Risk Of Drug Toxicity Research Articles

High frequency of NAT2 slow acetylator alleles in the Malay population of Indonesia: an awareness to the anti-tuberculosis drug induced liver injury and cancer

Background: Arylamine N-acetyltransferase 2 (NAT2) polymorphism was previously reported to have association with the risk of drug toxicities and the development of various diseases. Previous research on the Indonesian population, especially Javanese and Sundanese, showed that there were 33% NAT2 slow acetylator phenotype. The aim of this study was to map the NAT2 variation in the Malay ethnic to gain a deeper insight into NAT2 haplotypic composition in this ethnic.Methods: 50 healthy samples from the Indonesian Malay ethnic were obtained. They were interviewed about their ethnic backgrounds for the last three generations. DNA was extracted from peripheral blood and NAT2 genotyping was done using the PCR direct Sequencing. Data were compiled according to the genotype and allele frequencies estimated from the observed numbers of each specific allele. Haplotype reconstruction was performed using PHASE v2.1.1 software.Results: We found 7 haplotypes consisting of 6 SNPs and 14 NAT2 genotype variations in Indonesian Malay population. The most frequent allele was NAT2*6A (38%) which was classified as a slow acetylator allele. According to bimodal distribution, the predicted phenotype of the Malay population was composed of 62% rapid acetylator and 38% slow acetylator. According to trimodal distribution, the predicted phenotypes for rapid, intermediate and slow acetylators were 10%, 52% and 38% respectively.Conclusion: Our result indicates the presence of the allelic distribution and revealed the most frequent acetylator status and phenotype for the Indonesian Malay population. The result of this study will be helpful for future epidemiological or clinical studies and for understanding the genetic basis of acetylation polymorphism in Indonesia.

Modification of Bovine Serum Albumin (BSA) with a Maleimido‐functionalized, 8‐arm Polyethylene Glycol Backbone (Mal‐PEG8) as a Drug Delivery System

Due to its ability to transport hydrophobic materials through the bloodstream, human serum albumin (HSA) has become an intriguing drug delivery system with several formulations currently available. Key residues in the two main drug binding sites, DS1 and DS2, are conserved in BSA, providing a cheaper, more readily available alternative to HSA. Additionally, BSA may be selectively modified at its lone free sulfhydryl (Cys34), requiring no additional modifications. A multi‐BSA PEG8 complex (PEG8‐BSAx) would reduce the effect on osmotic pressure, avoid immunogenic response, and decrease the risk of drug toxicity while maintaining ligand binding capabilities. Several BSA molecules were successfully conjugated onto Mal‐PEG8 in a one‐pot reaction, requiring only BSA, Mal‐PEG8 and MOPS/NaCl buffer at pH 7.2. High molecular weight species (HMW) of PEG8‐BSAx were separated from the reaction mixture via Size Exclusion Chromatography (SEC). Helicity was maintained following PEGylation, as determined by Circular Dichroism (CD). Using a 4–15% gradient SDS‐PAGE gel, three bands of HMW material were visualized. Two bands corresponding to molecular weights of PEG8 complexed with two and three BSA molecules were seen in the separation zone. A heavy band was maintained in the stacking zone, indicating the presence of at least one other species of PEG8‐BSAx. Thermal stability of PEGylated‐BSA complexes was evaluated using UV‐VIS and CD. Fluorimetric assays were performed with Sulfamethoxazole (SMZ), Phenytoin (PHT) and 8‐Anilino‐1‐naphthalenesulfonic acid (ANS). SMZ has shown preference for DS1 while PHT prefers DS2. ANS is a fluorescent probe commonly used in binding studies. Dissociation constants (Kd) and the number of binding sites were consistent between unmodified BSA and PEG8‐BSAx. These results suggest that PEG8‐BSAx is a viable delivery system for water‐insoluble pharmaceuticals.Support or Funding InformationLoyola University Chicago

Classification of toxicity effects of biotransformed hepatic drugs using whale optimized support vector machines

