecdotal reports suggest that clenbuterol may have been administered by intratracheal (IT) injection to obtain beneficial effects and avoid post-race detection. The objectives of this study were (1) to measure the pharmacological efficacy of IT dose of clenbuterol and (2) to determine the analytical findings in urine in the presence and absence of furosemide. When administered intratracheally (90,,g/horse) to horses suffering from chronic obstructive pulmonary disease (COPD), clenbuterol had effects that were not significantly different from those of saline. In parallel experiments using a behavior chamber, no significant effects of IT clenbuterol on heart rate or spontaneous locomotor activity were observed. Clenbuterol concentrations in the urine were also measured after IT dose in the presence and absence of furosemide. Four horses were administered i.v. furosemide (5,mg/kg), and four horses were administered saline (5,mL). Two hours later, all horses were administrated clenbuterol (IT, 90,,g), and the furosemide-treated horses received a second dose of furosemide (2.5 mg/kg, i.v.). Three hours after clenbuterol dose (1,h after hypothetical ,post-time'), the mean specific gravity of urine samples from furosemide-treated horses was 1.024, well above the 1.010 concentration at which furosemide is considered to interfere with drug detection. There was no interference by furosemide with ,enhanced' ELISA screening of clenbuterol equivalents in extracted and concentrated samples. Similarly, furosemide had no effect on mass spectral identification or quantification of clenbuterol in these samples. These results suggest that the IT dose of clenbuterol (90,,g) is, in pharmacological terms, indistinguishable from the dose of saline, and that, using extracted samples, clenbuterol dose is readily detectable at 3,h after dosing. Furthermore, concomitant dose of furosemide does not interfere with detection or confirmation of clenbuterol. [source] Surrogate endpoints and emerging surrogate endpoints for risk reduction of cardiovascular diseaseNUTRITION REVIEWS, Issue 2 2008Crystal M Rasnake This article reviews surrogate endpoints and emerging biomarkers that were discussed at the annual "Cardiovascular Biomarkers and Surrogate Endpoints" symposium cosponsored by the US Food and Drug Administration (FDA) and the Montreal Heart Institute. The FDA's Center for Food Safety and Applied Nutrition (CFSAN) uses surrogate endpoints in its scientific review of a substance/disease relationship for a health claim. CFSAN currently recognizes three validated surrogate endpoints: blood pressure, blood total cholesterol, and blood low-density lipoprotein (LDL) concentration in its review of a health claim for cardiovascular disease (CVD). Numerous potential surrogate endpoints of CVD are being evaluated as the pathophysiology of heart disease is becoming better understood. However, these emerging biomarkers need to be validated as surrogate endpoints before they are used by CFSAN in the evaluation of a CVD health claim. [source] Chromium Picolinate Intake and Risk of Type 2 Diabetes: An Evidence-Based Review by the United States Food and Drug AdministrationNUTRITION REVIEWS, Issue 8 2006Paula R. Trumbo PhD The labeling of both health claims that meet significant scientific agreement (SSA) and qualified health claims on conventional foods and dietary supplements requires pre-market approval by the US Food and Drug Administration (FDA). Approval by the FDA involves, in part, a thorough review of the scientific evidence to support an SSA or a qualified health claim. This article discusses FDA's evidence-based review of the scientific evidence on the role of chromium picolinate supplements in reducing the risk of type 2 diabetes. Based on this evidence-based review, FDA issued a letter of enforcement discretion for one qualified health claim on chromium picolinate and risk of insulin resistance, a surrogate endpoint for type 2 diabetes. The agency concluded that the relationship between chromium picolinate intake and insulin resistance is highly uncertain. SUMMARY In summary (Table 1), there was one intervention study that showed a beneficial effect of chromium picolinate intake on risk of insulin resistance. One other intervention study that provided chromium chloride showed no beneficial effect on insulin resistance. None of the five intervention studies showed a statistically significant beneficial effect of chromium picolinate on FBS and/or OGTT. Furthermore, none of the 10 intervention studies using other forms of chromium showed a beneficial effect of on FBS or OGTT in individuals with normal glucose tolerance. Based on FDA's evidence-based review, the agency concluded that there is very limited credible evidence for a qualified health claim for chromium picolinate and reduced risk of insulin resistance, and therefore reduced risk of type 2 diabetes. The findings of Cefalu et al. have not been replicated, and