A manufactured product (Ectoplus®) composed by a cypermethrin (44.7%) and dichlorvos (4.2%) mixture was administered (10mg/kg/day, orally, by gavage) to pregnant rats, during the periods of gestation+lactation, gestation, and lactation. Control mothers received vehicle aqueous solution during the gestation+lactation period. With the progeny, in the 1-15 post-natal days (PNDI-15) there were observed alterations in the periods of occurrence of teeth, hair, unfolding of ears, and in the developmental period for following reflexes: postural, palmar grasp, negative geotaxis, and acoustic startle reflex. After weaning (PND21), there were observed the presence of cypermethrin and dichlorvos in the blood brain and liver; decrease in weight of liver, of cholinesterase activity in the plasma, liver, and brain, and hepatic metabolizing activity of drugs; alterations of levels of gamma glutamyl transferase enzymes, of creatinine, and of potassium in the serum of the animals. In conclusion, neonatal exposure to a formulated mixture of cypermethrin and dichlorvos is inductive to alterations in characteristics that indicate somatic and neuromuscular development of the progeny, and in certain biochemical parameters. The results suggest that enzymatic assessment associated with somatic and neuromotor assessment can be important markers of developmental characteristics in neonatal toxicity by pesticide formulations based on mixtures of insecticides.
We developed a new reporter cell line for human cytomegalovirus (HCMV) drug susceptibility testing. This cell line was obtained by incorporating the luciferase reporter gene under the control of an HCMV-specific promoter into the genome of astrocytoma cells (U373MG). We then used our reporter cell line to evaluate phenotypic changes conferred by the sequential emergence of HCMV UL54 and UL97 mutations following long-term drug exposure. The laboratory strain AD169 was passaged in the presence of increasing concentrations of ganciclovir (one viral line) or foscarnet (two viral lines). Resistant viruses were plaque purified at five different concentrations of ganciclovir and at three different concentrations of foscarnet. In addition to the previously described M460I and L595S UL97 mutations and the L545S and V812L UL54 mutations, exposition to ganciclovir (up to 3,000 μM) resulted in the selection of two unreported UL54 mutations (P829S and D879G). Passages in the presence of foscarnet (up to 3,000 μM) resulted in the selection of seven not previously described UL54 mutations (K500N, T552N, S585A, N757K, L802V, L926V, and L957F) in addition to the N408D mutation that has been associated with ganciclovir and cidofovir resistance. Long-term exposure of HCMV to either ganciclovir or foscarnet ultimately resulted in the selection of multiple UL54 mutations that conferred high levels of resistance to all approved HCMV DNA polymerase inhibitors...
As part of an ongoing study on all limb reduction defects occurring among 1,213,913 consecutive live births in the province of British Columbia, Canada, during 1952-1984, cases with documented maternal drug exposure and chronic maternal diseases were analyzed separately. This population-based study was made possible through the existence of an ongoing Health Surveillance Registry, which documents all infants born with congenital, genetic, or chronically handicapping conditions in the province of British Columbia. Strict rules of confidentiality are obeyed. For this part of the analysis of limb reduction defects, cases with documented maternal illness, drug abuse, and exposure to environmental hazards early in pregnancy were analyzed as a separate group to identify specific, recurring patterns of anomalies. A total of 51 cases with possibly related maternal factors were identified. Among them were five cases with maternal epilepsy, four cases with documented maternal diabetes, and three cases with uterine anomalies. Three infants, all born in 1962, had documented thalidomide exposure. It is rarely possible to identify particular teratogenic factors or specific maternal factors as etiologically related to the pattern of limb reduction defects or a spectrum of congenital malformations. Exposure to environmental factors during pregnancy is not reliably registered and can thus only occasionally be ascertained in retrospective studies. This means that very large numbers of cases and cross-referencing to other family members are required to assess whether a potential teratogen is related to limb defects or not.
