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Drug Exposure (drug + exposure)
Selected AbstractsTeratogenic Effects of Antiepileptic Drugs: Use of an International Database on Malformations and Drug Exposure (MADRE)EPILEPSIA, Issue 11 2000Carla Arpino Summary: Purpose: The study goal was to assess teratogenic effects of antiepileptic drugs (AEDs) through the use of a surveillance system (MADRE) of infants with malformations. Methods: Information on all malformed infants (1990,1996) with maternal first-trimester drug exposure was collected by the International Clearinghouse for Birth Defects and Monitoring Systems (ICBDMS). Cases were defined as infants presenting with a specific malformation, and controls were defined as infants presenting with any other birth defect. Exposure was defined by the use of AEDs during the first trimester of pregnancy. The association of AEDs with malformations was then estimated by calculating the odds ratios with 95% confidence intervals and testing their homogeneity among registries. Results: Among 8005 cases of malformations, 299 infants were exposed in utero to AEDs. Of those exposed to monotherapy, 65 were exposed to phenobarbital, 10 to methylphenobarbital, 80 to valproic acid, 46 to carbamazepine, 24 to phenytoin, and 16 to other AEDs. Associations were found for spina bifida with valproic acid. Infants exposed to phenobarbital and to methylphenobarbital showed an increased risk of oral clefts. Cardiac malformations were found to be associated with phenobarbital, methylphenobarbital, valproic acid, and carbamazepine. Hypospadias was associated with valproic acid. Porencephaly and other specified anomalies of brain, anomalies of face, coarctation of aorta, and limb reduction defects were found to be associated with valproic acid. Conclusions: Using the MADRE system, we confirmed known teratogenic effects of AEDs. We also found increased risks for malformations that had never been reported associated with AEDs or for which the association was suggested by case reports. [source] The inflammatory response in drug-induced acute urticaria: ultrastructural study of the dermal microvascular unitJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 9 2006PR Criado Abstract Background, Drug exposure is one of the main aetiologies of urticaria and represents the second most common cause in acute urticarias. Studies involving the ultrastructural aspects of urticaria are relatively rare in the literature. Most of the articles published report on skin biopsies of experimentally induced urticaria, and acute urticaria has been studied even less from a morphological point of view. Objectives, The aims of this study were to observe ultrastructural cell characteristics in five patients with drug-induced acute urticaria and possible aspects of the inflammatory skin response. Methods, Clinical manifestations, light microscopy and transmission electron microscopy were evaluated. Results, With light microscopy, a mild perivascular lymphocyte-monocyte infiltrate was observed with few neutrophils and dermal oedema in skin biopsies of five patients. With electron microscopy, a mild vascular dilatation was observed, with platelets in the lumen and several lymphocytes and dendritic cells close to the superficial dermal vessels. Some mast cells appeared normal, whereas others were granule-depleted. In some areas, mast cells, lymphocytes and satellite dendritic cells were closely associated, as well as some macrophages. A significant number of plasma cells, eosinophils and polymorphonuclear neutrophils were not observed; however, the presence of lymphocytes and macrophages was significant. The epidermis and the dermal-epidermal junction were preserved, except for a discrete oedema in keratinocytes. Conclusions, The ultrastructural aspect of drug-induced acute urticaria is similar to that observed in urticaria caused by Urtica dioica, intradermal histamine and cold urticaria. The presence of the cellular triad with mast cells, dendritic (or satellite) cells and lymphocytes suggests a functional interaction of these cells. These findings support the possible existence of mechanisms in the dermis that may participate in protective and/or injurious vasocentric immune reactions. [source] Foster mother care but not prenatal morphine exposure enhances cocaine self-administration in young adult male and female ratsDEVELOPMENTAL PSYCHOBIOLOGY, Issue 5 2007I. Vathy Abstract The present study was designed to investigate cocaine self-administration in adult male and female rats exposed prenatally to morphine. Pregnant dams were injected two times a day with either saline, analgesic doses of morphine or no drug at all (controls) on gestation Days 11,18. One day after birth, litters were cross-fostered such that control dams were paired with one another and their litters were crossed; saline- and morphine-treated dams were paired and half of each saline litter was crossed with half of each morphine litter. Thus, each mother (control, saline, and morphine) raised half of her own and half of the adopted litter. At the age of 60 days, males and females were trained first to lever press for sucrose pellets and then for cocaine. Once the lever-pressing behavior was learned and baseline level of this activity was established, animals received a cocaine (.5 mg/kg per infusion) reward for each correct response on the active lever during the next 9-day session. The data demonstrate that adult control, saline- and morphine-exposed male rats self-administer cocaine at a similar rate independent of their prenatal treatment. Adult female rats self-administer cocaine at a higher rate than male rats. Further, saline- and morphine-exposed females in diestrus self-administer more than females in proestrus phase of the estrous cycle, while control females show no such differences. In addition, fostering induces increase in cocaine self-administration in all groups of male rats regardless of prenatal drug exposure. In females, the only fostering-induced increase is in prenatally saline-exposed female rats raised by morphine-treated foster mother. Thus, our results suggest that the prenatal drug exposure does not induce changes in lever-pressing behavior for cocaine reward in adult male and female rats, but it sensitizes the animals to postnatal stimuli such as gonadal hormones and/or rearing conditions that result in increased drug self-administration. © 2007 Wiley Periodicals, Inc. Dev Psychobiol 49: 463-473, 2007. [source] Pharmacokinetics of dipeptidylpeptidase-4 inhibitorsDIABETES OBESITY & METABOLISM, Issue 8 2010A. J. Scheen Type 2 diabetes (T2DM) is a complex disease combining defects in insulin secretion and insulin action. New compounds have been developed for improving glucose-induced insulin secretion and glucose control, without inducing hypoglycaemia or weight gain. Dipeptidylpeptidase-4 (DPP-4) inhibitors are new oral glucose-lowering agents, so-called incretin enhancers, which may be used as monotherapy or in combination with other antidiabetic compounds. Sitagliptin, vildaglipin and saxagliptin are already on the market in many countries, either as single agents or in fixed-dose combined formulations with metformin. Other DPP-4 inhibitors, such as alogliptin and linagliptin, are currently in late phase of development. The present paper summarizes