replication of scientific findings is important to substantiate results. For these reasons, FDA concluded that the existence of a relationship between chromium picolinate intake and reduced risk of either insulin resistance or type 2 diabetes is highly uncertain. On August 25, 2005, FDA issued a letter of enforcement discretion for the labeling of dietary supplements with the following qualified health claim: "One small study suggests that chromium picolinate may reduce the risk of insulin resistance, and therefore possibly may reduce the risk of type 2 diabetes. FDA concludes, however, that the existence of such a relationship between chromium picolinate and either insulin resistance or type 2 diabetes is highly uncertain." The agency concluded that there was no credible evidence to suggest that chromium picolinate intake may reduce the risk of elevated blood glucose levels. [source] Retailers' tagging practices: a potential liability?PACKAGING TECHNOLOGY AND SCIENCE, Issue 1 2004Laura Bix Abstract This study investigates the coverage of federally mandated information on over-the-counter (OTC) drug labels by electronic article surveillance (EAS) tags applied to the exterior of cartons. Using adult-strength analgesics containing acetaminophen as a case study, researchers investigated the issue in Houston, Texas (24 stores) and Lansing, Michigan (33 stores). The information obscured by EAS tags was identified and classified for a total of 849 packages using a standardized data collection instrument. The results indicated that 293 packages examined, or 34.5%, had information mandated by the US Food and Drug Administration (US FDA) fully or partially obscured by the EAS tags. Retailers and manufacturers should be aware of such practices to reduce potential liability. Recommendations for improving EAS tag usage on OTC products are presented. Copyright © 2004 John Wiley & Sons, Ltd. [source] Is x-height a better indicator of legibility than type size for drug labels?PACKAGING TECHNOLOGY AND SCIENCE, Issue 5 2003Laura Bix Abstract In 1999 the US Food and Drug Administration published a regulation in an attempt to ensure the legibility of OTC drugs, specifying, among other things, a minimum type size of 6 points. This is problematic because different typefaces of the same size vary widely in type heights and, presumably, legibility. We hypothesized that specifying a minimum x-height, the height of the lowercase x, would produce more consistent legibility than the minimum type size specified within the regulation. Twenty-six subjects viewed two groups of typefaces using the Lockhart Legibility Instrument to quantify legibility. The first group contained typefaces that were all 6 points, but, by nature of their design, varied greatly in their x-heights. The second group was made from the same set of typefaces, but these were manipulated so that their x-heights were equal to the average x-height of group 1. A likelihood ratio test indicated that the group that varied in x-height, group 1, produced significantly more variable results than the group with equal x-heights, group 2. This indicates that specifying a minimum type size may not be the best approach for producing consistent legibility. Copyright © 2003 John Wiley & Sons, Ltd. [source] A randomized, controlled trial of aprotinin in neonates undergoing open-heart surgeryPEDIATRIC ANESTHESIA, Issue 9 2008GLYN D. WILLIAMS MBChB Summary Background:, Neonates undergoing open-heart surgery are especially at risk for massive bleeding and pronounced inflammation. The efficacy of aprotinin, a serine protease inhibitor, at ameliorating these adverse effects of cardiopulmonary bypass has not been clearly demonstrated in neonates. Methods:, Term neonates were enrolled and randomly assigned in a blinded fashion to receive saline (group P, placebo) or high-dose aprotinin (group A). Intraoperative management was standardized: surgeon, anesthesia, cardiopulmonary bypass and hemostasis therapy. Patients were admitted postoperatively to a pediatric cardiac intensive care unit. Primary outcome measure of efficacy was duration of the postoperative mechanical ventilation. Secondary outcome measures were total volume and units of blood products transfused intraoperatively and for 24 h after surgery, duration of chest tube in situ, and intensive care and hospital stays after surgery. Results:, Twenty-six neonates were enrolled; 13 received aprotinin and 13 received placebo. The study was halted prematurely because of US Food and Drug Administation's concerns about aprotinin's safety. Baseline patient, surgery and cardiopulmonary bypass characteristics were similar between groups. No outcome variables differed between groups (P > 0.05). Duration of postoperative ventilation was 115 ± 139 h (group A); 126 ± 82 h (group P); P = 0.29, and total blood product exposure was 8.2 ± 2.6 U (group A); 8.8 ± 1.4 U (group P); P = 0.1. Postoperative blood creatinine values