Development Of Adverse Drug Reactions Research Articles

Clinical and genetic characteristics of juvenile myoclonic epilepsy

Juvenile myoclonic epilepsy (JME) is reported as a clinically and genetically heterogeneous disease with a high risk of inheritance. The aim of the study was to establish phenotype features and genetic risk factors for juvenile myoclonic epilepsy to advance existing approaches of prevention, treatment, and observation of patients with JME. Methods: anamnestic; clinical; neurophysiological (EEG); neuroradiological (MRI), neuropsychological; laboratory (DNA-diagnostics). JME starts with absences more frequently in females as compared to males (32.0% vs. 15.4%), and with GTCS and myoclonic in males as compared to females (46.2% and 36.5% vs. 36.0% and 31.2%, respectively). The 1st phenotype of JME was more frequently encountered in male individuals in comparison with female ones (55.8% vs. 34.7%), and the 2nd phenotype was more frequently encountered in female individuals in comparison with male ones (16.9% vs. 5.8%). Homozygous carriage of the T allele of the GJD2 gene (rs3743123) was associated with the development of JME in the study population, OR = 2.66 (95% CI 1.24 to 5.74). 41.5% of patients with JME have a slow metabolizer pharmacogenetic status, which is a risk factor for pseudo-pharmacoresistance and the development of adverse drug reactions.

Study of Safety of Medicinal Products in Pregnant Women in Crimea

According to international epidemiological studies, about 80% of women have to use medicinal products during pregnancy, mainly during the first weeks of organogenesis in the case of an unplanned pregnancy, and for the treatment of chronic diseases or acute conditions developing during pregnancy. Specificity of pharmacokinetics and pharmacodynamics in pregnant women contributes to the development of adverse drug reactions (ADRs), many of which are serious and pose a threat to the life of the patient. The aim of the study was to retrospectively assess the frequency and development of ADRs in pregnant women living in the Republic of Crimea, based on the data in the regional safety database ARCADe (Adverse Reactions in Crimea, Autonomic Database). Materials and methods: the authors analysed spontaneous ADR reports registered in the ARCADe database from 1 January 2009 until 31 December 2018 for the category of patients described as “Pregnant women/childbirth”. Results: during the specified period, 268 ADR cases in pregnant women were added to the database. The most common reasons of ADRs in this category of patients were antibacterials for systemic use (130 cases, 48.5%), agents that have an effect on haematopoiesis and blood (54 cases, 20.15%), and agents that have an effect on the functions of the gastrointestinal tract (29 cases, 10.82%). The study of ADR clinical manifestations revealed a high incidence of local allergic reactions (140 cases, 52.2%), inhibition of haematopoiesis (60 cases, 22.4%), and dyspepsia (36 cases, 13.4%). The analysis of the severity of the registered ADRs demonstrated that in 15 cases (5.6%) the use of the prescribed medicinal product posed a threat to the patient’s life and required urgent pharmacotherapy and discontinuation of the suspected medicine, in 8 cases (3%) it resulted in hospitalisation or prolongation of hospital treatment, and in 3 cases (1.12%) it resulted in the temporary inability to work. Conclusions: the results of the study indicate the need for further retrospective and prospective studies aimed at analysing the safety of medicine use in pregnant women and assessing the risks of toxic effects on the foetus.

Medication Usage Evaluation in Patients Prescribed with Ganciclovir in Bone Marrow Transplantation

Background: Cytomegalovirus (CMV) is one of the leading risks in bone marrow transplantation for which Ganciclovir is choice of therapy requiring monitoring due to its cytotoxic potential.
 Study objectives: The aim of this study was to assess the use of Ganciclovir in the management of CMV in hemato-oncologic patients.
 Methods: The study was designed to assess the usage pattern of Ganciclovir in concordance with the predefined assessment criteria. The medical record of patients was extracted by a senior clinical pharmacist from the specialty of hematology-Oncology in a hospital located in Karachi, Pakistan. Patients’ records of 2016-2017 (24 months) were collected both retrospectively and prospectively to review with CMV positive infection; the nurses’ performance regarding drug storage, handling, and preparation for administration was also observed. Assessment criteria were developed to evaluate the appropriateness of Ganciclovir use by applying standard treatment guidelines adapted from the Lexicomp drug monograph specifying its usage details, USP 800 (United States Pharmacopeia) and NIOSH Guidelines The collected data were categorized and analyzed by using Statistical Package for Social Sciences software, version 16.0.
 Results: For this study, 42 cases with CMV positive infection were observed. Out of n= 42 cases, n= 23 (54.76%) had drug interaction with mycophenolate mofetil and n= 1 (2.38%) case had drug interaction with imipenem cilastatin. Ganciclovir was stopped in n= 8 (19.04%) patients due to development of adverse drug reaction (febrile neutropenia). It was observed by the senior clinical pharmacist that neither the pharmacists nor the nurses were aware of protocol for Ganciclovir handling as per standard treatment guidelines.
 Conclusion: Ganciclovir was inappropriately managed by the Nurses and Pharmacists which can be improved by developing and implementing local guidelines according to standard protocol.

