Risk Of Gastrointestinal Side Effects Research Articles

Metformin-Associated Gastrointestinal Adverse Events Are Reduced by Probiotics: A Meta-Analysis.

Metformin, one of the most frequently used oral glucose-lowering drugs (GLDs), is associated with the occurrence of gastrointestinal (GI) adverse events in approximately 20% of users. These unwanted actions result in non-compliance or even discontinuation of metformin therapy. The aim of the presented meta-analysis was to determine whether adding a drug from the group of sulfonylureas, glitazones, DPP-IV inhibitors, or probiotics to metformin monotherapy may affect the risk of GI side effects. The material for this meta-analysis comprised data from 26 randomized controlled clinical trials (RCTs) published in English. This meta-analysis included 41,048 patients. The PubMed, Cochrane Library, and Clinical Trials databases were thoroughly searched to find relevant RCTs. The Population, Intervention, Comparison, Outcomes, and Study Type (PICOT) structure was used to formulate study selection criteria and the research question. Cochrane Review Manager Software 5.4 was used to carry out analysis of collected data. The results were presented as relative risk (RR) and 95% confidence interval (95% CI) for each group, and p < 0.05 was considered as statistically significant. As expected from clinical practice, metformin was associated with a markedly increased risk of abdominal pain, nausea, and vomiting compared to placebo. In comparison to other GLDs, taking metformin was related to an elevated risk of diarrhea and abdominal pain and to a lowered risk of vomiting and bloating. In turn, adding other GLDs to metformin treatment was associated with an elevated risk of nausea and vomiting than treatment with metformin in monotherapy. However, adding probiotics to metformin therapy was related to a decreased risk of diarrhea, bloating, and constipation. The obtained results demonstrate that the combination of metformin with other GLDs may elevate the risk of nausea and vomiting, whereas combination with probiotics decreases the risk of diarrhea, bloating, and constipation. Thus, the results of our meta-analysis suggest that probiotics may reduce the risk of some GI side effects in people with type 2 diabetes mellitus (T2DM) who started treatment with metformin.

Consensus statement on the management of hyperkalaemia-An Asia-Pacific perspective.

Hyperkalaemia is an electrolyte imbalance that impairs muscle function and myocardial excitability, and can potentially lead to fatal arrhythmias and sudden cardiac death. The prevalence of hyperkalaemia is estimated to be 6%-7% worldwide and 7%-10% in Asia. Hyperkalaemia frequently affects patients with chronic kidney disease, heart failure, and diabetes mellitus, particularly those receiving treatment with renin-angiotensin-aldosterone system (RAAS) inhibitors. Both hyperkalaemia and interruption of RAAS inhibitor therapy are associated with increased risks for cardiovascular events, hospitalisations, and death, highlighting a clinical dilemma in high-risk patients. Conventional potassium-binding resins are widely used for the treatment of hyperkalaemia; however, caveats such as the unpalatable taste and the risk of gastrointestinal side effects limit their chronic use. Recent evidence suggests that, with a rapid onset of action and improved gastrointestinal tolerability, novel oral potassium binders (e.g., patiromer and sodium zirconium cyclosilicate) are alternative treatment options for both acute and chronic hyperkalaemia. To optimise the care for patients with hyperkalaemia in the Asia-Pacific region, a multidisciplinary expert panel was convened to review published literature, share clinical experiences, and ultimately formulate 25 consensus statements, covering three clinical areas: (i) risk factors of hyperkalaemia and risk stratification in susceptible patients; (ii) prevention of hyperkalaemia for at-risk individuals; and (iii) correction of hyperkalaemia for at-risk individuals with cardiorenal disease. These statements were expected to serve as useful guidance in the management of hyperkalaemia for health care providers in the region.