Measuring toxicity is an important step in drug development. Nevertheless, the current experimental methods used to estimate the drug toxicity are expensive and time-consuming, indicating that they are not suitable for large-scale evaluation of drug toxicity in the early stage of drug development. Hence, there is a high demand to develop computational models that can predict the drug toxicity risks. In this study, we used a dataset that consists of 553 drugs that biotransformed in liver. The toxic effects were calculated for the current data, namely, mutagenic, tumorigenic, irritant and reproductive effect. Each drug is represented by 31 chemical descriptors (features). The proposed model consists of three phases. In the first phase, the most discriminative subset of features is selected using rough set-based methods to reduce the classification time while improving the classification performance. In the second phase, different sampling methods such as Random Under-Sampling, Random Over-Sampling and Synthetic Minority Oversampling Technique (SMOTE), BorderLine SMOTE and Safe Level SMOTE are used to solve the problem of imbalanced dataset. In the third phase, the Support Vector Machines (SVM) classifier is used to classify an unknown drug into toxic or non-toxic. SVM parameters such as the penalty parameter and kernel parameter have a great impact on the classification accuracy of the model. In this paper, Whale Optimization Algorithm (WOA) has been proposed to optimize the parameters of SVM, so that the classification error can be reduced. The experimental results proved that the proposed model achieved high sensitivity to all toxic effects. Overall, the high sensitivity of the WOA+SVM model indicates that it could be used for the prediction of drug toxicity in the early stage of drug development.

Deep Learning to Predict the Formation of Quinone Species in Drug Metabolism.

Many adverse drug reactions are thought to be caused by electrophilically reactive drug metabolites that conjugate to nucleophilic sites within DNA and proteins, causing cancer or toxic immune responses. Quinone species, including quinone-imines, quinone-methides, and imine-methides, are electrophilic Michael acceptors that are often highly reactive and comprise over 40% of all known reactive metabolites. Quinone metabolites are created by cytochromes P450 and peroxidases. For example, cytochromes P450 oxidize acetaminophen to N-acetyl-p-benzoquinone imine, which is electrophilically reactive and covalently binds to nucleophilic sites within proteins. This reactive quinone metabolite elicits a toxic immune response when acetaminophen exceeds a safe dose. Using a deep learning approach, this study reports the first published method for predicting quinone formation: the formation of a quinone species by metabolic oxidation. We model both one- and two-step quinone formation, enabling accurate quinone formation predictions in nonobvious cases. We predict atom pairs that form quinones with an AUC accuracy of 97.6%, and we identify molecules that form quinones with 88.2% AUC. By modeling the formation of quinones, one of the most common types of reactive metabolites, our method provides a rapid screening tool for a key drug toxicity risk. The XenoSite quinone formation model is available at http://swami.wustl.edu/xenosite/p/quinone .

125 Risk perception of obstetrician for the prescription of magnesium sulfate in severe preeclampsia and eclampsia: A qualitative study in the public health system in Brazil

Introduction Magnesium sulfate is the drug of choice for the prevention and control of seizures in the management of severe preeclampsia/eclampsia. Despite its use in virtually 100% of eclampsia cases in Brazil, maternal mortality due to this disorder still remains elevated. It is assumed that there is a misuse of magnesium sulfate, leading to a delay in the management of severe cases of preeclampsia/eclampsia. Objective To describe the obstetrician’s perception on the major reasons for underutilizing magnesium sulfate in severe preeclampsia/eclampsia. Method A qualitative clinical study, based on phenomenological reference was carried out by semi-structured interviews and open-ended discussions with obstetricians of the public healthcare system in primary care units (PCU) and referral maternity hospitals (RMH), in Brazil. Results Fear instilled by awareness of the risk of drug toxicity was the major cause for not prescribing the medication in PCU. Fear was justified by insufficient technical, structural and organizational resources of healthcare facilities and by a shortage of physicians properly trained for correct drug use. Conclusion Fear of toxicity of magnesium sulfate was the main barrier towards timely and proper drug use. Periodic skill development and training of obstetricians, along with integration of the medical team in the work environment may contribute to decrease fear, broadening safety of drug prescription and thus reduce adverse outcomes related to PE and improving quality of maternal healthcare. Download : Download high-res image (576KB) Download : Download full-size image

Improving Care in Older Patients with Diabetes: A Focus on Glycemic Control.