Treating COVID-19: Review of Drug Hypersensitivity Reactions

The disease caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ie, coronavirus disease 2019 (COVID-19), has become a global pandemic since it was first reported in Wuhan, China in December 2019. Its severe clinical manifestations, which often necessitate admission to intensive care units, and high mortality rate represent a therapeutic challenge for the medical community. To date, no drugs have been approved for its treatment, and various therapeutic options are being assayed to address the pathophysiological processes underlying the clinical manifestations experienced by patients. New and old drugs administered as monotherapy or in combination to immunologically compromised patients may favor the development of adverse drug reactions, including drug hypersensitivity reactions, which must be identified and managed accordingly. Given the lack of herd immunity and the high rate of viral contagion, new cases are expected to emerge in the coming months. Thus, the probability of more adverse reactions or even new clinical manifestations may increase in parallel. Allergists must receive updated information on these treatments, as well as on the management of possible drug hypersensitivity reactions.

Withdrawal of antihypertensive drugs in older people.

Hypertension is an important risk factor for subsequent cardiovascular events, including ischaemic and haemorrhagic stroke, myocardial infarction, heart failure, chronic kidney disease, cognitive decline and premature death.Overall, the use of antihypertensive medications has led to reduction in cardiovascular disease, morbidity rates and mortality rates.However, the use of antihypertensive medications is also associated with harms, especially in older people, including the development of adverse drug reactions, drug-drug interactions and can contribute to increasing medication-related burden.As such, discontinuation of antihypertensives may be considered and appropriate in some older people. To investigate whether withdrawal of antihypertensive medications is feasible, and evaluate the effects of withdrawal of antihypertensive medications on mortality, cardiovascular outcomes, hypertension and quality of life in older people. The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to April 2019: the Cochrane Hypertension Specialised Register, CENTRAL (2019, Issue 3), Ovid MEDLINE, Ovid Embase, the WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also conducted reference checking, citation searches and, when appropriate, contacted study authors to identify any additional studies. The searches had no language restrictions. We included randomised controlled trials (RCTs) of withdrawal versus continuation of antihypertensive medications used for hypertension or primary prevention of cardiovascular disease in older adults (defined as 50 years and over). Participants were eligible if they lived in the community, residential aged care facilities, or were based in hospital settings. We sought to include trials looking at the complete withdrawal of the antihypertensive medication, and those focusing on a dose reduction of the antihypertensive medicine. We compared the intervention of discontinuing or reducing antihypertensive medication to usual treatment using mean differences (MD) and 95% confidence intervals (95% CIs) for continuous variables and we used Peto odds ratios (ORs) and 95% CI for binary variables. Our primary outcomes included: mortality, myocardial infarction, development of adverse drug reactions or adverse drug withdrawal reactions.Secondary outcomes included: blood pressure, hospitalisation, stroke, success of withdrawing from antihypertensives, quality of life, and falls.Two authors independently, and in duplicate,conducted all stages of study selection, data extraction and quality assessment. Six RCTs met the inclusion criteria and were included in the review (1073 participants). Study duration and follow-up ranged from 4 weeks to 56 weeks.Meta-analysis of studies showed that, in the discontinuation group compared to continuation, the odds for all-cause mortality were 2.08 (95% CI 0.79 to 5.46; low certainty of evidence), for myocardial infarction 1.86 (95% CI 0.19 to 17.98; very low certainty of evidence) and for stroke 1.44 (95% CI 0.25 to 8.35; low certainty of evidence). Blood pressure was higher in the discontinuation group than the continuation group (systolic blood pressure: MD = 9.75 mmHg, 95% CI 7.33 to 12.18; and diastolic blood pressure: MD = 3.5 mmHg, 95% CI 1.82 to 5.18; low certainty of evidence). For the development of adverse events, meta-analysis was not possible; antihypertensive discontinuation did not appear to increase the risk of adverse events and may lead to resolution of adverse drug reactions, although eligible studies had limited reporting of adverse effects of drug withdrawal (very low certainty of evidence).One study reported hospitalisation with an odds ratio of 0.83 for discontinuation compared to continuation (95% CI 0.33 to 2.10; low certainty of evidence). No studies were identified which reported falls. Between 10.5% and 33.3% of participants in the discontinuation group compared to 9% to 15% in the continuation group experienced raised blood pressure or other clinical criteria (as pre-defined by the studies) that would require restarting of therapy/removal from the study. The sources of bias included selective reporting (reporting bias), lack of blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), and lack of blinding of participants and personnel (performance bias). There is no evidence of an effect of discontinuing compared with continuing antihypertensives used for hypertension or primary prevention of cardiovascular disease in older adults on all-cause mortality and myocardial infarction. The evidence was low to very low certainty mainly due to small studies and low event rates. These limitations mean that we cannot make any firm conclusions about the effect of deprescribing antihypertensives on these outcomes. Future research should focus on populations with the greatest uncertainty of the benefit:risk ratio for use of antihypertensive medications, such as those with frailty, older age groups and those taking polypharmacy, and measure clinically important outcomes such as falls, quality of life and adverse drug events.