Drug exposure or pharmacodynamic breakpoints refer to a magnitude of drug exposure which separates a population into groups with high and low probabilities of attaining a desired outcome. We used a pharmacodynamic model of disseminated candidiasis to define an in vivo drug exposure breakpoint for flucytosine (5FC) against Candida albicans. The results were bridged to humans by using population pharmacokinetics and Monte Carlo simulation. An in vivo drug exposure breakpoint for 5FC was apparent when serum levels were above the MIC for 45% of the dosing interval. The Monte Carlo simulations suggested that using a human dose of 100 mg/kg of body weight/day in four divided doses, 5FC resistance was defined at an MIC of 32 mg/liter. Target attainment rates following administration of 25, 50, and 100 mg/kg/day were similar, suggesting that the use of a lower dose of 5FC is possible. Using six isolates of C. albicans with MICs ranging from 0.06 to >64 mg/liter, we also explored the influence that the MIC, the fraction of the dosing interval that the serum levels of 5FC remained above the MIC (T>MIC), the 5FC resistance genotype, and the in vivo growth rate had on the response to 5FC. The MIC and T>MIC were both critical measures affecting the generation of a drug effect but had no bearing on the magnitude of the maximal kill induced by 5FC. The in vivo growth rate was a critical additional determinant of the exposure-response relationship. There was a relationship between the 5FC resistance genotype and the exposure-response relationship.
The goal of this cross-sectional study was to compare cognitive functioning at age 5 years in prenatal drug-exposed children with nondrug-exposed children from a comparable inner-city environment. Children with prenatal drug exposure scored significantly lower on measures of language, school readiness skills, impulse control, and visual attention span/sequencing than controls matched for age and socioeconomic status. Intelligence, visual-motor, manual dexterity, and sustained attention scores were not significantly different between groups. The total sample scored significantly below the normative mean on standardized measures of intelligence, language, school readiness, visual-motor skills, impulse control, and sustained attention, with 40% scoring at least 1 standard deviation below the mean (IQ <85) on a measure of intelligence. Findings suggest that children with prenatal drug exposure are at increased risk for learning and attention problems and are in need of close developmental surveillance and possible intervention to support school success and improve behavioral outcome.
Recent advances in MR-based brain imaging methods have provided unprecedented capabilities to visualize the brain. Application of these methods has allowed identification of brain structures and patterns of functional activation altered in offspring of mothers who used licit (e.g., alcohol and tobacco) and illicit (e.g., cocaine, methamphetamine, and marijuana) drugs during pregnancy. Here we review that literature, which though somewhat limited by the complexities of separating the specific effects of each drug from other confounding variables, points to sets of interconnected brain structures as being altered following prenatal exposure to drugs of abuse. In particular, dopamine-rich cortical (e.g., frontal cortex) and subcortical (e.g., basal ganglia) fetal brain structures show evidence of vulnerability to intrauterine drug exposure suggesting that during brain development drugs of abuse share a specific profile of developmental neurotoxicity. Such brain malformations may shed light on mechanisms underlying prenatal drug-induced brain injury, may serve as bio-markers of significant intrauterine drug exposure, and may additionally be predictors of subsequent neuro-developmental compromise. Wider clinical use of these research-based non-invasive methods will allow for improved diagnosis and allocation of therapeutic resources for affected infants...
Drug use by pregnant women has been extensively associated with adverse mental, physical, and psychological outcomes in their exposed children. This manuscript reviews bioanalytical methods for in utero drug exposure monitoring for common drugs of abuse in urine, hair, oral fluid, blood, sweat, meconium, amniotic fluid, umbilical cord tissue, nails, and vernix caseosa; neonatal matrices are particularly emphasized. Advantages and limitations of testing different maternal and neonatal biological specimens including ease and invasiveness of collection, and detection time frames, sensitivities, and specificities are described, and specific references for available analytical methods included. Future research involves identifying metabolites unique to fetal drug metabolism to improve detection rates of in utero drug exposure and determining relationships between the amount, frequency, and timing of drug exposure and drug concentrations in infant biological fluids and tissues. Accurate bioanalytical procedures are vital to defining the scope of and resolving this important public health problem.
Current US guidelines for initial therapy of HIV-1 infection recommend daily, life-long treatment with a combination of three antiretroviral drugs consisting of two nucleoside analog reverse transcriptase (RT) inhibitors and a nonnucleoside RT inhibitor or a protease inhibitor. Although this approach has been successful in reducing morbidity and mortality from HIV-1 infection, concerns remain about adverse events from chronic drug exposure, the requirement for daily medication adherence, the risk of HIV-1 drug resistance, and high treatment costs. The availability of antiretrovirals that are co-formulated and dosed once-daily have reduced pill burden and have simplified dosing schedules, but have not lowered drug exposure or cost. These limitations have stimulated research into drug-sparing strategies including intermittent therapy and simplified maintenance regimens. Randomized clinical trials have shown greater mortality with intermittent therapy compared with continuous therapy leading to rejection of this strategy. Pilot studies of simplified maintenance therapy with a ritonavir-boosted protease inhibitor alone have shown more promise, although concerns remain. This article reviews progress in simplification of antiretroviral therapy...