Co-Occurrence of Familial Mediterranean Fever and Hematologic Malignancies: Case Report Series

Introduction: Familial Mediterranean Fever (FMF) is an autosomal recessive genetic disorder primarily found among individuals of Mediterranean descent, including Armenians, Italians, Greeks, Arabs, Turks and Jews. In the Armenian population, approximately 90% of FMF cases are associated with three main mutations (M694V, V726A, and M680I) in two alleles of MEFV gene, while more than 300 MEFV variants have been reported worldwide. The homozygous M694V genotype is associated with frequent renal failure due to amyloidosis. Clinical manifestations of FMF include periodic attacks of diffuse serositis with pain and fever that are treated with colchicine or biologic therapy. There is a scarcity of data on patients with FMF and hematologic malignancies. Limited data makes it difficult to generate evidence-based recommendations for the management of these patients, which is mostly based on expert opinions or few case reports. Here we report the case series of patients from Armenia with simultaneous presence of FMF and hematologic malignancies (FMFHM) and evaluate their management challenges. Methods: Data was collected from the Armenian National Registry of Blood Disorders, at the Hematology Center after Prof. R. Yeolyan, and through personal interviews conducted with each patient. Hematology Center is the only institution in Armenia managing hematologic malignancies. We have analyzed 8 patients diagnosed with both FMFHM during 2000-2020, treated in the pediatric (1 patient) and adult (7 patients) hematology departments. Results: 8 patients with FMFHM were identified, from which 4 were diagnosed with myeloproliferative neoplasms (MPN), 2 with acute leukemia (AL), and 2 with non-Hodgkin lymphoma (NHL). The median age of patients was 46, range 20-60 years. Only 5 (62.5%) of patients were regularly taking colchicine for FMF, while the rest refused it. Four MPN patients received treatment only with oral medications (tyrosine kinase inhibitors, hydroxyurea). Autologous hemopoietic stem cell transplantation (auto-HSCT) was performed in 1 NHL patient after indicated 1 st and 2 nd line immuno-chemotherapy. Another 2 AL patients and one NHL patient received protocol-based respective chemotherapy regimens. Moderate gastrointestinal (GI) complications (e.g., epigastric pain, nausea, vomiting, intestinal discomfort) was experienced by 7 (87.5%) patients. Allergic reactions (e.g., moderate skin rash, itching) were seen in 5 patient (62.5%), of which one developed severe anaphylactic shock. A patient with FMF and PMF had ischemic stroke caused by thrombi. Arterial hypertension occurred in 3 (37.5%). Only in one patient reduction of colchicine dosage was performed (1mg/day was reduced to 0.6mg/d), because of interaction with imatinib. The rest of patients received chemotherapy and colchicine treatment as indicated. All 8 patients are alive, 5 of them are in hematologic or molecular remission, two of which received concurrent colchicine treatment. One patient in remission developed renal failure due to FMF (colchicine was refused). Two patients with MPN treated with colchicine experienced disease stabilization. Conclusion: In conclusion, the concurrent appearance of FMFHM may potentially increase the risk of GI side effects, allergic complications, and arterial hypertension, however definitive conclusions require further investigations in larger patient cohorts. While the overall treatment responses were largely positive, the association between MEFV and HM mutations warrants deeper exploration to provide more precise drug administration recommendations for colchicine and cancer medications. Future studies in this area will contribute to a better understanding of the interplay between these conditions and guide optimal treatment strategies.

Pharmacist’s Comprehensive Medication Review in Deprescribing Chronic Medications at the End of Life

Appropriate medication management is essential to improve quality of life for patients with terminal illness. Individuals under hospice care are vulnerable to adverse drug events due to their terminal disease, multiorgan failure, and polypharmacy. Pharmacists are essential partners when it comes to participating in the care of hospice patients with complex medication regimens and to identifying treatments tailored to each patient. The purpose of this case report is to demonstrate the value of a pharmacist’s comprehensive medication review, assisted by a clinical decision support system, in deprescribing certain chronic medications for a patient in hospice care who had been chronically experiencing alternating episodes of constipation and diarrhea. This case describes a 64-year-old male with stage IV metastatic lung cancer who was presented to a pharmacist to complete a comprehensive medication review. Upon reviewing the patient’s medical history, goals of care, and medications, the pharmacist recommended to discontinue 1) aspirin to mitigate risk of gastrointestinal bleed; 2) simvastatin to improve quality of life and mitigate a Cytochrome P450 (CYP) 3A4 drug-drug interaction (DDI); 3) lactulose to mitigate risk of gastrointestinal side effects; 4) duloxetine to mitigate a CYP2D6 DDI; and 5) furosemide due to ineffective dose. The provider and the patient agreed to discontinue aspirin, simvastatin, and lactulose. The provider also deprescribed duloxetine and furosemide based on the pharmacist’s previous recommendations, and all discontinued medications were not restarted. Five months later, the patient reported to be doing well and continuing his weekly physical therapy sessions for gait and mobility.