Self-medication Practice of Antibiotics among Medical and Dental Undergraduate Students in a Medical College in Eastern Nepal: A Descriptive Cross-sectional Study.

Self-medication plays significant role in the development of adverse drug reactions, antibiotic resistance, and masking of underlying diseases. Medical students have some knowledge about the use of antibiotics and have a higher chance of irrational and injudicious use. This study aims to find the prevalence of self-medication practice of antibiotics among medical and dental undergraduate students. A descriptive cross-sectional study was done among medical and dental undergraduate students from the first year to the fifth year at BP Koirala Institute of Health Sciences from 1st June 2018 to 30th August 2018. Ethical approval was obtained from the Institutional Review Committee (IRC/1210/018). Whole sampling was done. Data was collected using a self-responding, semistructured questionnaire and analyzed using Statistical Package for the Social Sciences version 11.5. In total 558 students, the prevalence of self-medication practice of different antibiotics was 285 (51.1%) within the past year. Among self-medicated students, 152 (53.3%) were males. The common drug self-medicated was Azithromycin 80 (28.1%) and the common medical condition to use non-prescription antibiotics was for treatment of sore throat with runny nose 129 (45.3%). The main source for obtaining non-prescription antibiotics were retail pharmacies 157 (55.1%). Self-medication with antibiotics was at increasing rate with each succeeding years of the medical courses. Medical students should be made aware of the rational use of antibiotics by incorporating appropriate courses in their academic curriculum for more refined practice on antibiotics rather than advancement of theoretical knowledge alone.

Determinants of health-related quality of life in patients with hypertension

Background: Health-related quality of life (HRQOL) is emerging as an important outcome in hypertension and can be adversely affected by hypertension itself and side effects of antihypertensive drugs. Aim and Objective: The aim of the study was to analyze the HRQOL of hypertensive patients and to identify the factors affecting HRQOL, especially drug related factors. Materials and Methods: A total of 254 patients, who fulfilled the selection criteria, were enrolled for the study. Patients were approached after they finished consultation with the physician and their case record sheets were reviewed for gathering the necessary information as per case record form. Patients’ HRQOL was assessed using MINICHAL scale. Results: Among total 254 patients, patients with pre-hypertension, Stage 1, and Stage 2 of hypertension were 152, 73, and 29, respectively. Blood pressure (BP) controlled was achieved in only 31.5% of patients with drug therapy. The average scores in mental and somatic domains of MINICHAL scale were 2.5 ± 2.6 (95% confidence interval [CI]: 2.3–2.9) and 3.1 ± 3.5 (95% CI: 3.0–4.0), respectively, with mean total score of 5.5 ± 5.3 (95% CI: 4.6–6.0). Males have significantly lower MINICHAL score (P < 0.01) than females. Patients, who were living with family (P < 0.046), with illiterate (P = 0.001), with regular physical exercise (P = 0.004), and with controlled BP (P < 0.05), have significantly lower MINICHAL score. HRQOL was not significantly different in patients of any age, number of drugs prescribed, severity and duration of hypertension, concomitant disease, salt restriction, and selection of drugs, coprescription of antiplatelet, or statins or development of adverse drug reactions. Conclusion: This study has shown the lower HRQOL among hypertensive patients, and it was associated with gender, education, physical exercise, and BP control achieved.