We previously reported that foetal valproate exposure impairs intelligence quotient. In this follow-up investigation, we examined dose-related effects of foetal antiepileptic drug exposure on verbal and non-verbal cognitive measures. This investigation is an ongoing prospective observational multi-centre study in the USA and UK, which has enrolled pregnant females with epilepsy on monotherapy from 1999 to 2004. The study seeks to determine if differential long-term neurodevelopmental effects exist across four commonly used drugs (carbamazepine, lamotrigine, phenytoin and valproate). This report compares verbal versus non-verbal cognitive outcomes in 216 children who completed testing at the age of three years. Verbal and non-verbal index scores were calculated from the Differential Ability Scales, Preschool Language Scale, Peabody Picture Vocabulary Test and Developmental Test of Visual-Motor Integration. Verbal abilities were lower than non-verbal in children exposed in utero to each drug. Preconceptional folate use was associated with higher verbal outcomes. Valproate was associated with poorer cognitive outcomes. Performance was negatively associated with valproate dose for both verbal and non-verbal domains and negatively associated with carbamazepine dose for verbal performance. No dose effects were seen for lamotrigine and phenytoin. Since foetal antiepileptic drug exposure is associated with lower verbal than non-verbal abilities...
Abuse of drugs by pregnant women both in the United States and worldwide has raised many questions regarding the effects of prenatal drug exposure on the developing fetus and subsequent child outcomes. Studies using the neurobehavioral teratology model have been undertaken to determine specific prenatal drug effects on cognitive and behavioral development. Here we summarize the findings of studies that have investigated the developmental effects of prenatal exposure to tobacco, marijuana, stimulants, and opiates. These studies consider the timing and amount of prenatal exposure; other drug exposures; maternal characteristics; and other health, nutritional, and environmental factors. We review treatment options for pregnant, substance-dependent women and therapeutic interventions for exposed children.
Identification of patients’ drug exposure information is critical to drug-related research that is based on electronic medical records (EMRs). Drug information is often embedded in clinical narratives and drug regimens change frequently because of various reasons like intolerance or insurance issues, making accurate modeling challenging. Here, we developed an informatics framework to determine patient drug exposure histories from EMRs by combining natural language processing (NLP) and machine learning (ML) technologies. Our framework consists of three phases: 1) drug entity recognition - identifying drug mentions; 2) drug event detection - labeling drug mentions with a status (e.g., “on” or “stop”); and 3) drug exposure modeling - predicting if a patient is taking a drug at a given time using the status and temporal information associated with the mentions. We applied the framework to determine patient warfarin exposure at hospital admissions and achieved 87% precision, 79% recall, and an area under the receiver-operator characteristic curve of 0.93.
Brender, Jean D.; Werler, Martha M.; Kelley, Katherine E.; Vuong, Ann M.; Shinde, Mayura U.; Zheng, Qi; Huber, John C.; Sharkey, Joseph R.; Griesenbeck, John S.; Romitti, Paul A.; Langlois, Peter H.; Suarez, Lucina; Canfield, Mark A.;
Fonte: Oxford University PressPublicador: Oxford University Press
Nitrosatable drugs, such as secondary or tertiary amines and amides, form N-nitroso compounds in the presence of nitrite. Various N-nitroso compounds have been associated with neural tube defects in animal models. Using data from the National Birth Defects Prevention Study, the authors examined nitrosatable drug exposure 1 month before and 1 month after conception in 1,223 case mothers with neural tube defect-affected pregnancies and 6,807 control mothers who delivered babies without major congenital anomalies from 1997 to 2005. Nitrite intakes were estimated from mothers’ responses to a food frequency questionnaire. After adjustment for maternal race/ethnicity, educational level, and folic acid supplementation, case women were more likely than were control women to have taken tertiary amines (odds ratio = 1.60, 95% confidence interval (CI): 1.31, 1.95). This association was strongest with anencephalic births (odds ratio = 1.96, 95% CI: 1.40, 2.73); odds ratios associated with tertiary amines from the lowest tertile of nitrite intake to the highest tertile were 1.16 (95% CI: 0.59, 2.29), 2.19 (95% CI: 1.25, 3.86), and 2.51 (95% CI: 1.45, 4.37), respectively. Odds ratios for anencephaly with nitrosatable drug exposure were reduced among women who also took daily vitamin supplements that contained vitamin C. Prenatal exposure to nitrosatable drugs may increase the risk of neural tube defects...