did not differ between groups. In-hospital mortality rate was 4%. Conclusions:, Aprotinin was not shown to be efficacious in neonates undergoing open-heart surgery. It is unclear whether adult aprotinin safety data are relevant to neonates undergoing open-heart surgery. [source] Hemostatic complications of angiogenesis inhibitors in cancer patients,AMERICAN JOURNAL OF HEMATOLOGY, Issue 11 2008Francesca Elice Tumor vasculature and tumor-associated neo-angiogenesis have recently become major targets for rational drug design of antineoplastic agents. Five such agents with angiogenesis inhibiting activity (thalidomide, lenalidomide, bevacizumab, sunitinib, sorafenib) have already obtained US Food and Drug Administration approval for clinical use and many others have entered clinical trials. Vascular complications, including venous or arterial thromboembolism and hemorrhage, have emerged as relevant toxicities in several clinical trials with angiogenesis inhibitors. Given the well-known interplay between the blood clotting system, angiogenesis, and tumor growth, a better understanding of the impact of these new drugs on overall hemostatic balance is required. In this brief overview, we discuss the incidence of hemostatic complications, the likely pathogenetic mechanisms involved, and the critical need to establish in randomized clinical trials the usefulness of thrombosis prophylaxis to prevent these complications. Careful documentation of hemostatic complications during treatment with each of the new antiangiogenic drugs is warranted. Further studies are urgently required to better define the causal association of these new agents with hemostatic complications and to establish the best prophylactic strategy. Am. J. Hematol., 2008. © 2008 Wiley-Liss, Inc. [source] Sample size for post-marketing safety studies based on historical controls,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 8 2010Yu-te Wu Abstract Purpose As part of a drug's entire life cycle, post-marketing studies are an important part in the identification of rare, serious adverse events. Recently, the US Food and Drug Administration (FDA) has begun to implement new post-marketing safety mandates as a consequence of increased emphasis on safety. The purpose of this research is to provide exact sample size formula for the proposed hybrid design, based on a two-group cohort study with incorporation of historical external data. Methods Exact sample size formula based on the Poisson distribution is developed, because the detection of rare events is our outcome of interest. Performance of exact method is compared to its approximate large-sample theory counterpart. Results The proposed hybrid design requires a smaller sample size compared to the standard, two-group prospective study design. In addition, the exact method reduces the number of subjects required in the treatment group by up to 30% compared to the approximate method for the study scenarios examined. Conclusions The proposed hybrid design satisfies the advantages and rationale of the two-group design with smaller sample sizes generally required. Copyright © 2010 John Wiley & Sons, Ltd. [source] Topical bovine thrombin: a 21-year review of topical bovine thrombin spontaneous case safety reports submitted to FDA's Adverse Event Reporting SystemPHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 2 2010John A. Clark MD Abstract Purpose To review topical bovine thrombin spontaneous adverse event (AE) reports that were forwarded to the US Food and Drug Administration's (FDA) Adverse Event Reporting System (AERS) between January 1986 and December 2006. Methods Forty-one spontaneous AE reports were summarized for reported AE profile and chronological reporting patterns. Each AE report was adjudicated by a hematologist for the topical bovine thrombin product that was given and the AE(s) that were reported. AEs were grouped as allergic, coagulopathy/bleeding, and all other AEs combined. Grouped AE serial analyses were carried out using successive 3-year time increments between 1986 (the year an AE report was first noted for a bovine thrombin product) and 2006 (the first full year that was available at the time of initiation of the data summary). Main outcome measures The primary outcome measures were every 3-year trend lines for all-AE reports, all reporters, and topical bovine thrombin brand mentions for 2 AE groups of interest (allergic events and coagulopathy/bleeding events). Results The all-AE spontaneous reporter trend showed a downward appearance for AE reporting activity that started in 1995,1998 and continued through 2004,2006. The all-AE reports trend showed two potential safety signals that could be identified serially: (1) a prominent 1989,1991 peak that was attributable to allergic events (in particular, anaphylaxis), and (2) a small 1995,2000 broad peak that was attributable in part to coagulopathy/bleeding events. Allergic events were predominantly