Diabetes affects more than 25% of Americans older than age 65 years. The medical care of older patients must differ from the care of their younger counterparts. Older patients are at high risk of drug toxicity. A hemoglobin A1c (HbA1c) level less than 7.0% has historically been the goal of all patients with diabetes, regardless of age. Recent research has demonstrated that using medications to achieve such tight glycemic control is not necessary and is often not safe.This article discusses the seminal research findings that strongly suggest that HbA1c goals should be relaxed in older patients. The authors then recommend an age-specific and functionally appropriate HbA1c reference range for patients receiving medications to improve glycemic control. Other interventions are suggested that should make diabetes care safer in older patients receiving hypoglycemic medications.

Treatment outcomes of reduced-dose intravitreal ganciclovir for cytomegalovirus retinitis.

BackgroundCytomegalovirus retinitis (CMVR) is one of the most common opportunistic infection in immunocompromised individuals. Intravitreal ganciclovir injection has been used successfully but no standard regimen was established. Risks of drug toxicity, endophthalmitis, and injection-related complications increased with number and frequency of injection. The aim of this study is to evaluate the outcomes of reduced-dose intravitreal ganciclovir (2 mg/0.04 mL) for the treatment of CMVR.MethodsA prospective observational cohort study involving 67 eyes of 49 patients with CMVR was performed. Induction therapy involved intravenous ganciclovir (10 mg/kg/day) for 2 weeks unless contraindicated or patients refused. Patients were then treated with reduced-dose intravitreal ganciclovir every week for 4 weeks, and then every other week until the lesion healed. The patients’ demographic data were recorded, and vision parameters were examined every visit.ResultsTwenty eyes (29.9 %) presented with initial visual acuities less than 6/60. The majority of patients were diagnosed with CMVR in zones 1 or 2 (63 eyes, 94 %), and, at least, one quadrant of the retina was involved (56 eyes, 83.6 %). Forty-one eyes (61.2 %) completely resolved after treatment within the 6-month follow-up. There was no significant difference in healing time, whether or not patients received induction treatment with intravenous ganciclovir (111.00 ± 12.96 vs 105.00 ± 28.32 days, p = 0.8). Five eyes (12.2 %) of patients with healed CMVR had visual acuities less than 6/60.ConclusionsReduced-dose intravitreal ganciclovir is a safe and effective treatment option. It provides comparable results to other weekly regimens. Induction with intravenous ganciclovir is not crucial in a resolution of retinitis, although it may be necessary to reduce systemic cytomegalovirus loads and mortality rates.Trial registrationThe trial was registered with Thai Clinical Trials Registry (TCTR) on 16 March 2016 – TCTR20160316001.

Undernutrition & tuberculosis in India: Situation analysis & the way forward.

Undernutrition and tuberculosis (TB) are linked and have a bidirectional relationship. Undernutrition increases the risk of TB which in turn, can lead to malnutrition. Undernutrition not only is a risk factor for progression of latent TB infection to active disease, but also increases the risk of drug toxicity, relapse and death once TB develops. The dietary intake of TB patients in the country is inadequate. Nutritional supplementation in patients with TB is associated with faster sputum conversion, higher cure and treatment completion rates, significant gain in body weight and body composition as well as better performance status.The Government of India has various social support schemes (including nutrition supplementation schemes) and policies, at the Centre as well as State levels. Here we discuss some successful examples and suggest a few solutions to address this gap; like considering TB patients as a vulnerable group for “Targeted Public Distribution System” and providing extra rations for the duration of treatment. Recommendations for the research community, civil societies, government organizations, non-governmental and corporate sector on the actions needed to achieve the goals of the End TB Strategy are also provided. Ultimately, reduction of TB burden in India and its elimination will require improving the nutritional status of the community as a whole.