and compares the main pharmacokinetics (PK) properties, that is, absorption, distribution, metabolism and elimination, of these five DPP-4 inhibitors. Available data were obtained in clinical trials performed in healthy young male subjects, patients with T2DM, and patients with either renal insufficiency or hepatic impairment. PK characteristics were generally similar in young healthy subjects and in middle-aged overweight patients with diabetes. All together gliptins have a good oral bioavailability which is not significantly influenced by food intake. PK/pharmacodynamics characteristics, that is, sufficiently prolonged half-life and sustained DPP-4 enzyme inactivation, generally allow one single oral administration per day for the management of T2DM; the only exception is vildagliptin for which a twice-daily administration is recommended because of a shorter half-life. DPP-4 inhibitors are in general not substrates for cytochrome P450 (except saxagliptin that is metabolized via CYP 3A4/A5) and do not act as inducers or inhibitors of this system. Several metabolites have been documented but most of them are inactive; however, the main metabolite of saxagliptin also exerts a significant DPP-4 inhibition and is half as potent as the parent compound. Renal excretion is the most important elimination pathway, except for linagliptin whose metabolism in the liver appears to be predominant. PK properties of gliptins, combined with their good safety profile, explain why no dose adjustment is necessary in elderly patients or in patients with mild to moderate hepatic impairment. As far as patients with renal impairment are concerned, significant increases in drug exposure for sitagliptin and saxagliptin have been reported so that appropriate reductions in daily dosages are recommended according to estimated glomerular filtration rate. The PK characteristics of DPP-4 inhibitors suggest that these compounds are not exposed to a high risk of drug,drug interactions. However, the daily dose of saxagliptin should be reduced when coadministered with potent CYP 3A4 inhibitors. In conclusion, besides their pharmacodynamic properties leading to effective glucose-lowering effect without inducing hypoglycaemia or weight gain, DPP-4 inhibitors show favourable PK properties, which contribute to a good efficacy/safety ratio for the management of T2DM in clinical practice. [source] Teratogenic Effects of Antiepileptic Drugs: Use of an International Database on Malformations and Drug Exposure (MADRE)EPILEPSIA, Issue 11 2000Carla Arpino Summary: Purpose: The study goal was to assess teratogenic effects of antiepileptic drugs (AEDs) through the use of a surveillance system (MADRE) of infants with malformations. Methods: Information on all malformed infants (1990,1996) with maternal first-trimester drug exposure was collected by the International Clearinghouse for Birth Defects and Monitoring Systems (ICBDMS). Cases were defined as infants presenting with a specific malformation, and controls were defined as infants presenting with any other birth defect. Exposure was defined by the use of AEDs during the first trimester of pregnancy. The association of AEDs with malformations was then estimated by calculating the odds ratios with 95% confidence intervals and testing their homogeneity among registries. Results: Among 8005 cases of malformations, 299 infants were exposed in utero to AEDs. Of those exposed to monotherapy, 65 were exposed to phenobarbital, 10 to methylphenobarbital, 80 to valproic acid, 46 to carbamazepine, 24 to phenytoin, and 16 to other AEDs. Associations were found for spina bifida with valproic acid. Infants exposed to phenobarbital and to methylphenobarbital showed an increased risk of oral clefts. Cardiac malformations were found to be associated with phenobarbital, methylphenobarbital, valproic acid, and carbamazepine. Hypospadias was associated with valproic acid. Porencephaly and other specified anomalies of brain, anomalies of face, coarctation of aorta, and limb reduction defects were found to be associated with valproic acid. Conclusions: Using the MADRE system, we confirmed known teratogenic effects of AEDs. We also found increased risks for malformations that had never been reported associated with AEDs or for which the association was suggested by case reports. [source] Considerations when choosing oral chemotherapy: identifying and responding to patient needEUROPEAN JOURNAL OF CANCER CARE, Issue 2010S. IRSHAD mrcp, specialist registrar in medical oncology IRSHAD S. & MAISEY N. (2010) European Journal of Cancer Care19, 5,11 Considerations when choosing oral chemotherapy: identifying and responding to patient need Oral chemotherapeutics are becoming increasingly accepted for the treatment of cancers and their future has never been brighter. They offer a more convenient and less invasive therapeutic option, moving cancer treatment from a predominantly hospital-based day unit into the ambulatory setting. Oral chemotherapy has the potential to maintain patient's quality of life and avoid the complications and costs of intravenous chemotherapy. It offers sustained drug exposure by providing prolonged therapy compared with intermittent IV exposure and lends itself more easily to the delivery of combination therapy. In this article we highlight the expansion of oral chemotherapeutic drug development in cancer treatment and the challenges posed by this change in treatment delivery. [source] GENETIC STUDY: The interaction between the dopamine transporter gene and age at onset in relation to tobacco and alcohol use among 19-year-oldsADDICTION BIOLOGY, Issue 4 2009Brigitte Schmid ABSTRACT Recent evidence suggests that heterogeneity in the age at onset could explain the inconsistent findings of association studies relating the dopamine transporter (DAT1) gene with alcohol and nicotine consumption. The aim of this study was to examine interactions between two DAT1 polymorphisms and different initiation ages with regard to alcohol and tobacco consumption levels and dependence. Two hundred and ninety-one young adults (135 males, 156 females) participating in the Mannheim Study of Children at Risk were genotyped for the 40-bp variable number of tandem repeats (VNTR) and rs27072 polymorphisms of DAT1. Age at initiation was assessed at age 15 and 19 years. Information about current alcohol and tobacco consumption was obtained at age 19 years using self-report measures and structured interviews. Results suggest that age at onset of intensive consumption moderated the association of the DAT1 gene with early adult substance use and dependence, revealing a DAT1 effect only among individuals homozygous for the 10r allele of the 40-bp VNTR who had started daily smoking or being intoxicated early in life. Equally, carriers of the T allele of the rs27072 polymorphism reporting an early age at first intoxication showed higher current alcohol consumption at age 19 years. In contrast, no interaction between rs27072 and the age at first cigarette with regard to later smoking was observed. These findings provide evidence that the DAT1 gene interacts with an early heavy or regular drug exposure of the maturing adolescent brain to predict substance (ab)use in young adulthood. Further studies are required to confirm these findings. [source] Overview of adverse reactions