Resistance to the experimental human cytomegalovirus (CMV) UL97 kinase inhibitor maribavir has been mapped to UL97 mutations at codons 353, 397, 409 and 411, in the kinase ATP-binding region, and to mutations in the UL27 gene. We studied the maribavir susceptibility phenotypes of additional UL97 mutations observed in vitro and in clinical trials, and the effect of simultaneous mutation in both UL97 and UL27. In vitro selection under maribavir identified a new locus of UL97 mutation within the conserved kinase p-loop (L337M), which conferred low grade maribavir resistance (3.5-fold increased EC50) without ganciclovir cross-resistance. During maribavir Phase III CMV prevention clinical trials, 3 previously unknown UL97 sequence variants were detected in plasma samples after 27 to 98 days of drug exposure (I324V, S334G and S386L). These variants did not confer any drug resistance despite proximity to mutations that confer maribavir resistance. The UL27 resistance mutation R233S, when added to strains containing UL97 mutations L337M or V353A, doubled their maribavir EC50s. These results expand the range of UL97 maribavir-resistance mutations into another part of the kinase ATP-binding region, but offer no genotypic evidence that development of drug resistance affected the outcomes of Phase III maribavir clinical trials after drug exposure of up to 14 weeks. There is a potential for increased maribavir resistance in UL27–UL97 double mutants.
Historically, dosing regimens for the treatment of tuberculosis (TB) have been proposed in an empirical manner. Dose selection has often been the result of efficacy trials in which drugs were administered regardless of the magnitude of the effect of demographic factors on drug disposition. This has created challenges for the prescription of fixed-dose combinations with novel therapeutic agents. The objectives of this investigation were to evaluate the impact of body weight on the overall systemic exposure to pyrazinamide (PZA) and to assess whether the use of one fixed dose, without adjustment according to weight, would ensure target exposure and safety requirements across the overall patient population. Using a population pharmacokinetic model, simulation scenarios were explored based on population demographics from clinical trials in TB patients and on historical hepatotoxicity data. The systemic drug exposure (area under the concentration-time curve [AUC]), peak concentrations (the maximum concentration of drug in serum [Cmax]), the time above the MIC (t > MIC), and the risk of hepatotoxicity were evaluated for the current weight-banded regimen and compared to fixed doses under the assumption that pharmacokinetic differences are the primary drivers of toxicity. Evaluation of the standard weight banding reveals that more than 50% of subjects in the weight range of 45 to 55 kg remain below the proposed target exposure to PZA. In contrast...
We present a unified quantitative approach to predict the in vivo alteration in drug exposure caused by either cytochrome P450 (CYP) gene polymorphisms or CYP-mediated drug–drug interactions (DDI). An application to drugs metabolized by CYP2C19 is presented. The metrics used is the ratio of altered drug area under the curve (AUC) to the AUC in extensive metabolizers with no mutation or no interaction. Data from 42 pharmacokinetic studies performed in CYP2C19 genetic subgroups and 18 DDI studies were used to estimate model parameters and predicted AUC ratios by using Bayesian approach. Pharmacogenetic information was used to estimate a parameter of the model which was then used to predict DDI. The method adequately predicted the AUC ratios published in the literature, with mean errors of −0.15 and −0.62 and mean absolute errors of 0.62 and 1.05 for genotype and DDI data, respectively. The approach provides quantitative prediction of the effect of five genotype variants and 10 inhibitors on the exposure to 25 CYP2C19 substrates, including a number of unobserved cases. A quantitative approach for predicting the effect of gene polymorphisms and drug interactions on drug exposure has been successfully applied for CYP2C19 substrates. This study shows that pharmacogenetic information can be used to predict DDI. This may have important implications for the development of personalized medicine and drug development.
Previous studies have reported that exercise decreases cocaine self-administration in rats with long-term access (8+ weeks) to activity wheels in the home cage. The purpose of this study was to (1) examine the importance of the temporal relationship between physical activity and initial drug exposure, (2) determine the effects of exercise on responding maintained by a nondrug reinforcer (i.e., food), and (3) investigate the effects of exercise on cocaine-induced increases in locomotor activity. To this end, female rats were obtained at weaning and divided into four groups: (1) EXE-SED rats were housed in exercise cages for six weeks and then transferred to sedentary cages after the first day of behavioral testing; (2) SED-EXE rats were housed in sedentary cages for six weeks and then transferred to exercise cages after the first day of behavioral testing; (3) SED-SED rats remained in sedentary cages for the duration of the study; and (4) EXE-EXE rats remained in exercise cages for the duration of the study. Relative to the sedentary group (SED-SED), exercise reduced cocaine self-administration in both groups with access to activity wheels after initial drug exposure (EXE-EXE, SED-EXE), but did not reduce cocaine self-administration in the group with access to activity wheels only before drug exposure (EXE-SED). Exercise also decreased the effects of cocaine on locomotor activity...