Clinical implication of thiopurine methyltransferase polymorphism in children with acute lymphoblastic leukemia: A preliminary Egyptian study.

Background:6-mercaptopurine (6-MP) is an essential component of pediatric acute lymphoblastic leukemia (ALL) maintenance therapy. Individual variability in this drug-related toxicity could be attributed in part to genetic polymorphism thiopurine methyltransferase (TPMT).Aim:To investigate the frequency of common TPMT polymorphisms in a cohort of Egyptian children with ALL and the possible relation between these polymorphisms and 6-MP with short-term complications.Materials and Methods:This study included 25 children. Data related to 6-MP toxicity during the maintenance phase were collected from the patients’ files. DNA was isolated and genotyping for TPMT G460A, and A719G mutations were performed by polymerase chain reaction-restriction fragment length polymorphism.Results:Twenty (80%) of the included 25 patients had a polymorphic TPMT allele. TPMT*3A was the most frequent (14/25, 56%), 8 patients were homozygous and 6 were heterozygous. TPMT*3C mutant allele was found in 4 patients (16%) in the heterozygous state while 2 patients (8%) were found to be heterozygous for TPMT*3B mutant allele. TPMT mutant patients, especially homozygous, were at greater risk of 6-MP hematological toxicity without significant difference regarding hepatic toxicity.Conclusions:TPMT polymorphism was common among the studied group and was associated with increased risk of drug toxicity. A population-based multi-center study is required to confirm our results.

Actionable pharmacogenetic markers for prediction and prognosis in breast cancer.

Breast cancer is a heterogeneous disease that necessitates proper patient classification to direct surgery, pharmacotherapy, and radiotherapy. Despite patients within the same subgroup receiving similar pharmacotherapy, substantial variation in clinical outcomes is observed. Pharmacogenetic variations with direct effect on pharmacokinetics and pharmacodynamics play a central role in clinical outcomes. Pharmacogenetic markers associated with clinical outcome are known as biomarkers. They are termed prognostic biomarkers when their presence is associated with a specific clinical outcome. If the presence of such biomarkers guides treatment, they are termed predictive biomarkers. A number of pharmacogenetic markers have been described in relation to breast cancer pharmacotherapy both in the adjuvant and neoadjuvant setting. CYP2D6 allelic variants produce variable rates of tamoxifen metabolism and are associated with survival outcomes. Other biomarkers have been described in relation to other forms of endocrine therapy and trastuzumab. In neoadjuvant and adjuvant breast cancer chemotherapy, specific biomarkers were correlated with clinical outcomes and risk of drug toxicity. This review highlights key biomarkers in breast cancer pharmacotherapy with the potential of translating such study outcomes into clinical practice.

Personalised Medicine: The Rising Sun

Inter individual genetic variation contributes to both disease susceptibility and response to drugs. The genetic makeup of every individual isdistinctive, henceforth there are variations in the gene products. It is also responsible for the phenotypic diversity, which results in the differentcapacity of each individual to respond to exogenous substances, such as drugs and xenobiotics, and in the different propensity to induceundesirable health effects. So, the aim of personalised medicine is to increase the possibility of therapeutic efficiency and to decrease the drugtoxicity risk for an individual patient.Int J Appl Sci Biotechnol, Vol 3(2): 139-142 DOI: http://dx.doi.org/10.3126/ijasbt.v3i2.12545