to nefopam: an analysis of the French Pharmacovigilance databaseFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2007G. Durrieu Abstract Nefopam is widely used for the relief of moderate acute pain. Its safety profile remains to be specified. The objective of the study was to review adverse reactions to nefopam spontaneously reported to the French Pharmacovigilance system. All cases of adverse drug reactions (ADRs) associated with nefopam, registered in the French Pharmacovigilance database from January 1, 1995 to December 31, 2004, were reviewed. For each reported ADR, information about patient (age, gender, medical history), drug exposure (suspected and concomitantly used drugs), characteristics of ADRs (imputability score, time of onset, seriousness, outcome) were collected. A total of 114 ADRs with an imputability rated from ,plausible' (I2) to ,likely' (I3) and ,very likely' (I4) was analysed. The most frequent ADRs included ,expected' ADRs such as sweating, nausea, tachycardia, malaise or vomiting; 61 ADRs were ,unexpected. No overdose was reported; 26 ADRs (23%) were considered as ,serious'. Most of them were ,unexpected', including neuropsychiatric (hallucinations, convulsions) or cutaneous (pruritus, erythema, urticaria) ADRs. Six cases of anaphylactic ADRs (two angioedema and four anaphylactic shocks) were reported, all occurring shortly after use of nefopam during the post-operative period. Physicians should be aware of the possible occurrence of some serious ADRs when using nefopam such as convulsions and anaphylactic shocks, especially when the drug is used in special medical conditions, like post-operative periods. [source] Rats bred for high alcohol drinking are more sensitive to delayed and probabilistic outcomesGENES, BRAIN AND BEHAVIOR, Issue 7 2008C. J. Wilhelm Alcoholics and heavy drinkers score higher on measures of impulsivity than nonalcoholics and light drinkers. This may be because of factors that predate drug exposure (e.g. genetics). This study examined the role of genetics by comparing impulsivity measures in ethanol-naive rats selectively bred based on their high [high alcohol drinking (HAD)] or low [low alcohol drinking (LAD)] consumption of ethanol. Replicates 1 and 2 of the HAD and LAD rats, developed by the University of Indiana Alcohol Research Center, completed two different discounting tasks. Delay discounting examines sensitivity to rewards that are delayed in time and is commonly used to assess ,choice' impulsivity. Probability discounting examines sensitivity to the uncertain delivery of rewards and has been used to assess risk taking and risk assessment. High alcohol drinking rats discounted delayed and probabilistic rewards more steeply than LAD rats. Discount rates associated with probabilistic and delayed rewards were weakly correlated, while bias was strongly correlated with discount rate in both delay and probability discounting. The results suggest that selective breeding for high alcohol consumption selects for animals that are more sensitive to delayed and probabilistic outcomes. Sensitivity to delayed or probabilistic outcomes may be predictive of future drinking in genetically predisposed individuals. [source] Telithromycin-associated hepatotoxicity: Clinical spectrum and causality assessment of 42 cases,HEPATOLOGY, Issue 1 2009Allen D. Brinker Telithromycin is the first of a new class of ketolide antibiotics with increased activity against penicillin-resistant and erythromycin-resistant pneumococci. This agent received approval by the United States Food and Drug Administration (FDA) in 2004 for treatment of upper and lower respiratory infections. Following market introduction, spontaneous reports of telithromycin-associated hepatotoxicity, including frank liver failure, were received. To address these reports, an ad hoc group with expertise in spontaneous adverse events reporting and experience in evaluating drug-induced liver injury was formed, including members of the FDA, other federal agencies, and academia. The primary objective of this group was to adjudicate case reports of hepatic toxicity for causal attribution to telithromycin. After an initial screening of all cases of liver injury associated with telithromycin reported to FDA as of April 2006 by one of the authors, 42 cases were comprehensively reviewed and adjudicated. Five cases included a severe outcome of either death (n = 4) or liver transplantation (n = 1); more than half were considered highly likely or probable in their causal association with telithromycin. Typical clinical features were: short latency (median, 10 days) and abrupt onset of fever, abdominal pain, and jaundice, sometimes with the presence of ascites even in cases that resolved. Concurrence in assignment of causality increased after agreement on definitions of categories and interactive discussions. Conclusion: Telithromycin is a rare cause of drug-induced liver injury that may have a distinctive clinical signature and associated high mortality rate. Consensus for attribution of liver injury to a selected drug exposure by individual experts can be aided by careful definition of terminology and discussion. (HEPATOLOGY 2009;49:250-257.) [source] Atazanavir and lopinavir with ritonavir alone or in combination: analysis of pharmacokinetic interaction and predictors of drug exposureHIV MEDICINE, Issue 4 2008S Di Giambenedetto Objectives Studies on the pharmacokinetic interaction between atazanavir and lopinavir with ritonavir (lopinavir/ritonavir) report contradictory results. We aimed to establish the in vivo interaction between these two protease inhibitors as well as the variables influencing drug exposure. Methods Pharmacokinetic parameters were investigated in HIV-infected patients treated with atazanavir 300 mg with ritonavir 100 mg q24h (group A) or lopinavir/ritonavir 400/100 mg q12h (group B) or atazanavir 300 mg q24h with lopinavir/ritonavir 400/100 mg q12h (group C). Patients receiving other concomitant protease inhibitors or non-nucleoside reverse transcriptase inhibitors were excluded. Results In group A (n=10), mean ± standard deviation atazanavir Cmin was 390 ± 460 ng/mL, Cmax 3051 ± 1996 ng/mL and AUC24 29 913 ± 17 686 ng/mL/h. In group B (n=9), lopinavir Cmin was 7562 ± 4292 ng/mL, Cmax 12 944 ± 4838 ng/mL and AUC0,12 122 313 ± 38 225 ng/mL/h. In group C (n=7), atazanavir Cmin was 876 ± 460 ng/mL (P=0.039 vs. group A), Cmax 3421 ± 3399 ng/mL and AUC0,24 65 055 ± 49 843 ng/mL/h (two-sided P>0.05 for each comparison with group A), lopinavir Cmin was 7471 ± 3745 ng/mL, Cmax 10 143 ± 5217 ng/mL and AUC0,12 104 501 ± 43 565 ng/mL/h (P>0.05 for each comparison with group B). When analysing all the groups, including controls from routine clinical practice, higher body mass index was associated with lower atazanavir Cmin and with lower lopinavir Cmax. Atazanavir Cmin showed a correlation with total bilirubin levels. Conclusions Combination with lopinavir/ritonavir provides higher atazanavir Cmin than combination with ritonavir alone, possibly because of an effect of the additional ritonavir dose. Low BMI may be associated with higher drug exposure. [source] Vorinostat increases carboplatin and paclitaxel activity in non-small cell lung cancer cellsINTERNATIONAL JOURNAL OF CANCER, Issue 3 2010Taofeek K. Owonikoko Abstract We observed a 53% response