RISK MANAGEMENT OF USE DRUGS WITH NARROW THERAPEUTIC INDEX IN CLINICAL PRACTICE. Review

Relevance. Today, the pharmacotherapy of many diseases is significantly expanded. However, the amount of pathological conditions associated with the use of drugs has increased. Drug related problems in some cases can be fatal and increase health care costs. It is necessary to be able to anticipate in advance the possibility of developing such conditions, to prevent them. Therefore, the analysis of the causes and mechanisms of development of these conditions is relevant.&#x0D; Objective. To find out the most common causes of drug related problems and consider the mechanisms of such states.&#x0D; Methods. Analysis of scientific publications in PubMed by keywords for the period 2001-2018.&#x0D; Results. The therapeutic index is the ratio of the dose that causes toxic effects in 50% of patients to the dose that causes the expected therapeutic effect in 50% of patients. The therapeutic index ≤ 3 is an indicator that defines drugs with narrow (small) therapeutic index. These drugs include insulin, digoxin, warfarin, levothyroxine, aminoglycoside antibiotics, carbamazepine, lithium, phenytoin, etc.&#x0D; The risks associated with these drugs are: the use of generic drugs with insufficient bioequivalence, pharmacokinetic interaction and polymorphism of genes of drug metabolism. The main mechanisms of their pharmacokinetic interaction at the stages of absorption (alteration of digestive tract motility, influence on the activity of P-glycoprotein), distribution (competition for blood plasma proteins and tissue proteins), and biotransformation (inhibition or induction of metabolism). The role of polymorphism of genes encoding the activity of isoenzymes cytochrome P450 2C9 and 1A2 and glycoprotein P in the development of adverse drug reactions of drugs with a narrow therapeutic index is presented.&#x0D; Conclusion. Risk management of using drugs with a narrow therapeutic index should include therapeutic drug monitoring of especially generic drugs, assessment of the risks of pharmacokinetic interaction, widespread introduction pharmacogenetic tests for determine the polymorphism of the genes of metabolism enzymes and drug transporters in the clinical practice.

Safety of Cholinesterase Inhibitors and NMDA Receptors Antagonists for the Treatment of Patients with Dementia

For the treatment of dementia and Alzheimer’s disease, acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) and/or the non-competitive inhibitor of N-methyl-D-aspartate receptors (NMDA receptors) memantine are currently used. The administration of these drugs can help temporarily improve or stabilize memory impairments and other cognitive functions, regress behavioral disorders, reduce the patient’s dependence on others, but at the same time can lead to the development of adverse drug reactions. The aim of this study was to analyze the information on the safety of acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the non-competitive inhibitor of NMDA receptors used to treat dementia. It was shown that stimulation of cholinergic receptors can lead to adverse drug reactions as contraction and narrowing of the pupil (miosis), an increase in lens curvature, accommodation spasm (visual impairment and an increased risk of falls), a decrease in heart rate (bradycardia) and inhibition of conduction of impulses through the conducting system heart, increased tone of the bronchi, gastrointestinal tract, gall and bladder, decreased tone of the sphincters of the digestive tract and bladder, increased secretion of exocrine and glands of the stomach, agitation, confusion. Blockade of NMDA receptors due to impairment of glutamate metabolism in the central nervous system may be the cause of neurotoxicity of NMDA receptor antagonists, and also causes dizziness, feeling of tiredness, hallucinations, drowsiness, and confusion. In case of development of adverse reactions, if possible, it is necessary to stop using the drug or reduce its dose, in case of an overdose or other need, prescribe symptomatic therapy. Information on the safety of cholinesterase inhibitors and NMDA receptor antagonists presented in the article is of practical importance for healthcare professionals, as it allows them to assess the possible risks associated with the use of drugs of these groups more accurately. In addition, the information can be used to optimize and individualize the pharmacotherapy regimens for patients with dementia, including the development of domestic protocols for the deprescribing of drugs (evidence-based practice of withdrawal, replacement or gradual dose reduction) in the elderly.

Adverse Drug Reactions Associated with CYP 2B6 Polymorphisms in HIV/AIDS-Treated Patients in Yaoundé, Cameroon.