Preferences for Anaemia Treatment Attributes among Patients with Non-Dialysis-Dependent Chronic Kidney Disease.

Information about patient preferences for the treatment of anaemia associated with chronic kidney disease (CKD) is scarce. Hence, our aim was to examine how patients with non-dialysis-dependent CKD valued attributes of alternative hypothetical anaemia treatments. A discrete choice experiment (DCE) was conducted in adult patients who reported a clinical diagnosis of CKD-related anaemia. Treatment attributes included mode and frequency of administration, need for iron supplementation, risk of gastrointestinal side effects, risk of major cardiovascular events and impact on energy levels (as defined by the vitality section of the SF-6D health index). Logit models were used to analyse patients' preferences. The DCE was completed by 200 patients in four countries. Patients preferred an oral mode of administration. Patients were willing to tolerate a 5.1% (95% CI 2.0-8.3%) increase in the risk of a major cardiovascular event and an 11.7% (95% CI 5.0-18.5%) increase in the risk of gastrointestinal side effects to switch from an at-home subcutaneous injection administered once every 2weeks to an at-home oral pill administered three times a week. Patients were willing to tolerate a 20.3% (95% CI 15.0-25.6%) increase in the risk of gastrointestinal side effects and an 8.9% (95% CI 6.1-11.7%) increase in the risk of a major cardiovascular event to transition from 'Sometimes having a lot of energy' to 'Always having a lot of energy'. Patients with non-dialysis-dependent CKD-related anaemia demonstrated clear treatment preferences and were willing to accept increased gastrointestinal or cardiovascular risks in exchange for more energy or an oral treatment.

Protocol for a multicenter, double-blinded placebo-controlled randomized controlled trial comparing intravenous ferric derisomaltose to oral ferrous sulfate for the treatment of iron deficiency anemia in pregnancy: The IVIDA2 trial

BackgroundIron deficiency anemia (IDA) is common during pregnancy and associated with adverse maternal and neonatal outcomes. Treatment with iron supplementation is recommended during pregnancy, but the optimal delivery route is unclear. Oral iron risks has high risk of gastrointestinal side effects and low absorption. Intravenous iron is infused directly but is expensive. The American College of Obstetricians and Gynecologists currently recommends oral iron to treat IDA in pregnancy with intravenous iron reserved as second-line therapy, if needed. This approach is associated with persistent anemia, increasing the risk of peripartum blood transfusion. We aim to provide data on optimal route of iron repletion for IDA in pregnancy. MethodsIn IVIDA2, a double-blind, placebo controlled, multicenter randomized trial in the United States, 746 pregnant people with moderate-to-severe IDA (hemoglobin <10 g/dL and ferritin <30 ng/mL) at 24–28 weeks' gestation will be randomized 1:1 to either a single 1000 mg dose of intravenous ferric derisomaltose and oral placebo (1–3 times daily) or a single placebo infusion with 1–3 times daily 325 mg ferrous sulfate (65 mg elemental iron) tablet. The primary outcome is peripartum blood transfusion (blood transfusion from delivery to 7 days postpartum). Secondary outcomes include adverse medication reactions, maternal and neonatal hematologic indices, and offspring neurodevelopment. Ethics and disseminationA central ethical review board—Advarra—granted ethical approval (Pro00060930). Participating centers—Women & Infants Hospital of Rhode Island, University of Michigan Medical Center, Washington University School of Ethics and dissemination: A central ethical review board—Advarra—granted ethical approval (Pro00060930). Participating centers—Women & Infants Hospital of Rhode Island, University of Michigan Medical Center, Washington University School of.