rate in non-small cell lung cancer (NSCLC) patients treated with vorinostat plus paclitaxel/carboplatin in a Phase I trial. Studies were undertaken to investigate the mechanism (s) underlying this activity. Growth inhibition was assessed in NSCLC cells by MTT assay after 72 hr of continuous drug exposure. Vorinostat (1 ,M) inhibited growth by: 17% ± 7% in A549, 28% ± 6% in 128-88T, 39% ± 8% in Calu1 and 41% ± 7% in 201T cells. Vorinostat addition to carboplatin or paclitaxel led to significantly greater growth inhibition than chemotherapy alone in all 4 cell lines. Vorinostat (1 ,M) synergistically increased the growth inhibitory effects of carboplatin/paclitaxel in 128-88T cells. When colony formation was measured after drug withdrawal, vorinostat significantly increased the effects of carboplatin but not paclitaxel. The % colony formation was control 100%; 1 ,M vorinostat, 83% ± 10%; 5 ,M carboplatin, 41% ± 11%; carboplatin/vorinostat, 8% ± 4%; 2 nM paclitaxel, 53% ± 11%; paclitaxel/vorinostat, 46% ± 21%. In A549 and 128-88T, vorinostat potentiated carboplatin induction of gamma-H2AX (a DNA damage marker) and increased ,-tubulin acetylation (a marker for stabilized mictrotubules). In A549, combination of vorinostat with paclitaxel resulted in a synergistic increase in ,-tubulin acetylation, which reversed upon drug washout. We conclude that vorinostat interacts favorably with carboplatin and paclitaxel in NSCLC cells, which may explain the provocative response observed in our clinical trial. This likely involves a vorinostat-mediated irreversible increase in DNA damage in the case of carboplatin and a reversible increase in microtubule stability in the case of paclitaxel. [source] Potential for Alcohol and Prescription Drug Interactions in Older PeopleJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 11 2005Kristine E. Pringle PhD Objectives: To examine the patterns and prevalence of concomitant alcohol and alcohol-interactive (AI) drug use in older people. Design: Cross-sectional analysis of survey and prescription claims data. Setting: The Pennsylvania Pharmaceutical Assistance Contract for the Elderly (PA-PACE) program, a state-funded program providing prescription benefits to older people with low to moderate incomes. Participants: A total of 83,321 PA-PACE cardholders (age range 65,106) who were using any prescription medications at the time of survey completion. Measurements: All AI drugs were identified using a database of medication warning labels obtained from First DataBank. Prescription drug claims were used to characterize AI drug exposure according to therapeutic class of prescription drug use. A mail survey of PA-PACE cardholders was used to examine alcohol use, as well as sociodemographic and health factors associated with concomitant use of alcohol and AI drugs. Results: Seventy-seven percent of all prescription drug users were exposed to AI medications, with significant variation in exposure and concomitant alcohol use according to therapeutic class. Overall, 19% of AI drug users reported concomitant alcohol use, compared with 26% of non-AI drug users (P<.001). Multinomial logistic regression analyses showed that certain groups of older people, including younger older people, men, and those with higher educational levels, were at greater risk for concomitant exposure to alcohol and AI drugs. Conclusion: Many older people use alcohol in combination with AI prescription drugs. Clinicians should warn every patient who is prescribed an AI drug about alcohol,drug interactions, especially those at high risk for concomitant exposure. [source] Striatal regulation of ,FosB, FosB, and cFos during cocaine self-administration and withdrawalJOURNAL OF NEUROCHEMISTRY, Issue 1 2010Erin B. Larson J. Neurochem. (2010) 115, 112,122. Abstract Chronic drug exposure induces alterations in gene expression profiles that are thought to underlie the development of drug addiction. The present study examined regulation of the Fos-family of transcription factors, specifically cFos, FosB, and ,FosB, in striatal subregions during and after chronic intravenous cocaine administration in self-administering and yoked rats. We found that cFos, FosB, and ,FosB exhibit regionally and temporally distinct expression patterns, with greater accumulation of ,FosB protein in the nucleus accumbens (NAc) shell and core after chronic cocaine administration, whereas ,FosB increases in the caudate-putamen (CPu) remained similar with either acute or chronic administration. In contrast, tolerance developed to cocaine-induced mRNA for ,FosB in all three striatal subregions with chronic administration. Tolerance also developed to FosB expression, most notably in the NAc shell and CPu. Interestingly, tolerance to cocaine-induced cFos induction was dependent on volitional control of cocaine intake in ventral but not dorsal striatal regions, whereas regulation of FosB and ,FosB was similar in cocaine self-administering and yoked animals. Thus, ,FosB-mediated neuroadaptations in the CPu may occur earlier than previously thought with the initiation of intravenous cocaine use and, together with greater accumulation of ,FosB in the NAc, could contribute to addiction-related increases in cocaine-seeking behavior. [source] Long-lasting up-regulation of orexin receptor type 2 protein levels in the rat nucleus accumbens after chronic cocaine administrationJOURNAL OF NEUROCHEMISTRY, Issue 1 2007Guo-Chi Zhang Abstract Hypothalamic orexin (hypocretin) neurons project to the key structures of the limbic system and orexin receptors, both orexin receptor type 1 (OXR1) and type 2 (OXR2), are expressed in most limbic regions. Emerging evidence suggests that orexin is among important neurotransmitters that regulate addictive properties of drugs of abuse. In this study, we examined the effect of psychostimulant cocaine on orexin receptor protein abundance in the rat limbic system in vivo. Intermittent administration of cocaine (20 mg/kg, i.p., once daily for 5 days) caused a typical behavioral sensitization response to a challenge cocaine injection at a 14-day withdrawal period. Repeated cocaine administration at the same withdrawal time also increased OXR2 protein levels in the nucleus accumbens while repeated cocaine had no effect on OXR1 and orexin neuropeptide (both orexin-A and orexin-B) levels in this region. In contrast to the nucleus accumbens, OXR2 levels in the frontal cortex, the ventral tegmental area, the hippocampus, and the dorsal striatum (caudate putamen) were not altered by cocaine. Remarkably, the up-regulated OXR2 levels in the nucleus accumbens showed a long-lasting nature as it persisted up to 60 days after the discontinuation of repeated cocaine treatments. In contrast to chronic cocaine administration, an acute cocaine injection was insufficient to modify levels of any orexin receptor and peptide. Our data identify the up-regulation of OXR2 in the nucleus accumbens as an enduring molecular event that is correlated well with behavioral plasticity in response to chronic psychostimulant administration. This OXR2 up-regulation may reflect a key adaptation of limbic orexinergic transmission to chronic drug exposure and may thus be critical for the expression of motor plasticity. [source] Insight Into the Relationship Between Impulsivity and Substance Abuse From Studies