PurposeThe metabolism of antiretroviral drugs is subject to individual variations of the CYP 2B6 gene. The objective of this study was to evaluate the prevalence of CYP 2B6 516 G>T and 983 T>C polymorphisms and investigate their association with the development of adverse drug reactions (ADRs) in people living with HIV/AIDS in Cameroon.Patients and methodsA total number of 122 patients, attending the Yaoundé Central Hospital HIV Day Clinic, consented to take part in this study. Blood specimens were collected and DNA was extracted using the Chelex method. Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) was performed for the detection of CYP 2B6 Single-Nucleotide Polymorphisms (SNPs). Genotype frequencies were compared between groups with or without ADRs. Logistic regression analysis was performed to assess association between genotype and adverse effects of antiretroviral therapy (ART).ResultsThree types of metabolizers were identified: extensive, intermediate and slow. For the 516G>T polymorphism, prevalences of 8.2% GG, 65.6% GT and 26.2% TT were obtained. For the 983T>C polymorphism, 89.3% TT, 4.1% CT and 6.6% CC prevalences were obtained. Those homozygous for the wild-type allele (516GG) were less likely to develop ADR with a statistically significant difference (OR=0.885, P=0.029). For the CYP2B6 T983C SNP, homozygous mutants (CC) may present a higher risk (threefold) of developing adverse reactions (OR=2.677, P=0.164).ConclusionThese findings demonstrate that ADRs among HIV/AIDS patients under ART may be associated with the genetic variability of the metabolizing enzyme CYP 2B6. Genotyping for this gene may guide the better administration of Efavirenz and Nevirapine to Cameroonian patients.

Predictors of adverse drug reactions associated with ribavirin in direct-acting antiviral therapies for chronic hepatitis C.

To identify factors associated with the development of adverse drug reactions (ADR) in ribavirin therapeutic regimens. A multicenter, prospective study was conducted in three public health hospitals in Rio de Janeiro between November 2015 and March 2018. Inclusion criteria were defined by patient follow-up at pharmaceutical consultation at the time of drug dispensing as those who used sofosbuvir in combination with simeprevir, daclatasvir, and/or ribavirin. All patients were invited to participate in the study during the first interview. Adverse drug reactions were reported according to the treatment regimen and frequency of occurrence. Statistical analysis was used to compare adverse reactions between treatments and their associated factors. A total of 405 patients were included in the study (mean age 59.6 ± 9.6 years); 61.0% were female, 88.1% were infected with genotype 1, and 65.4% were cirrhotic. The most prescribed treatment was the combination of sofosbuvir, daclatasvir, and ribavirin (55.3%). The majority of patients reported at least one ADR during treatment (83.2%), of which fatigue, anemia, and headache were the most common. Being female (OR = 1.86, [1.08-3.20]) and use of ribavirin (OR: 2.39; 95% CI [1.38-4.13]) were predictors for the development of ADR, which was also associated with development of anemia (OR: 10.28; 95% CI: [5.78-18.30]). Treatment efficacy was 98.1%. Direct-acting antiviral has been shown to be safe and effective. Therefore, use of ribavirin is questionable due to associated adverse reactions and similar efficacy to other treatments.

The study of adverse drug reactions of antihypertensive medicines in essential hypertension patients in Hi-Tech Medical College and Hospital, Bhubaneswar, Odisha, India

Background: Every drug has the potentiality to cause an adverse drug reaction (ADR). ADRs are a major problem in drug therapy .The aim of this study was to assess the incidence and causality of ADRs to antihypertensive agents used for the essential hypertensive patients attending at the general medicine out patients departments of Hi-Tech Medical College and Hospital, Bhubaneswar Odisha, during the time period of November 2016 to October 2018.Methods: This prospective-observational study was carried out in general medicine outpatient department of Hi-Tech Medical College and Hospital, Bhubaneswar, Odisha.Results: Out of 254 patients, 78 (30.71%) patients were developed ADRs to antihypertensive drugs. 51 (65.38%) were female and 27 (34.62%) were male. Calcium channel blockers were the commonest therapeutic class of antihypertensive drugs associated with ADRs (n = 50, 64.10%). According to WHO causality assessment scale most of the ADRs were “probable” 41 (52.56%), followed by “possible” 21 (26.92%), unclassifiable 13 (16.67%) and unlikely 3 (3.85%).Conclusions: The results of this study concluded that antihypertensive drugs able to induce the development of adverse drug reactions, which were significant cause of increase burden on health care system and decrease the quality of life, the health care professionals should take care about the rational use of antihypertensive agents. Thus, to minimize the incidence of adverse drug reaction and to increase the quality of life.