Systematic 3D Screening of Amino Acid Mutations in Pharmacogenes

The identification of genetic factors that influence drug responses often focuses on genes whose variants are predicted to alter pharmacokinetic and/or pharmacodynamic parameters—leading to an increased risk of drug toxicity or therapeutic failure. In this study, we selected 48 genes identified as “Very Important Pharmacogenes (VIPs)” by the PharmGKB database, and developed a fivefeature Structural Disturbance Score (SDS) for their amino acid variants. “SDS Pharmacogenes” is a score that categorizes distinguishable characteristic profiles that annotate VIP variants as functional rather than neutral mutations. Unlike most existing conservation-based measures, SDS Pharmacogenes can be used to evaluate unknown variants of currently 45/48 VIPs and predict the degree to which each one will have strong impacts towards pharmacogenomics, potentially aiding optimization of drug therapy. SDS Pharmacogenes is built upon a systematic screening for structural disturbance of amino acid mutations within the 45/48 VIPs in the context of their 3-dimensional (3D) protein structures. Our variant evaluation pipeline focuses on the changes in inter-residue bonding, protein stability, protein flexibility, drug binding capability, protein-protein interactions, and amino acid dissimilarity, in addition to the localization of the variants and the amino acid secondary structure preference. While expertise in 3D-protein analysis is beneficial, our implementation does not require that an individual with experience in protein structures be engaged in the personalized genome evaluation, nor expect the users must have bioinformatic backgrounds. In addition, the analysis pipeline is systematic and scalable, thus expected to keep pace with the rapid accumulation of pharmacogenomic data. The SDS Pharmacogenes web application is publicly available at http://sdsp. cig.biology.gatech.edu. Keywords: 3D protein structures, amino acid mutations, PharmGKB, SDS pharmacogenes, structural analysis, structural disruption index (SDI), structural disturbance score (SDS), very important pharmacogenes (VIP).

Mechanism of Altered Metformin Distribution in Nonalcoholic Steatohepatitis.

Metformin is an antihyperglycemic drug that is widely prescribed for type 2 diabetes mellitus and is currently being investigated for the treatment of nonalcoholic steatohepatitis (NASH). NASH is known to alter hepatic membrane transporter expression and drug disposition similarly in humans and rodent models of NASH. Metformin is almost exclusively eliminated through the kidney primarily through active secretion mediated by Oct1, Oct2, and Mate1. The purpose of this study was to determine how NASH affects kidney transporter expression and metformin pharmacokinetics. A single oral dose of [14C]metformin was administered to C57BL/6J (wild type [WT]) and diabetic ob/ob mice fed either a control diet or a methionine- and choline-deficient (MCD) diet. Metformin plasma concentrations were slightly increased in the WT/MCD and ob/control groups, whereas plasma concentrations were 4.8-fold higher in ob/MCD mice compared with WT/control. The MCD diet significantly increased plasma half-life and mean residence time and correspondingly decreased oral clearance in both genotypes. These changes in disposition were caused by ob/ob- and MCD diet–specific decreases in the kidney mRNA expression of Oct2 and Mate1, whereas Oct1 mRNA expression was only decreased in ob/MCD mice. These results indicate that the diabetic ob/ob genotype and the MCD disease model alter kidney transporter expression and alter the pharmacokinetics of metformin, potentially increasing the risk of drug toxicity.

Pharmacokinetic studies in infants using minimal-risk study designs.

Infants are therapeutic orphans. Many drugs used in infants are used "off-label", increasing the risk of drug toxicity and suboptimal efficacy in this vulnerable population. This knowledge gap in clinical pharmacology is partly attributed to challenges associated with conducting clinical trials in infants. Consequently, there is a need for novel and efficient study designs more suited to this population. Available literature describing the use of minimal-risk approaches to characterize the pharmacokinetics (PK) of drugs in infants was critically reviewed. Population PK approach with sparse sampling was found to be well established. Other, more recent alternatives, like dried blood spots sampling, opportunistic design, and the use of non-blood matrices are promising strategies with an increasing number of applications in infants. Physiologically based pharmacokinetic modeling provides valuable insight in drug disposition but still needs more prospective validation. Increasing experience with these methods provides understanding of their strengths and limitations and will help improve the design of future PK studies in infants.

Evolution trends over three decades of HIV infection late diagnosis: the experience of a Portuguese cohort of 705 HIV-infected patients.