Using Animal ModelsALCOHOLISM, Issue 8 2010Catharine A. Winstanley Drug use disorders are often accompanied by deficits in the capacity to efficiently process reward-related information and to monitor, suppress, or override reward-controlled behavior when goals are in conflict with aversive or immediate outcomes. This emerging deficit in behavioral flexibility and impulse control may be a central component of the progression to addiction, as behavior becomes increasingly driven by drugs and drug-associated cues at the expense of more advantageous activities. Understanding how neural mechanisms implicated in impulse control are affected by addictive drugs may therefore prove a useful strategy in the search for new treatment options. Animal models of impulsivity and addiction could make a significant contribution to this endeavor. Here, some of the more common behavioral paradigms used to measure different aspects of impulsivity across species are outlined, and the importance of the response to reward-paired cues in such paradigms is discussed. Naturally occurring differences in forms of impulsivity have been found to be predictive of future drug self-administration, but drug exposure can also increase impulsive responding. Such data are in keeping with the suggestion that impulsivity may contribute to multiple stages within the spiral of addiction. From a neurobiological perspective, converging evidence from rat, monkey, and human studies suggest that compromised functioning within the orbitofrontal cortex may critically contribute to the cognitive sequelae of drug abuse. Changes in gene transcription and protein expression within this region may provide insight into the mechanism underlying drug-induced cortical hypofunction, reflecting new molecular targets for the treatment of uncontrolled drug-seeking and drug-taking behavior. [source] Population pharmacokinetics of isoniazid in the treatment of Mycobacterium tuberculosis among Asian and African elephants (Elephas maximus and Loxodonta africana)JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2005J. N. MASLOW We recently described the clinical presentation and treatment of 18 elephants from six herds infected with TB. Treatment protocols and methods varied between herds to include both oral and rectal dosing using multiple drug doses and formulations. In this paper we present information regarding the pharmacokinetics (PK) of isoniazid (INH) in elephants and provide suggestions regarding initial treatment regimens. Forty-one elephants received INH daily by either oral or rectal administration with different formulations. Population PK analysis was performed using Non-linear Mixed Effect Modeling (NONMEM). Results of oral administration indicated that compared with premixed INH solution, the drug exposure was highest with a suspension prepared freshly with INH powder. When INH was concomitantly given as an admixture over food, Tmax was delayed and variability in drug absorption was significantly increased. Compared with oral administration, similar drug exposures were found when INH was dosed rectally. The data generated suggest that a starting dose of 7.5 mg/kg of INH is appropriate for initial TB treatment in elephants when premixed solution is administered directly into the oropharynx or rectal vault and 4 mg/kg are when INH is administered following immediate suspension from powdered form. [source] The identification of circular extrachromosomal DNA in the nuclear genome of Trypanosoma bruceiMOLECULAR MICROBIOLOGY, Issue 2 2003N. S. Alsford Summary Nuclear extrachromosomal DNA elements have been identified in several kinetoplastids such as Leishmania and Trypanosoma cruzi, but never in Trypanosoma brucei. They can occur naturally or arise spontaneously as the result of sublethal drug exposure of parasites. In most cases, they are represented as circular elements and are mitotically unstable. In this study we describe the presence of circular DNA in the nucleus of Trypanosoma brucei. This novel type of DNA was termed NR-element (NlaIII repeat element). In contrast to drug-induced episomes in other kinetoplastids, the T. brucei extrachromosomal NR-element is not generated by drug selection. Furthermore, the element is stable during mitosis over many generations. Restriction analysis of tagged NR-element DNA, unusual migration patterns during pulsed field gel electrophoresis (PFGE) and CsCl/ethidium bromide equilibrium centrifugation demonstrates that the NR-element represents circular DNA. Whereas it has been found in all field isolates of the parasites we analysed, it is not detectable in some laboratory strains notably the genome reference strain 927. The DNA sequence of this element is related to a 29 bp repeat present in the subtelomeric region of VSG-bearing chromosomes of T. brucei. It has been suggested that this subtelomeric region is part of a transition zone on chromosomes separating the relatively stable telomeric repeats from the recombinationaly active region downstream of VSG genes. Therefore, we discuss a functional connection between the occurrence of this circular DNA and subtelomeric recombination events in T. brucei. [source] Pharmacokinetic monitoring of intravenous cyclosporine A in pediatric stem-cell transplant recipients.PEDIATRIC TRANSPLANTATION, Issue 4 2009The trough level is not enough Abstract:, In order to monitor CsA serum levels after SCT, trough levels (C0) are widely used. The aim of this study was to estimate the population and individual PK parameters for patients receiving intravenous CsA after SCT. In 27 pediatric patients after SCT receiving CsA (3 mg/kg/day) every 12 h, a total of 289 CsA concentrations was obtained. To describe the PK parameters of CsA, a two-compartment model with first order elimination was used. Covariate analysis identified body weight, age, and the co-administration with itraconazole and tobramycine as factors influencing the Cl. The statistical comparison of AUC, trough level, and C2 indicates a correlation between AUC and C2, but no correlation between the AUC and C0, r = 0.24 (p = 0.146) vs. r = 0.526 (p = 0.000692), respectively. Our results underscore the fact that CsA trough levels do not reflect the drug exposure in patients receiving intravenous CsA after SCT. By contrast, CsA blood levels measured 2,6 h after CsA infusion showed a better correlation with the AUC. Our data provide new information to optimize the balancing act between GvHD-prophylaxis, graft vs. leukemia effect, and CsA side-effects after SCT. [source] Duration of therapy with metoclopramide: a prescription claims data study,,§PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 8 2007B Pharm, Sigal Kaplan PhD Abstract Purpose Metoclopramide-induced tardive dyskinesia is associated with cumulative drug exposure, which can result from prolonged use of the drug. We estimated therapy duration with metoclopramide, and measured the extent of therapy beyond the maximum time period of 12 weeks evaluated in the clinical trials and recommended in the label. Methods Prescription claims for metoclopramide from 2002 to 2004 were extracted for participants residing throughout the US and contained within the Caremark pharmacy benefit manager (PBM) database. An episode of therapy was defined as one or a series of consecutive claims with no more than a 30-day