Formulation Optimization of Extemporaneous Oral Liquids Containing Naloxone and Propranolol for Pediatric Use

There is a need to develop dosage forms suitable for children to improve drug treatment. Extemporaneous compounding of drugs for children is one way to meet these needs. However, excipients generally considered as safe in adults may not be appropriate in dosage forms intended for children. The aim was to optimize the composition of two pediatric liquid preparations by substituting paraben as a microbiological preservative and ethanol as a solubilizer, with excipients more suitable for pediatric use. The oral liquids were Naloxone 1 mg/mL and Propranolol 10 mg/mL. Twelve different formulations were tested with propranolol and naloxone, respectively, during the screening process to select appropriate formulations. Sodium benzoate and glycerol were used as a preservative and solubilizer, respectively, and different pH of the formulations were evaluated. The formulations were characterized according to dispensed dose (dosing accuracy), viscosity and osmolality. The optimized formulations from the screening process were tested with two amounts of sodium benzoate and microbiological assays were performed. These formulations were shown to have satisfactory preservative properties and dosing accuracy. The results showed that the oral liquids could be prepared without the addition of solubilizer and with lower osmolality (naloxone), thus reducing the risk of gastrointestinal side effects.

Assessment of TRM-201 (Rofecoxib) Efficacy and Safety for Chronic Pain in Hemophilic Arthropathy: The Rofecoxib Efficacy and Safety Evaluation Trial in Hemophilic Arthropathy (RESET-HA), a Randomized, Double-Blind Placebo-Controlled Phase III Clinical Trial

Assessment of TRM-201 (Rofecoxib) Efficacy and Safety for Chronic Pain in Hemophilic Arthropathy: The Rofecoxib Efficacy and Safety Evaluation Trial in Hemophilic Arthropathy (RESET-HA), a Randomized, Double-Blind Placebo-Controlled Phase III Clinical Trial

Colchicine in Patients With Coronary Artery Disease: A Systematic Review and Meta‐Analysis of Randomized Trials

BackgroundInflammation plays a pivotal role in coronary artery disease (CAD). The anti‐inflammatory drug colchicine seems to reduce ischemic events in patients with CAD. So far there is equipoise about its safety and impact on mortality.Methods and ResultsTo evaluate the utility of colchicine in patients with acute and chronic CAD, we performed a systematic review and meta‐analysis. MEDLINE, EMBASE, Cochrane CENTRAL and conference abstracts were searched from January 1975 to October 2020. Randomized trials assessing colchicine compared with placebo/standard therapy in patients with CAD were included. Data were combined using random‐effects models. The reliability of the available data was tested using trial sequential analyses . Of 3108 citations, 13 randomized trials (n=13 125) were included. Colchicine versus placebo/standard therapy in patients with CAD reduced risk of myocardial infarction (odds ratio [OR] 0.64; 95% CI, 0.46–0.90; P=0.01; I 2 41%) and stroke/transient ischemic attack (OR 0.50; 95% CI, 0.31–0.81; P=0.005; I 2 0%). But treatment with colchicine compared with placebo/standard therapy had no influence on all‐cause and cardiovascular mortality (OR 0.96; 95% CI, 0.65–1.41; P=0.83; I 2 24%; and OR 0.82; 95% CI, 0.55–1.22; P=0.45; I 2 0%, respectively). Colchicine increased the risk for gastrointestinal side effects (P<0.001). According to trial sequential analyses, there is only sufficient evidence for a myocardial infarction risk reduction with colchicine.ConclusionsAmong patients with CAD, colchicine reduces the risk of myocardial infarction and stroke, but has a higher rate of gastrointestinal upset with no influence on all‐cause mortality.

Enteric-Coated Aspirin and the Risk of Gastrointestinal Side Effects: A Systematic Review.

IntroductionAspirin appeared as a medicine to deal with aches and inflammation, but due to its antiplatelet properties, it has evolved into a drug mainly used to avert cardiovascular disease. Regardless of its therapeutic uses, the limiting aspect for aspirin use has been its affiliation with gastrointestinal (GI) toxicity, classifying from acute mucosal damage to GI problems and death.ObjectiveThe aim of this systematic review is to address the question regarding the ECA effect on the gastric mucosa.MethodsA systematic search of the literature was conducted in the PubMed electronic databases from April 10th to April 23rd, 2020. Eligibility has been set, and based on those criteria, initially a total of 637 results were obtained, from these 58 of them were not written in English. Then, 168 articles which were free from duplication were screened and all the included articles were RCTs published after 2000. Based on these, final number of articles included on this review was 6.ResultsData were obtained from 6 published articles which reported on 15,621 participants. The reports were from 3 different countries. Most of the studies revealed that enteric-coated aspirin (ECA) treatment was not an effective mechanism against GI protection. ECA administration with omeprazole can hugely reduce the incidence of endoscopic GI damage compared to the impact of ECA used alone. Even short-term administration of a low dose of ECA was significantly associated with an apparent small bowel injury.ConclusionECA treatment is not an effective mechanism against GI protection, and it is highly associated with small bowel injury. So the coating does not reduce risk of GI complications.