Examining the effect of prescription sequence on developing adverse drug reactions: The case of renal failure in diabetic patients

ObjectivesWhile the effect of medications in development of Adverse Drug Reactions (ADRs) have been widely studied in the past, the literature lacks sufficient coverage in investigating whether the sequence in which [ADR-prone] drugs are prescribed (and administered) can increase the chances of ADR development. The present study investigates this potential effect by applying emergent sequential pattern mining techniques to electronic health records. Materials and methodsUsing longitudinal medication and diagnosis records from more than 377,000 diabetic patients, in this study, we assessed the possible effect of prescription sequences in developing acute renal failure as a prevalent ADR among this group of patients. Relying on emergent sequential pattern mining, two statistical case-control approaches were designed and employed for this purpose. ResultsThe results taken from the two employed approaches (i.e. 76.7% total agreement and 68.4% agreement on the existence of some significant effect) provide evidence for the potential effect of prescription sequence on ADRs development evidenced by the discovery that certain sequential patterns occurred more frequently in one group of patients than the other. ConclusionGiven the significant effects shown by our data analyses, we believe that design and implementation of automated clinical decision support systems to constantly monitor patients’ medication transactions (and the sequence in which they are administered) and make appropriate alerts to prevent certain possible ADRs, may decrease ADR occurrences and save lives and money.

Recent Advances in Tuberculosis Drug Development

The emergence of drug-resistant tuberculosis is a growing disease worldwide. The lack of safe and effective drugs, together with the frequent development of adverse drug reactions could result in worse condition. Therefore, new drugs able to booster the current tuberculosis treatment regimen are urgently required. Novel drugs that are effective and safe against Mycobacterium tuberculosis are required to reduce the number of drugs and the duration of treatment in both drug-susceptible tuberculosis and multi-drug-resistant tuberculosis. Due to increased number of multidrugresistant and extensively drug-resistant strains and the ineffectiveness of the current treatment against latent tuberculosis are challenges to be overcome in future. The scenario of drug discovery becomes upsetting when it is considered that the number of new drugs does not increase proportionally to the emergence of drug resistance. In this review, we will demonstrate the recent advances in anti-tubercular drug discovery, centre of attention on the research of compounds with potent anti-tuberculosis activity against multidrug-resistant tuberculosis strains. Although, the best treatment regimen for achieving better results and preventing adverse drug reactions remains yet to be determined, with safety concerns regarding cardiac events due to QT prolongation still to be addressed. Therefore a simple and short treatment with higher efficacy, and lesser adverse drug reactions and drug-drug interaction is expected for patients with multidrug-resistant and extensively drug-resistant tuberculosis.

Role of personality traits in reporting the development of adverse drug reactions: a prospective cohort study of the Estonian general population

ObjectiveTo examine the role of the Five Factor Model (FFM) personality traits in reporting the development of adverse drug reactions (ADRs) when controlling for sociodemographic variables and health status.DesignProspective cohort...

Drug-Drug Interactions in Cocaine-users and their Clinical Implications.

Drug-Drug Interactions (DDIs) represent a common problem in clinical practice during drug treatments. DDIs can both induce the development of adverse drug reactions or reduce the clinical efficacy of each drug. The main objective of this review was to analyze the pharmacokinetic and pharmacodynamic DDIs in cocaine consumers, focusing the interest on their clinical implications. The PubMed, Embase and Cochrane library databases were searched for articles published until January 10, 2017. Secondary search included articles cited in reference lists identified by the primary search. Papers were deemed eligible if they included any form of words: "adverse drug reaction", "drug interactions", "poly-therapy", "cocaine", "systemic diseases". In this review, the nodal points treated concern: i) cocaine biochemical metabolism described for both, inactive benzoylecgonine and ecgonine methyl esters and norcocaine active metabolites. We provided evidences of concepts deriving from rat/mice experimental studies speculating a translation approach to human in order to treat cocaine overdose. ii) Drug-drug interactions, which come out from clinical evidences as the case of CYP450 family enzyme inhibitors or inductors modulating cocaine toxicity. Particularly, we highlighted the lack of knowledge concerning cocaine and CYP3A4 inhibitors (such as ketoconazole, nefazodone, erythromycin, and clarithromycin). We recorded the worst association of cocaine and beta-blockers by direct and indirect action, particularly at postsynaptic levels on dopamine and norepinephrine reuptake, sympathetic activation and increase of heart rate, blood pressure and cardiovascular toxicity. Cocaine also induces increase in serotonin synaptic activity leading to the development of a serotoninergic syndrome when used with drugs that affect serotonin pathway. Genetic (i.e. glutathione peroxidase-1 deficiency) and epigenetic factors (i.e. microRNAs) may be involved in drug-drug interactions in cocaine-users are also being introduced. DDIs represent an important potential complication in cocaine users in clinical setting. The knowledge of DDIs can also be used to select treatments for patients, thus optimizing clinical response and minimizing toxicity.