IntroductionLate HIV diagnosis is common and associated with an increased risk of clinical progression, blunted immune response on antiretroviral (ARV) therapy and higher risk of drug toxicity. Across Europe, more than a third of patients are diagnosed late and consequently delay medical care. European Consensus definition group identify as late presentation (LP) persons, presenting for care, with a CD4 count below 350 cell/mm3 or presenting with AIDS-defining event, regardless of CD4 cell count. Additionally, advanced HIV disease (AD) is defined by a CD4 count below 200 cell/mm3 or an AIDS defining condition in persons presenting to care.Materials and MethodsRetrospective observational study of a cohort of 705 HIV-infected patients diagnosed between 1986 and 2014 and medically followed at an Infectious Diseases Service in Lisbon.ObjectivesEvaluate LP rate evolution in the last three decades (10-year time intervals considered: 1986–1995; 1996–2005; 2006–2014); compare clinic, immunologic, virologic and therapeutic response over time. Identify main reasons responsible for late HIV diagnosis in order to promote optimized intervention strategies. SPSS version 20.0 was used for statistical analysis.ResultsStudy included 705 patients HIV diagnosed during 3 time intervals: group A n=82 [1986–1995]; group B n=332 [1996–2005]; group C n=291 [2006–2014]. Demographic and epidemiological characterization revealed (A vs B vs C): male predominance of 79% vs 66% vs 66%; mean age at diagnosis 30 vs 36 vs 42 years; Portugal (82% vs 70% vs 58%) and Africa (13% vs 23% vs 29%) as the main places of birth; transmission by heterosexual contact in 21% vs 47% vs 62%, MSM in 21% vs 15% vs 23% and IVDU in 57% vs 35% vs 13%. Mean CD4 at diagnosis was 362 vs 344 vs 377 cell/mm3. Considering the time intervals, LP was found in 52% vs 56% vs 52% of patients and AD in 31% vs 38% vs 35%, respectively. At first health care encounter, 46% vs 43% vs 39% of individuals presented with AIDS. Over follow up, the vast majority initiated ARV (95% vs 98% vs 84%) and mean CD4 at that time was 254 vs 282 vs 250 cell/mm3. The last immunologic and virologic determination available registered mean CD4 of 657 vs 644 vs 584 cell/mm3 and undetectable HIV plasma RNA in 92% vs 84% vs 82% of treated patients.ConclusionsThis study evidenced a maintained LP rate, slightly above 50% in each of the three analyzed last decades, and one-third of patients presented AD at HIV diagnosis. At initial health care contact, nearly 40% of individuals met AIDS clinical or immunological criteria.

The effect of two novel cholesterol-lowering agents, disodium ascorbyl phytostanol phosphate (DAPP) and nanostructured aluminosilicate (NSAS) on the expression and activity of P-glycoprotein within Caco-2 cells.

BackgroundMany drugs are substrates for P-glycoprotein (P-gp) and interactions involving P-gp may be relevant to clinical practice. Co-administration with P-gp inhibitors or inducers changes the absorption profile as well as the risk for drug toxicity, therefore it is important to evaluate possible P-gp alterations. The purpose of this study was to investigate the effect of two novel cholesterol-lowering agents, disodium ascorbyl phytostanol phosphate (DAPP) and nanostructured aluminium silicate (NSAS), a protonated montmorillonite clay, on mdr-1 gene expression and its protein, P-glycoprotein (P-gp) within Caco-2 cells.MethodsThe effects of DAPP and NSAS on the regulation of mdr-1 gene, P-gp protein expression and activity within Caco-2 cells, were determined using cell viability and cytotoxicity tests, RT-PCR, Western Blot analysis and bi-directional transport studies.ResultsWe observed a significant down-regulation of mdr-1 mRNA (e.g. 38.5 ± 17% decrease vs. control at 5 μM DAPP and 61.2 ± 25% versus control at 10 μM DAPP; n = 6, P* < 0.05) within Caco-2 cells. Western Blot analysis of P-gp expression showed that changes in mdr-1 gene expression lead to correlating changes in P-gp protein expression. This down-regulation of P-glycoprotein also resulted in decreased activity of P-glycoprotein compared to untreated control. In contrast, when Caco-2 cells were treated with NSAS, no changes in mdr-1 gene expression, P-gp protein expression nor P-gp activity were observed.ConclusionsDAPP but not NSAS decreases P-gp mediated drug efflux through decreased mdr-1 gene expression and consequently decreased P-gp protein expression. These findings have to be taken into consideration when DAPP is concurrently given with other drugs that are substrates for P-gp since drug-drug interactions harbour a safety issue and alter bioavailability profiles.NSAS does not have any P-gp altering properties and therefore might not affect drug-drug interactions. We conclude from this study that NSAS might make a safer drug candidate compared to DAPP for lowering LDL-cholesterol.