Impact of metformin treatment during pregnancy on maternal outcomes: a systematic review/meta-analysis

We systematically assessed the impact of metformin treatment on maternal pregnancy outcomes. PubMed, Ovid Embase, Medline, Web of Science, ClinicalTrials.gov and Cochrane databases were systematically searched (inception-1st February 2021). Randomised controlled trials reporting pregnancy outcomes in women randomised to metformin versus any other treatment for any indication were included. Outcomes included gestational weight gain (GWG), pre-eclampsia, gestational hypertension, preterm birth, gestational age at delivery, caesarean section, gestational diabetes, glycaemic control, and gastrointestinal side-effects. Two independent reviewers conducted screening, with a third available to evaluate disagreements. Risk-of-bias and GRADE assessments were conducted using Cochrane Risk-of-Bias and GRADE-pro software. Thirty-five studies (n = 8033 pregnancies) met eligibility criteria. GWG was lower in pregnancies randomised to metformin versus other treatments (1.57 kg ± 0.60 kg; I2 = 86%, p < 0.0001), as was likelihood of pre-eclampsia (OR 0.69, 95% CI 0.50–0.95; I2 = 55%, p = 0.02). The risk of gastrointestinal side-effects was greater in metformin-exposed versus other treatment groups (OR 2.43, 95% CI 1.53–3.84; I2 = 76%, p = 0.0002). The risk of other maternal outcomes assessed was not significantly different between metformin-exposed versus other treatment groups. Metformin for any indication during pregnancy is associated with lower GWG and a modest reduced risk of pre-eclampsia, but increased gastrointestinal side-effects compared to other treatments.

Electrical stimulation therapy of the lower esophageal sphincter in GERD patients—a prospective single-center study

Summary Background Electrical stimulation therapy (EST) of the lower esophageal sphincter (LES) for gastro esophageal reflux disease (GERD) treatment increases LES pressure through chronic stimulation, with a low risk for gastrointestinal side effects and preservation of hiatal anatomy. The aim of this study was to evaluate the efficacy and safety of this novel technique in a high-output specialized reflux center. Methods This is a prospective single-center study including GERD patients indicated for anti-reflux therapy who consented to undergo LES-EST. Patients underwent prospective scheduled follow-up visits including interrogation of the stimulation device, clinical examination, and assessment of health-related quality of life (HRQL). Results Within a 4-year period, 37 LES-EST implantations were performed. The majority of patients were male (54.1%), mean BMI was 25.8 (SD 4.4), and mean age was 54.0 (SD 15.8). The median GERD HRQL composite score was 41 (IQR 21–49). Median total % of pH &lt;4 was 10.1 (IQR 4.4–17.3). Six (16.2%) individuals underwent explantation of the entire system (IPG and leads) due to technical defect (n = 4) or failure of therapy (n = 2). HRQL score improved from 41 (IQR 21–49) to 8.50 (IQR 4.25–20.5, p &lt; 0.001) and 9 (23.7%) patients were on at least occasional PPI treatment. Conclusion Due to the low rate of GI side effects and its minimal invasive character preserving the hiatal anatomy, this novel technique might find its place in anti-reflux surgery. However, the considerably high rate of device dysfunction needs further investigation.