lag between the dispensing date of a new claim and the ending date of the preceding claim. Episode duration was calculated by subtracting the start date from the end date for each episode. Results During the study period, almost 80% of participants (total,=,200,907) had only one episode of therapy. The length of the longest episode for most patients (85%) varied from 1 to 90 days, yet 15% of the patients appeared to have received prescriptions for metoclopramide for a period longer than 90 days. Cumulative therapy for longer than 90 days was recorded for almost 20% of the patients. Conclusions These results suggest that despite the known risk of tardive dyskinesia and the labeled recommendations on duration of metoclopramide use, many patients appear to use the drug for relatively long time periods beyond the labeled recommendations. Physicians should carefully consider the risk-benefit profile of the drug and, if possible, avoid increased risk of tardive dyskinesia due to prolonged exposure. Published in 2007 by John Wiley & Sons, Ltd. [source] Application of lag-time into exposure definitions to control for protopathic bias,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 3 2007H. Tamim Abstract Purpose To control for protopathic bias, some studies have incorporated the concept of lag-time into their exposure definition (time period before the index date that was not considered in assessing exposure). The objective of this study was to introduce a procedure to identify the best lag-time to be applied in studies where control for protopathic bias is required. Methods We used data from a case-control study carried out to assess the association between exposure to proton pump inhibitors (PPIs) and risk of gastric cancer, using RAMQ databases. Exposure was defined as the number of defined daily doses of PPIs dispensed during the 5-year period prior to the index date (divided into four quartiles). Thirty-one different lag-times were applied (0,30 months) based on 1-month intervals. Logistic regression was used to estimate the matched odds ratio (OR) for each lag-time. The change point in the ln(ORs) was identified by applying a two-compartmental model and a segmented regression model. Results A trend of decreasing ORs was found with the application of an increasing lag-time. As an illustration, the ORs for the 1st quartile of defined daily doses, when applying the 31 different lag-times, ranged between 3.52 when applying a 0 lag-time and 0.97 when applying a 30 months lag-time. Applying the two methods for the different lag-times showed that the ORs stabilized at around 6 months. Conclusion For the purpose of controlling for protopathic bias in pharmacoepidemiological studies, we have provided a method to assess the most appropriate lag-time that should be applied for the assessment of drug exposure. Copyright © 2007 John Wiley & Sons, Ltd. [source] The potential of the European network of congenital anomaly registers (EUROCAT) for drug safety surveillance: a descriptive study,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 9 2006Willemijn M. Meijer PharmD Abstract Background European Surveillance of Congenital Anomalies (EUROCAT) is a network of population-based congenital anomaly registries in Europe surveying more than 1 million births per year, or 25% of the births in the European Union. This paper describes the potential of the EUROCAT collaboration for pharmacoepidemiology and drug safety surveillance. Methods The 34 full members and 6 associate members of the EUROCAT network were sent a questionnaire about their data sources on drug exposure and on drug coding. Available data on drug exposure during the first trimester available in the central EUROCAT database for the years 1996,2000 was summarised for 15 out of 25 responding full members. Results Of the 40 registries, 29 returned questionnaires (25 full and 4 associate members). Four of these registries do not collect data on maternal drug use. Of the full members, 15 registries use the EUROCAT drug code, 4 use the international ATC drug code, 3 registries use another coding system and 7 use a combination of these coding systems. Obstetric records are the most frequently used sources of drug information for the registries, followed by interviews with the mother. Only one registry uses pharmacy data. Percentages of cases with drug exposure (excluding vitamins/minerals) varied from 4.4% to 26.0% among different registries. The categories of drugs recorded varied widely between registries. Conclusions Practices vary widely between registries regarding recording drug exposure information. EUROCAT has the potential to be an effective collaborative framework to contribute to post-marketing drug surveillance in relation to teratogenic effects, but work is needed to implement ATC drug coding more widely, and to diversify the sources of information used to determine drug exposure in each registry. Copyright © 2006 John Wiley & Sons, Ltd. [source] Prevalence, incidence and persistence of antipsychotic drug prescribing in the Italian general population: retrospective database analysis, 1999,2002,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 6 2006Mersia Mirandola StatD Abstract Purpose To investigate the prevalence, incidence and persistence with antipsychotic drug therapy in a large and geographically defined catchment area of Italian general population. Methods All antipsychotic drug prescriptions dispensed during 1999, 2000, 2001 and 2002 were extracted from an administrative prescription database covering a population of 2,640,379 individuals. Antipsychotic drug users were defined as patients who had at least one recorded prescription in the current year. New users were defined as patients receiving a first prescription without any recorded antipsychotic drug treatment in the previous 12 months. Prevalence data were calculated by dividing users by the total number of male and female residents in each age group. Incidence data were calculated as the number of new users divided by the person-time free from antipsychotic drugs in the current year. The cumulative persistence of each medication was calculated by dividing the total prescribed amount of antipsychotic drug by the recommended daily dose, according to each agent's defined daily dose (DDD). Results A progressive rise in prevalence and incidence rates was observed during the 4-year period. In each census year, the prevalence and incidence of prescribing was higher in females than males, and progressively rose with age, with the highest rates in old and very old subjects. The analysis of persistence with therapy revealed that 3176 individuals (78.5%) were occasional antipsychotic drug users, and that occasional use was more frequent among individuals receiving conventional antipsychotic drugs than among individuals receiving novel antipsychotic drugs. This difference was not explained by differences in the occurrence of neurologic adverse reactions, as shown by the concurrent prescribing of anticholinergic drugs, which was fairly similar between the two groups of new drug users. Additionally, we found that conventioal antipsychotic drugs were more often used in older individuals, where occasional use is very frequent, while novel antipsychotic drugs were more often prescribed in young and adult individuals, where regular