English

INTRODUCTION: Central neuraxial blocks with local anaesthetics are popular techniques of anaesthesia which have been extensively used for lower abdominal surgery. Subarachnoid block is a simple technique which requires a small dose of local anaesthetic to provide rapid and reliable surgical anaesthesia and minimal risk of drug toxicity. Duration of spinal anaesthesia may be prolonged by addition of opioids, clonidine, neostigmine, or vasoconstrictor agents to the local anesthetic drug for better post-op pain relief. Intrathecal addition of a low dose of α2-agonist like clonidine or dexmedetomidine results in significant prolongation of the duration of the sensory and motor blockade induced by hyperbaric bupivacaine. This study is designed to investigate the effects of intravenous dexmedetomidine on the duration of sensory and motor blockade induced by intrathecal administration of bupivacaine, and its associated adverse events. AIMS AND OBJEVCTIVES: To determine effect of intravenous Dexmedetomidine on the duration of analgesia with spinal Bupivacaine for adult patients undergoing herniorrhaphy and to assess the incidence of intra operative side effects, if any. STUDY SETTING: This study was done under the department of Anaesthesiology, Azeezia Medical College from March 2013 to October 2013. STUDY DESIGN: A double blind prospective randomized control study was done.50 adults aged 20 to 60 years scheduled for herniorrhaphies were allocated into two study groups, named A and B using computer generated randomization. INTERPRETATIONS AND CONCLUSION: The duration of analgesia of subarachnoid block with heavy 0.5% bupivacaine with intravenous infusion of saline and dexmedetomidine were compared. Post-operative pain was evaluated by Visual Analogue Scale. Duration of analgesia is the time taken from the administration of the drug to the time when the patient complains of pain of > 50 in Visual Analogue Scale. The duration of analgesia was longest in patients received intravenous dexmedetomidine along with spinal bupivacaine. There were no significant differences between the groups for the time of onset of sensory blockade and time to achieve maximum sensory blockade. Incidence of hypotension and bradycardia were not clinically and statistically significant in both groups. Incidence of postoperative nausea and vomiting was also similar in both the groups. Side effect like respiratory depression not observed in either group. In conclusion, Intravenous infusion of dexmedetomidine added to subarachnoid block with bupivacaine offered prolonged analgesia in adult patients undergoing herniorrhaphies, without increasing the

Incidence of Antiretroviral Drug Interactions During Hospital Course: The Role of a Pharmacist-Led Antiretroviral Stewardship Program.

Background: Human immunodeficiency virus (HIV) providers are treating more comorbid conditions with additional pharmacologic agents, resulting in patients with HIV being disproportionately at risk for clinically significant drug-drug interactions (CSDDIs). There is a potential to overlook these interactions and ultimately place patients at risk for drug toxicity, resistance, and virologic failure. Objective: To assess the burden of CSDDIs among patients receiving antiretroviral therapy (ART) within 24 hours of admission and to evaluate the effect of a clinical pharmacist operating through an antiretroviral stewardship (ARVSP) program in identifying and correcting potential drug interactions. Methods: Adult HIV-positive patients receiving ART who were admitted to The Brooklyn Hospital Center from November 2010 through January 2012 were included in the analysis. Drug interactions were categorized according to time frame (ie, within 24 hours of admission vs after 24 hours of admission) and type (ie, contraindicated combinations, dosage modifications, and frequency alterations). The Liverpool HIV drug reference, Micromedex drug database, and the Department of Health and Human Services Guidelines were used as comprehensive tools for identification of antiretroviral drug errors. Results: Eighty-four CSDDIs were identified from 252 admissions among 158 patients receiving ART during the study period. Of the identified CSDDIs, 61 (73%) occurred within 24 hours of admission and 23 (27%) later in the hospital course. Forty-eight drug interactions (57%) represented contraindicated drug combinations. Protease inhibitor-based regimens were associated with the highest percentage of CSDDIs (98%). Of all CSDDIs, the most common interacting drug class was acid-suppressive therapy (63%). Clinical pharmacists identified and intervened in 80% of the CSDDIs that occurred on patient admission with all interventions accepted. Conclusions: CSDDIs are common among patients receiving ART at the time of admission and throughout the hospital course. Interventions including medication review by clinical pharmacists are critical in the prevention of CSDDIs on admission.