Ibuprofen in the current practice of the pharmacist in the community pharmacy

The pharmacist from the community pharmacy plays a key role in the case of patients who seek directly for pathologies related to pain. Being a health specialist, he has the ability to offer pharmaceutical healthcare for drugs that need a medical prescription and also for the ones that are registered as OTC’s. Ibuprofen (IBU) is a part of the drug group called nonsteroidal anti-inflammatory drugs (NSAIDs) being registered in Romania under 17 pharmaceutical formulation by the National Agency of Drugs and Medical Devices. Due to its pharmacological profile which consists of a low risk of gastrointestinal side effects, IBU is an OTC recommended and frequently prescribed for decreasing the low and moderate pain. World Health Organization (WHO) indicates IBU as a drug that can be used to babies aged over three months. Through this paper, we try to analyze the pharmacist’s vision from the community pharmacy in IBU recommendation. In this paper were mentioned some legal aspects that are linked to the pharmacist competences, and also its approach regarding IBU recommendation during pregnancy and breastfeeding and also to children and to a category of patients who have various associated pathologies.

Oral Administration System Based on Meloxicam Nanocrystals: Decreased Dose Due to High Bioavailability Attenuates Risk of Gastrointestinal Side Effects.

Meloxicam (MLX) is widely applied as a therapy for rheumatoid arthritis (RA); however, it takes far too long to reach its peak plasma concentration for a quick onset effect, and gastrointestinal toxicity has been observed in RA patients taking it. To solve these problems, we designed MLX solid nanoparticles (MLX-NPs) by the bead mill method and used them to prepare new oral formulations. The particle size of the MLX-NPs was approximately 20-180 nm, and they remained in the nano-size range for 1 month. The tmax of MLX-NPs was shorter than that of traditional MLX dispersions (MLX-TDs), and the intestinal penetration of MLX-NPs was significantly higher in comparison with MLX-TDs (P < 0.05). Caveolae-dependent endocytosis (CavME), clathrin-dependent endocytosis (CME), and micropinocytosis (MP) were found to be related to the high intestinal penetration of MLX-NPs. The area under the plasma MLX concentration-time curve (AUC) for MLX-NPs was 5-fold higher than that for MLX-TDs (P < 0.05), and the AUC in rats administered 0.05 mg/kg MLX-NPs were similar to rats administered the therapeutic dose of 0.2 mg/kg MLX-TDs. In addition, the anti-inflammatory effect of the MLX-NPs was also significantly higher than that of MLX-TDs at the corresponding dose (P < 0.05), and the therapeutic effect of 0.2 mg/kg MLX-TDs and 0.05 mg/kg MLX-NPs in adjuvant-induced arthritis (AA) rats showed no difference. Furthermore, the gastrointestinal lesions in AA rats treated repetitively with 0.05 mg/kg MLX-NPs were fewer than in rats receiving 0.2 mg/kg MLX-TDs (P < 0.05). In conclusion, we demonstrate that MLX solid nanoparticles allow a quick onset of therapeutic effect and that three endocytosis pathways, CavME, CME, and MP, are related to the high absorption of solid nanoparticles. In addition, we found that MLX solid nanoparticles make it possible to reduce the amount of orally administered drugs, and treatment with low doses of MLX-NPs allows RA therapy without intestinal ulcerogenic responses to MLX. These findings are useful for designing therapies for RA patients.

Inhibitory effect of Artocarpus lakoocha Roxb and oxyresveratrol on α-glucosidase and sugar digestion in Caco-2 cells

Long-term diabetic complications are exacerbated by post-prandial hyperglycemia which could be ameliorated by α-glucosidase inhibitor including oxyresveratrol. Puag-Haad is an aqueous extract from Artocarpus lakoocha Roxb. containing ~65% oxyresveratrol. Oxyresveratrol is an inhibitor of isolated yeast α-glucosidase enzyme but has not been tested on intact gut enterocytes where the enzyme is membrane-bound. Accordingly, differentiated Caco-2 cells that contain the native enzyme were used to test maltose hydrolysis in the present study. The results demonstrated that purified yeast α-glucosidase was non-competitively inhibited by oxyresveratrol (Ki 54.4 ± 0.7 μg/mL) and Puag-Haad (2.7 ± 0.1 μg/mL) compared to 153.8 ± 4.3 μg/mL acarbose, an anti-diabetic drug. In differentiated Caco-2 cells, both oxyresveratrol and Puag-Haad inhibited maltose hydrolysis with lesser potency compared to acarbose. Thus, although weaker than acarbose, oxyresveratrol and Puag-Haad do not inhibit pancreatic amylase which might be a therapeutic asset in preventing fermentation of unabsorbed carbohydrate causes abdominal bloating, flatulence, or diarrhea. Oxyresveratrol and Puag-Haad may help control postprandial hyperglycemia with low risk of gastrointestinal side effects.