use is more frequent. Conclusions An epidemiologically relevant proportion of everyday individuals is annually exposed to antipsychotic drugs. The distribution of prevalence and incidence rates by age highlighted an emerging public health issue related to the adverse and beneficial consequences of antipsychotic drug exposure in the elderly. The finding that persistence with therapy was longer in new users of novel antipsychotic drugs compared with new users of conventional agents might be explained by the different demographic and clinical characteristics of individuals receiving these two drug classes and not by the different tolerability profile of these two drug classes. Copyright © 2005 John Wiley & Sons, Ltd. [source] Estimation of time-dependent rate ratios in case-control studies: comparison of two approaches for exposure assessment,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 5 2006Geneviève Lefebvre Abstract Purpose In pharmacoepidemiology, it is well recognized that the rate of adverse events may vary as a function of the cumulative duration of the drug exposure and/or the time since the end of the exposure. In case-control studies, two different approaches have been used to estimate temporal effects of drug exposure: the time-windows (T-Ws) approach and the duration-specific (D-S) approach. We decided to conduct a simulation study to compare the two approaches when the rate ratios (RRs) vary as a function of the cumulative duration of exposure and/or the time since the end of exposure. Methods We generated three cohorts of 500,000 individuals in which the rate of the event was varying as a function of the cumulative duration of exposure and the time since the end of exposure. For each cohort, a nested case-control analysis was performed using both the D-S and the T-Ws approaches. In the T-Ws approach, a RR is estimated within specific periods of time prior to the outcome, while a RR is estimated within periods of cumulative duration of exposure and time since the end of exposure in the D-S approach. Results We found that the RRs obtained from the D-S approach exactly corresponded to the RRs obtained from the cohort analyses, while the RRs obtained from the T-Ws approach generally not. RRs obtained from the T-Ws approach were difficult to interpret in terms of the effect of the duration and timing of the exposure. Conclusion The D-S approach should be used to investigate the duration-related effects of exposure in case-control studies. Copyright © 2005 John Wiley & Sons, Ltd. [source] An algorithm to derive a numerical daily dose from unstructured text dosage instructions,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 3 2006Anoop D. Shah BSc Abstract Purpose The General Practice Research Database (GPRD) is a database of longitudinal patient records from general practices in the United Kingdom. It is an important data source for pharmacoepidemiology studies, but until now it has been tedious to calculate the daily dose and duration of exposure to drugs prescribed. This is because general practitioners routinely record dosage instructions as free text rather than in a structured way. The objective was to develop and assess the validity of an automated algorithm to derive the daily dose from text dosage instructions. Methods A computer program was developed to derive numerical information from unstructured text dosage instructions. It was tested on dosage texts from a random sample of one million prescription entries. A random sample of 1000 of these converted texts were manually checked for their accuracy. Results Out of the sample of one million prescription entries, 74.5% had text containing the daily dose, 14.5% had text but did not include a quantitative daily dose statement and 11.0% had no text entered. Of the 1000 texts which were checked manually, 767 stated the daily dose. The program interpreted 758 (98.8%) of these correctly, produced errors in four cases and failed to extract the dose from five texts. Conclusions An automated algorithm has been developed which can accurately extract the daily dose from almost 99% of general practitioners' text dosage instructions. It increases the utility of GPRD and other prescription data sources by enabling researchers to estimate the duration of drug exposure more efficiently. Copyright © 2005 John Wiley & Sons, Ltd. [source] Evaluation of gestational age and admission date assumptions used to determine prenatal drug exposure from administrative data,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 12 2005Marsha A. Raebel PharmD Abstract Objective Our aim was to evaluate the 270-day gestational age and delivery date assumptions used in an administrative dataset study assessing prenatal drug exposure compared to information contained in a birth registry. Study Design and Setting Kaiser Permanente Colorado (KPCO), a member of the Health Maintenance Organization (HMO) Research Network Center for Education and Research in Therapeutics (CERTs), previously participated in a CERTs study that used claims data to assess prenatal drug exposure. In the current study, gestational age and deliveries information from the CERTs study dataset, the Prescribing Safely during Pregnancy Dataset (PSDPD), was compared to information in the KPCO Birth Registry. Sensitivity and positive predictive value (PPV) of the claims data for deliveries were assessed. The effect of gestational age and delivery date assumptions on classification of prenatal drug exposure was evaluated. Results The mean gestational age in the Birth Registry was 273 (median,=,275) days. Sensitivity of claims data at identifying deliveries was 97.6%, PPV was 98.2%. Of deliveries identified in only one dataset, 45% were related to the gestational age assumption and 36% were due to claims data issues. The effect on estimates of prevalence of prescribing during pregnancy was an absolute change of 1% or less for all drug exposure categories. For Category X, drug exposures during the first trimester, the relative change in prescribing prevalence was 13.7% (p,=,0.014). Conclusion Administrative databases can be useful for assessing prenatal drug exposure, but gestational age assumptions can result in a small proportion of misclassification. Copyright © 2005 John Wiley & Sons, Ltd. [source] PSA surge/flare-up in patients with castration-refractory prostate cancer during the initial phase of chemotherapyTHE PROSTATE, Issue 16 2009T. Nelius Abstract BACKGROUND Docetaxel-based chemotherapy has shown great promise for the treatment of CRPC and is considered the current standard of care. PSA is mainly used as marker to monitor the treatment response. Several articles were published reporting an initial PSA surge/flare-up after starting chemotherapy. The cause and the impact of this phenomenon are discussed controversially. The intention of this review is to define the significance of initial PSA surge/flare-up and to increase awareness to this phenomenon in the urological community. MATERIALS AND METHODS A comprehensive literature search was performed in different data bases using various key words. Relevant articles and references between 1999 and 2009 were reviewed and analyzed for data on the association between chemotherapy and initial PSA surge/flare. RESULTS The incidence of a PSA surge/flare-up ranges according to the reported