reported with products approved prior to 1995, were not temporally associated with prior medical literature case reports, and continued to be forwarded to the FDA at low levels up to the end of this study in 2006. Coagulopathy/bleeding events were reported only with products approved prior to 1995, were temporally associated with medical literature case reports, and were not forwarded to the FDA after 2000. Conclusions Overall, spontaneous AE reporting for topical bovine thrombin occurs at very low levels, and appears to have been decreasing since 1995. The serial reporting patterns for topical bovine thrombin are best explained as a strong safety signal for allergic events with ongoing, low level reporting, and a weak safety signal for coagulopathy/bleeding events that ceased on or before 2000. Although this descriptive trend analysis cannot measure associations or causation, the coagulopathy/bleeding signal may have been prompted by multiple, antecedent published case reports. The subsequent diminishment of signal attributed to thrombin likewise may coincide with lack of such reporting in larger follow-up clinical trials or, alternatively, in the introduction and growing market share of thrombin brands of greater purity. Currently marketed topical bovine thrombin formulations are rarely volunteered as possible causes of adverse events. Copyright © 2009 John Wiley & Sons, Ltd. [source] Safety of medications prescribed before and during early pregnancy in a cohort of 81,975 mothers from the UK General Practice Research Database,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 8 2006Janet R. Hardy PhD Abstract Purpose To demonstrate a linkage methodology for mother and baby automated medical records, and describe frequency, type, and pregnancy risk level of medications prescribed during pregnancy in a GPRD cohort, 1991,1999. Methods We linked records using a two-stage algorithm and selected pairs with ,7 months prenatal records and ,2 records in baby's first year of life. Periods of interest were: 90 days prior to a woman's earliest identified pregnancy record (Period I), and this record plus 70 days (Period II, approximate early pregnancy). Medications were classified using the British National Formulary and US Food and Drug Administration Pregnancy Risk Categories. Results We achieved over 80% record linkage and defined a cohort of 81,975. Sixty-five per,cent of mothers had ,1 prescription during both periods combined. Most frequent medications in Period I were anti-bacterial, contraceptive, topical steroid, and bronchodilator. In Period II, they were folic acid, anti-bacterial, antacid, and gynecological anti-infective. In Period I, 4% were FDA category A (considered safest), 34% B, and 49% C and D combined. By Period II, prescription of category A medications increased (folic acid, iron) while other categories declined. Category X medications, with potential teratogenic risk that outweighs maternal benefit, were prescribed to 5714 (7%) women in Period I, and 501 (0.6%) women in Period II (46% progesterone). Conclusions One in every 164 women received a category X prescription in early pregnancy. The visit when pregnancy is first medically recognized represents an opportunity to review prescribed medications in light of contraindication and/or fetal risk. Copyright © 2006 John Wiley & Sons, Ltd. [source] Contribution of perospirone and risperidone to reduce delirium in senile patientsPSYCHOGERIATRICS, Issue 1 2008Michikazu USHIJIMA Abstract Background:, Serotonin,dopamine antagonists (SDAs) inhibit dopaminergic transmission in the mesolimbic system less than in the nigrostriatal dopaminergic pathway, which relates to the extrapyramidal side-effects of these drugs. The SDAs seem to have an adequate receptor binding profile for the management of the behavioral and psychiatric symptoms of dementia. However, clinicians are discouraged from prescribing SDAs for elderly patients because of an advisory statement from the US Food and Drug Administration that warns about an increased mortality rate among elderly patients treated with atypical antipsychotics. Methods:, We conducted a retrospective study involving 16 elderly patients (mean age 84.9 years; range 67,94 years) with delirium who were treated with one of two SDAs, namely perospirone (4,12 mg/day) or risperidone (1,2 mg/day). The time-course of their psychiatric symptoms was assessed using subcategories of the Delirium Rating Scale (DRS) before treatment and on Days 10 and 24 of treatment. Results:, Total DRS scores were significantly decreased from baseline in both treatment groups. Both agents led to significant improvements from baseline in psychomotor behavior and lability of mood. Of interest, perospirone decreased hallucinations and delusions and improved sleep,awake cycle disturbances compared with baseline. No serious side-effects were seen with either drug. Conclusions:, Both perospirone and risperidone are effective in