Increased incidence of antiretroviral drug discontinuation among patients with viremic hepatitis C virus coinfection and high hyaluronic acid, a marker of liver fibrosis

Most antiretroviral drugs are metabolized by the liver; hepatic disease or liver damage as a result of hepatitis C virus (HCV) could impair this metabolism leading to an increased risk of drug toxicity. This study aimed to determine the risk of antiretroviral drug discontinuation among HCV/HIV coinfected patients. EuroSIDA patients taking combination antiretroviral therapy were included. Poisson regression identified factors associated with antiretroviral treatment discontinuation. A total of 9535 HIV-positive patients with known HCV status were included (6939 HCVAb-negative; 2596 HCVAb-positive at baseline). Viremic HCV infection was associated with a 44% increased risk of antiretroviral drug discontinuation compared with aviremic infection [adjusted incidence rate ratio, aIRR: 1.44 (95% confidence interval, CI 1.22-1.69)]; this relationship was largest among nonnucleoside reverse transcriptase inhibitors [aIRR: 1.59 (95% CI 1.18-2.14)]. In the subset of 935 HIV-positive patients also HCV-positive or HBV-positive with plasma hyaluronic acid measured, hyaluronic acid more than 100 ng/ml was associated with a 37% increased risk of antiretroviral drug discontinuation [aIRR: 1.37 (95% CI 1.08-1.73) vs. hyaluronic acid ≤100 ng/ml] and the effect of HCV viremia became nonsignificant; the largest drug association was seen for protease inhibitors [aIRR: 1.40 (95% CI 1.04-1.89)]. HCV viremia and high levels of hyaluronic acid predict antiretroviral drug discontinuation. Evidence was also found to suggest a link between impaired liver function and protease inhibitor toxicity.

Ganciclovir-resistant cytomegalovirus infection in renal transplantation

Cytomegalovirus (CMV) infection is an important cause of morbidity in renal transplant recipients, due to both direct and indirect effects of the virus on the graft and patient [1]. Ganciclovir (GCV) remains the most common first-line therapy, but its low oral bioavailability was identified as a risk factor for the emergence of resistant strains [1], and intravenous (IV) administration is inconvenient for use in prophylactic or pre-emptive therapy. Valganciclovir (VGCV) is a prodrug of GCV with a much higher oral bioavailability, which makes it very useful for prophylaxis and pre-emptive therapy, as well as for treatment in selected patients [2–4]. Although initially associated with a negligible risk of drug resistance [5], subsequent papers identified patients with GCV-resistant CMV infection after VGCV prophylaxis and treatment [6, 7]. Patients with drug-resistant CMV strains often have more tissue-invasive disease and unfavourable clinical outcomes [8, 9], but there is some heterogeneity, and reports of asymptomatic infection, particularly in non-lung transplant recipients, suggest that some mutations are less pathogenic than others [10]. The therapeutic approach is a challenge and must balance the severity of the infection against the risks of drug toxicity and reduction of immunosuppression. We report two cases of GCV-resistant CMV from our unit: the first is a case of invasive CMV disease in a low-risk renal transplant recipient while on therapy with VGCV, and the second is a high-risk patient who developed GCV-resistant CMV infection while on VGCV prophylaxis.