studies between 7.6% and 13.6%. A PSA surge/flare-up was reported up to 404% from baseline PSA level followed by PSA response. The median duration of a PSA surge/flare-up is 2,3 weeks and can last up to 6,8 weeks. However, the occurrence of a PSA surge/flare-up did not impact outcome and survival negatively compared to patients with an immediate PSA response. CONCLUSIONS A considerable portion of CRPC patients experience an initial PSA surge/flare-up under systemic chemotherapy. The definitions used for PSA surge/flare-up differ slightly in the literature. This issue needs to be solved since it might impact defining treatment response. As a PSA surge/flare-up did not impact outcome and survival negatively, chemotherapy should be continued according to the literature addressing specifically the phenomenon of a PSA surge/flare-up for a minimum of 8 weeks or 3 rounds of a 3-weekly cycle chemotherapy regimen before further decisions are made about efficacy. However, Scher et al. recommended a 12-week period drug exposure based on their results on PSA progression-free survival and overall survival. This dilemma needs to be addressed in further data analysis in order to establish a general rule regarding when to stop chemotherapy. Physicians should be aware of this effect to avoid inadequate early discontinuation of chemotherapy. The underlying mechanisms of a PSA surge/flare-up are still elusive and need further clarification. Prostate 69: 1802,1807, 2009. © 2009 Wiley-Liss, Inc. [source] Proton Pump Inhibitors Reduce Mycophenolate Exposure in Heart Transplant Recipients,A Prospective Case-Controlled StudyAMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2009S. Kofler This prospective study investigates the impact of proton pump inhibitors (PPI) on mycophenolic acid (MPA) pharmacokinetics in heart transplant recipients receiving mycophenolate mofetil (MMF) and tacrolimus. MPA plasma concentrations at baseline (C0 h), 30 min (C0.5 h), 1(C1 h) and 2 h (C2 h) were obtained by high-performance liquid chromatography (HPLC) in 22 patients treated with pantoprazole 40 mg and MMF 2000 mg. Measurements were repeated 1 month after pantoprazole withdrawal. A four-point limited-sampling strategy was applied to calculate the MPA area under the curve (MPA-AUC). Predose MPA concentrations with PPI were 2.6 ± 1.6 mg/L versus 3.4 ± 2.7 mg/L without PPI (p = ns). Postdose MPA concentrations were lower with PPI at C0.5 h (8.3 ± 5.7 mg/L vs. 18.3 ± 11.3 mg/L, p = 0.001) and C1 h (10.0 ± 5.6 mg/L vs. 15.8 ± 8.4 mg/L, p = 0.004), without significant differences at C2 h (8.3 ± 6.5 mg/L vs. 7.6 ± 3.9 mg/L). The MPA-AUC was significantly lower with PPI medication (51.2 ± 26.6 mg × h/L vs. 68.7 ± 30.3 mg × h/L; p = 0.003). The maximum concentration of MPA (MPA-Cmax) was lower (12.2 ± 7.5 mg/L vs. 20.6 ± 9.3 mg/L; p = 0.001) and the time to reach MPA-Cmax (tmax) was longer with PPI (60.0 ± 27.8 min vs. 46.4 ± 22.2 min; p = 0.05). This is the first study to document an important drug interaction between a widely used immunosuppressive agent and a class of drugs frequently used in transplant patients. This interaction results in a decreased MMF drug exposure which may lead to patients having a higher risk for acute rejection and transplant vasculopathy. [source] Heart Rate Variability by Triangular Index in Infants Exposed Prenatally to CocaineANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 4 2002M.B.A., Sudhir Ken Mehta M.D. Background: In adults, heart rate variability triangular index (HRVi) is a highly reproducible measure of heart rate variability (HRV), which makes it more suitable for use in longitudinal studies. Although normative data have been published for newborns, studies in infants with pathological conditions are lacking. Methods: From 1997 to 2000, within the first 4 days of life, we prospectively evaluated HRVi in cocaine-exposed asymptomatic newborns (N = 97) by Holter monitoring. Their data were compared with infants from two control groups (one with no in utero drug exposure, N = 102; the other with exposure to alcohol, nicotine, or marijuana but no cocaine, N = 111). Results: In assessing concordance between and within operators for HRVi, the intraclass correlations were 0.983 (95% Cl: 0.958, 0.994) and 0.997 (95% Cl: 0.984, 0.999), respectively. Infants with in utero cocaine exposure had significantly (P < 0.0001) lower HRVi than those exposed to other drugs and to no drugs in utero. If abnormal HRVi is defined as < fifth percentile for the no drug exposed group (HRVi < 8), 10% of the cocaine-exposed newborns, in contrast to 2% in each of the control groups (P = 0.003) had abnormal values. Conclusion: HRVi is a reliable measure to study heart rate variability in newborns. Asymptomatic infants with in utero cocaine exposure have lower HRVi. Our study supports the clinical use of an abnormal HRVi as a value < 8 for newborn infants. A.N.E. 2002;7(4):374,378 [source] Antimalarial treatment may have a time-dependent effect on lupus survival: Data from a multinational Latin American inception cohortARTHRITIS & RHEUMATISM, Issue 3 2010Samuel K. Shinjo Objective To evaluate the beneficial effect of antimalarial treatment on lupus survival in a large, multiethnic, international longitudinal inception cohort. Methods Socioeconomic and demographic characteristics, clinical manifestations, classification criteria, laboratory findings, and treatment variables were examined in patients with systemic lupus erythematosus (SLE) from the Grupo Latino Americano de Estudio del Lupus Eritematoso (GLADEL) cohort. The diagnosis of SLE, according to the American College of Rheumatology criteria, was assessed within 2 years of cohort entry. Cause of death was classified as active disease, infection, cardiovascular complications, thrombosis, malignancy, or other cause. Patients were subdivided by antimalarial use, grouped according to those who had received antimalarial drugs for at least 6 consecutive months (user) and those who had received antimalarial drugs for <6 consecutive months or who had never received antimalarial drugs (nonuser). Results Of the 1,480 patients included in the GLADEL cohort, 1,141 (77%) were considered antimalarial users, with a mean duration of drug exposure of 48.5 months (range 6,98 months). Death occurred in 89 patients (6.0%). A lower mortality rate was observed in antimalarial users compared with nonusers (4.4% versus 11.5%; P< 0.001). Seventy patients (6.1%) had received antimalarial drugs for 6,11 months, 146 (12.8%) for 1,2 years, and 925 (81.1%) for >2 years. Mortality rates among users by duration of antimalarial treatment (per 1,000 person-months of followup) were 3.85 (95% confidence interval [95% CI] 1.41,8.37), 2.7 (95% CI 1.41,4.76), and 0.54 (95% CI 0.37,0.77), respectively, while for nonusers, the mortality rate was 3.07 (95% CI 2.18,4.20) (P for trend < 0.001). After adjustment for potential confounders in a Cox regression model, antimalarial use was associated with a 38% reduction in the mortality rate (hazard ratio 0.62, 95% CI 0.39,0.99). Conclusion Antimalarial drugs were shown to have a protective effect, possibly in a time-dependent manner, on SLE survival. These results suggest that the use of antimalarial treatment should be recommended for patients with lupus. [source] | |||||||||||||||||||||||||||||||||||||