In recent years, the increased interest in pediatric research has enforced the role of physiologically based pharmacokinetic (PBPK) models in pediatric drug development. However, an existing lack of published examples contributes to some uncertainties about the reliability of their predictions of oral drug exposure. Developing and validating pediatric PBPK models for oral drug application shall enrich our knowledge about their limitations and lead to a better use of the generated data. This study was conducted to investigate how whole-body PBPK models describe the oral pharmacokinetics of sotalol over the entire pediatric age. Two leading software tools for whole-body PBPK modeling: Simcyp® (Simcyp Ltd, Sheffield, UK) and PK-SIM® (Bayer Technology Services GmbH, Leverkusen, Germany), were used. Each PBPK model was first validated in adults before scaling to children. Model input parameters were collected from the literature and clinical data for 80 children were used to compare predicted and observed values. The results obtained by both models were comparable and gave an adequate description of sotalol pharmacokinetics in adults and in almost all pediatric age groups. Only in neonates, the mean ratio(Obs/Pred) for any PK parameter exceeded a twofold error range...
Significant drug-nutrient interactions are possible when drugs and nutrients share the same absorption and disposition mechanisms. During postnatal development, the outcomes of drug-nutrient interactions may change with postnatal age since these processes undergo ontogenesis through the postnatal period. Our study investigated the dependence of a significant drug-nutrient interaction (cefepime-carnitine) on the timing and duration of drug exposure relative to postnatal age. Rat pups were administered cefepime (5 mg/kg) twice daily subcutaneously according to different dosing schedules (postnatal day 1-4, 1-8, 8-11, 8-20, or 1-20). Cefepime significantly reduced serum and heart L-carnitine levels in postnatal day 1-4, 1-8 and 8-11 groups and caused severe degenerative changes in ventricular myocardium in these groups. Cefepime also altered the ontogeny of several key L-carnitine homeostasis pathways. The qualitative and quantitative changes in levels of hepatic γ-butyrobetaine hydroxylase mRNA and activity, hepatic trimethyllysine hydroxlase mRNA, intestinal organic cation/carnitine transporter (Octn) mRNA, and renal Octn2 mRNA depended on when during postnatal development the cefepime exposure occurred and duration of exposure. Despite lower levels of heart L-carnitine in earlier postnatal groups...
How much, how often and how fast a drug reaches the brain determine the behavioural and neuroplastic changes associated with the
addiction process. Despite the critical nature of these variables, the drug addiction field often ignores pharmacokinetic issues, which
we argue can lead to false conclusions. First, we review the clinical data demonstrating the importance of the speed of drug onset and
of intermittent patterns of drug intake in psychostimulant drug addiction. This is followed by a review of the preclinical literature
demonstrating that pharmacokinetic variables play a decisive role in determining behavioural and neurobiological outcomes in animal
models of addiction. This literature includes recent data highlighting the importance of intermittent, ‘spiking’ brain levels of drug in
producing an increase in the motivation to take drug over time. Rapid drug onset and intermittent drug exposure both appear to push
the addiction process forward most effectively. This has significant implications for refining animal models of addiction and for better
understanding the neuroadaptations that are critical for the disorder.
peer-reviewed; Background: Older adults are susceptible to adverse effects from the concomitant use of prescription medications
and alcohol. This study estimates the prevalence of exposure to alcohol interactive (AI) medications and
concomitant alcohol use by therapeutic class in a large, nationally representative sample of older adults.
Methods: Cross-sectional analysis of a population based sample of older Irish adults aged ≥60 years using data
from The Irish Longitudinal Study on Ageing (TILDA) (N = 3,815). AI medications were identified using Stockley’s
Drug Interactions, the British National Formulary and the Irish Medicines Formulary. An in-home inventory of
medications was used to characterise AI drug exposure by therapeutic class. Self-reported alcohol use was classified
as non-drinker, light/moderate and heavy drinking. Comorbidities known to be exacerbated by alcohol were also
recorded (diabetes mellitus, hypertension, peptic ulcer disease, liver disease, depression, gout or breast cancer), as
well as sociodemographic and health factors.
Results: Seventy-two per cent of participants were exposed to AI medications, with greatest exposure to
cardiovascular and CNS agents. Overall, 60% of participants exposed to AI medications reported concomitant