Severe eye complications from toxic epidermal necrolysis following initiation of Nevirapine based HAART regimen in a child with HIV infection: a case from Cameroon

BackgroundToxic epidermal necrolysis (TEN) is a rare life threatening dermatological disorder characterized by extensive epidermal detachment and erosion of mucous membranes. It is typically a side effect of some medications. Nevirapine, a nonnucleoside reverse transcriptase inhibitor (NNRTI) is one of the frequently used components of highly active antiretroviral therapy (HAART). Skin rash is its common adverse reaction, usually mild and rarely progressing to TEN. Ophthalmic involvement is common as well but rarely progresses to blindness especially in the pediatric population.Case presentationWe report the case of a 3 year 5 month old child diagnosed with HIV who developed TEN 8 days after starting a Nevirapine based HAART regimen. Drug withdrawal and supportive treatment alone were the modalities employed to achieve complete re-epithelization of lesions. Patient was lost to follow-up 6 months after being in care and was only seen 3 years later with total loss of vision.ConclusionBlindness, though rare, can be a long-term complication of TEN in children especially with HIV infection. Physicians and patient caregivers should closely monitor these patients, especially during their early stages of treatment amongst others for development of adverse drug reactions. Long-term retention in care is pivotal for identification and prompt management of ocular and other chronic complications, albeit recognizing management challenges in low resourced settings.

P.1.003 - Pharmacodynamics and pharmacokinetics related gene polymorphisms affect adverse drug reactions of haloperidol

The antipsychotic action of haloperidol is due to the blockade of D2 receptors in the mesolimbic dopamine pathway, while the adverse drug reactions are associated with striatal D2 receptors blockade. Contradictory data concerning the effects of genetic polymorphisms of genes encoding these receptors and associated structures (catechol-O-Methyltransferase, glycine transporter and gene encoding the density of D2 receptors on the neuronal membrane) [1,2], and also genes encoding the elements of haloperidol biotransformation system on haloperidol metabolism rate as well as plasma drug concentration ratio is described in patients with different genotypes [3,4]. To evaluate the correlation between DRD2, SLC6A3 (DAT) and COMT genetic polymorphisms and to investigate their effect on the development of adverse drug reactions in patients with alcohol use disorder who received haloperidol. The second objective of this study was to investigate the effects of CYP2D6 and CYP3A5 genetic polymorphisms on haloperidol equilibrium concentration in patients with alcohol use disorder. The study included 114 male patients (average age 38.12±9.08; median age 39; LQ 34; UQ 48). Bio-Rad CFX Manager™ software (USA) and "SNP-Screen" sets of "Syntol" (Russia) were used to determine polymorphisms rs4680, rs1800497, rs1124493, rs2242592, rs2298826, and rs2863170. In every “SNP-Screen” set, two allele-specific hybridizations were used, which allowed to determine two alleles of studied polymorphism separately on two fluorescence channels. Genotyping was performed using the allele-specific real-time PCR. CYP2D6 and CYP3A were phenotyped with high-performance liquid chromatography-mass spectrometry using concentration of endogenous substrate of the enzyme and its urinary metabolites (6-hydroxy-1,2,3,4-tetrahydro-beta-carboline(6-HO-THBC) to pinoline ratio [5] for CYP2D6 and 6-beta-hydroxycortisol to cortisol ratio for CYP3A). The equilibrium plasma concentration was determined using LC-MS-MS. Statistical analysis of the results was performed with non-parametric methods using the ”Statsoft Statistica v. 10.0“ (Dell Statistica, Tulsa, OK, USA). The normality of samples distribution was evaluated using W-Shapiro-Wilk test and taken into account when choosing a method. The differences were considered as statistically significant at р<0.05 (power in excess of 80 %). To compare two independent groups Mann-Whitney U test was used. Results of this study detected a statistically significant difference in the adverse drug reactions intensity in patients receiving haloperidol with genotypes 9/10 and 10/10 of polymorphic marker SLC6A3 rs28363170. In patients receiving haloperidol in tablets the increases in the UKU score of 10.99 ± 2.12 (10/10) vs 13.14 ± 2.08 (9/10) (p<0.001) and in the SAS score of 5.17 ± 1.49 (10/10) vs 6.88 ± 1.37 (9/10) (p=0.006) were revealed. The results of this study showed that equilibrium concentration level / dose index depends on CYP2D6 genetic polymorphism (0.19 [0.07; 0.43] vs 0.48 [0.38; 0.55], p=0.012). Polymorphism of the SCL6A3 gene can affect the safety of haloperidol, and that should be taken into account during the choice of drug and its dosage regimen. Also our study demonstrates that CYP2D6 genetic polymorphism (1846G>A) can affect haloperidol concentration levels in patients with alcohol use disorder.