the management of delirium in elderly patients. The improvement in the sleep,awake cycle with perospirone may be derived from its short pharmacological half-life. [source] Pivotal studies of orphan drugs approved for neurological diseases,ANNALS OF NEUROLOGY, Issue 2 2009Jun Mitsumoto MPH Objective To identify design elements of clinical trials leading to US Food and Drug Administration approval of drugs for neurological diseases with and without orphan indications. Methods We used publicly available information to identify approvals for drugs for neurological diseases with an orphan indication (n = 19) and compared them with recent approvals for drugs for neurological diseases without an orphan indication (n = 20). We identified "pivotal trials" from drug labels and drug approval packages, and assessed them on four elements of clinical trial design: control, blinding, randomization, and size. Results All drugs for neurological diseases (100%) approved without an orphan indication included at least two randomized, double-blind, placebo-controlled trials. In comparison, 32% of drugs with an orphan indication had at least two such trials (p < 0.001) and 74% had at least one (p = 0.02). Thirty-three pivotal trials were conducted for the 19 drugs approved with an orphan indication. Of the 33 trials, 11 (33%) did not use a placebo control, 9 (27%) were not double blind, and 4 (12%) were not randomized. Drugs approved without an orphan indication had more pivotal trials per drug (3.8 vs 1.7 trials; p < 0.001) and a larger mean trial size (506 vs 164 trial participants; p < 0.001). Interpretation The US Food and Drug Administration has approved orphan drugs for neurological diseases without randomized, doubled-blind, placebo-controlled pivotal trials. As orphan drug development grows, demand will likely increase for alternative designs for conducting adequate and well-controlled studies to demonstrate drug efficacy. Ann Neurol 2009;66:184,190 [source] A real reason for patients with pseudobulbar affect to smileANNALS OF NEUROLOGY, Issue 2 2007Howard J. Rosen MD Pseudobulbar affect (PBA) is a dramatic disorder of emotional expression and regulation characterized by uncontrollable episodes of laughing and crying that often cause embarrassment, curtailment of social activities, and reduction in quality of life. The disorder occurs in patients with brain injury caused by many types of neurological disease, including stroke, tumors, and neurodegenerative gray and white matter disorders. Although the pathophysiology is unknown, PBA may relate to release of brainstem emotional control centers from regulation by the frontal lobes. Diagnosis of PBA can be difficult and relies on careful characterization of episodes and differentiation from depression. Although there are no US Food and Drug Administration,approved treatments for PBA, several agents have been shown to be effective, including tricyclic antidepressants, selective serotonin reuptake inhibitors, and a new agent containing dextromethorphan and quinidine. The growing number of treatment options, some of great benefit to patients, highlights the importance of accurate diagnosis of this disorder. Ann Neurol 2007 [source] Tumor necrosis factor antagonist therapy and lymphoma development: Twenty-six cases reported to the Food and Drug Administration,ARTHRITIS & RHEUMATISM, Issue 12 2002S. Lori Brown PhD Objective Etanercept and infliximab are tumor necrosis factor (TNF) antagonists that have been recently approved for the treatment of rheumatoid arthritis (RA) and Crohn's disease (CD). This study was undertaken to investigate the occurrence of lymphoproliferative disorders in patients treated with these agents. Methods Relevant data in the MedWatch postmarket adverse event surveillance system run by the US Food and Drug Administration were reviewed. Results We identified 26 cases of lymphoproliferative disorders following treatment with etanercept (18 cases) or infliximab (8 cases). The majority of cases (81%) were non-Hodgkin's lymphomas. The interval between initiation of therapy with etanercept or infliximab and the development of lymphoma was very short (median 8 weeks). In 2 instances (1 infliximab, 1 etanercept), lymphoma regression was observed following discontinuation of anti-TNF treatment, in the absence of specific cytotoxic therapy directed toward the lymphoma. Conclusion Although data from a case series such as this cannot establish a clear causal relationship between exposure to these medications and the risk of lymphoproliferative disease, the known predisposition of patients with RA and CD to lymphoma, the known excess of lymphoma in other immunosuppressed populations, and the known immunosuppressive effects of the anti-TNF drugs provide a biologic basis for concern and justification for the initiation of additional epidemiologic studies to formally evaluate this possible association. [source] | |||||||||||||||||||||||||||||||