Outcome of paracetamol poisoning after treatment with intravenous or oral N-acetylcysteine.

Introduction: Paracetamol (PCM) is one of the most common drug in clinical practice and it is generally safe for use at recommended doses. However, its overdose can cause mild hepatotoxicity to severe hepatic necrosis and even hepatic failure. N-acetylcysteine (NAC) is the standard recommended antidote for PCM poisoning which is available in both intravenous (IV) and oral formulations. This study aimed to measure outcome in PCM poisoning after treatment with oral or IV NAC.Methods: A descriptive cross-sectional study was conducted in randomly selected 50 consecutive patients presented within 72 hours of PCM poisoning. Comparative outcomes measured in correlation of dynamics of liver enzymes alanine aminotransferase, aspartate aminotransferase and prothrombin time along with development of adverse drug reactions and clinical cure rate. Comparison of categorical variables by Chi-square test and Fisher's test and the comparison of mean between groups by Student's t-test with p-value &lt;0.05 as statistically significant.Results: Among 50 cases 20 (40%) were treated with oral NAC and 30 (60%) with IV NAC. PCM poisoning was more common in young adults (15-30 years) with mean age of 19 (n=43; 86%) and most of them had taken with an intent of suicide (n=47; 94%). Majority of patients were asymptomatic at presentation with female preponderance (M:F=1:4; 80%). There was no statistical difference in both the treatment groups and as an outcome measure there were no severe liver enzymes derangement, no serious adverse drug reactions and 100% clinical cure rate.Conclusion: NAC in both IV and oral forms are equally effective as an antidote in PCM poisoning.

Time to development of adverse drug reactions and associated factors among adult HIV positive patients on antiretroviral treatment in Bahir Dar City, Northwest Ethiopia.

BackgroundAdverse drug reactions (ADRs) are harmful and unintended reactions to medicines given at standard doses. Although the antiretroviral treatment (ART) changed the global HIV epidemic significantly, it’s associated adverse events is huge. Therefore, investigating the rate and development of ADRs of ART provides vital information for monitoring risks.MethodsRetrospective study was conducted among patients on ART from July1/2011—June 30/2016 at Felege Hiwot referral hospital. Data were collected using checklist and document review. The p-value and hazard ratio with its confidence interval was used to show presence and strength of association.ResultsA total of 602 subjects were studied. The rate of occurrence of major ADRs was 4.3/100PY. Patients with no formal and completed primary education were at higher risk of developing ADRs compared to those with higher level education [AHR = 8, 95% CI: 2.53–25.20, AHR = 4.9, 95% CI: 1.65–14.44]. The risks of ADRs among patients working in NGOs were more than four times compared to those in governmental organizations [AHR = 4.3, 95% CI: 1.42–13.31]. The risks of ADRs in WHO clinical stage II, III and IV were much higher than in stage I [AHR = 4, 95% CI: 1.33–11.93, AHR = 5.3, 95% CI: 2.02–13.79 and AHR = 7, 95% CI: 2.51–20.10] respectively. Moreover, patients didn’t receive OI prophylaxis were more three times at risk of ADRs compared to those received [AHR = 3.2, 95% CI: 1.47–7.08].ConclusionsMost of the ADRs cases were occurred within a year after initiation of ART. Educational status, occupation, advanced clinical stage and OI prophylaxis therapy were predictors ADRs. Continuous counseling for non-educated patients and clients in clinical stage II and above, and patients didn’t take OI prophylaxis need to get close follow up to prevent the associated ADRs by the concerned parties.