Metformin for ovulation induction (excluding gonadotrophins) in women with polycystic ovary syndrome.

Metformin for ovulation induction (excluding gonadotrophins) in women with polycystic ovary syndrome.

48 - META-ANALYSIS OF CYP2C19 ASSOCIATION WITH EFFICACY AND SIDE EFFECTS OF CITALOPRAM AND ESCITALOPRAM USING DATA FROM GENOME-WIDE ASSOCIATION STUDIES

Background Major Depressive Disorder (MDD) is a leading cause of disability-adjusted life years worldwide. Genetic polymorphisms may have the potential to guide antidepressant treatment to increase current remission rates. Cytochrome P450 (CYP450) enzymes are responsible for antidepressant metabolism, with CYP2C19 playing a major role in citalopram/escitalopram metabolism. This study is the first meta-analysis to investigate how CYP2C19 polymorphisms predict citalopram/escitalopram efficacy and side effects. Methods CYP2C19 phenotypes comprise poor metabolizers (PM), intermediate and intermediate+ metabolizers (IM; IM+), extensive and extensive+ metabolizers (EM [wild type]; EM+) and ultra-rapid metabolizers (UM) defined by the two most common CYP2C19 functional polymorphisms (rs4244285 and rs12248560). These polymorphisms were directly genotyped or imputed from genome-wide data in four MDD pharmacogenetic samples treated with citalopram or escitalopram (GENDEP, STAR*D, GenPod and PGRN-AMPS). Treatment efficacy was (1) percentage symptom improvement (corrected for covariates and standardized) and (2) remission at endpoint. Side effect data were available only in GENDEP and STAR*D, where side effect from shared categories were analysed (gastro-intestinal, cardiovascular, CNS, sleep and sexual side effects). Presence of side effects were considered at weeks 2, 6 and 9. A fixed-effects meta-analysis was performed, all phenotypic groups were compared among each other using EM (wild type) as the reference group. Standardized mean difference (SMD) or odds ratio (OR) with 95% confidence intervals (CI) were calculated. Results Meta-analyses included 2558 patients for efficacy endpoints and 1644 patients for side effects. Imputed genotypes showed good quality. Compared to EMs, PMs had higher symptom improvement scores (SMD=0.43, CI=0.19–0.66, I2=11.5%) and higher remission rates (OR=1.55, CI=1.23–1.96, I2=0%). At week 2, PMs showed higher risk of gastro-intestinal side effects (OR=1.25, CI=1.06–1.48; week 6 values similar), of CNS side effects (OR=1.29, CI=1.06–1.58) and of sexual side effects (OR=1.56, CI=1.19–2.05; week 6 values similar) with low heterogeneity (I2 range 0% -37%). No difference was seen at week 9 for any side effect; no difference in total side effects burden was observed at any time point. Discussion This meta-analysis supports an association between CYP2C19 metabolizing level and citalopram/escitalopram efficacy and side effects. CYP2C19 polymorphisms may provide helpful information for guiding treatment in PMs.

Physico-chemical and pharmaceutical characterization of sulindac–proglumide binary system

Sulindac is a nonsteroidal anti-inflammatory drug with poor water solubility. This study presents a way to increase its dissolution rate while reducing the risk of gastrointestinal side effects. This approach considers the paired administration of sulindac with the gastroprotector proglumide, in the form of eutectic mixture. Theoretical and experimental methods proved that sulindac and proglumide form a simple eutectic system containing a molar fraction of proglumide of 0.7 at the eutectic point. The product with the eutectic composition, obtained by solvent evaporation, shows a significant improvement in the sulindac dissolution rate compared to the corresponding physical mixture.

Pharmacologic Glycemic Management of Type 2 Diabetes in Adults.

Pharmacologic Glycemic Management of Type 2 Diabetes in Adults.

Antibiotics for uncomplicated skin abscesses: systematic review and network meta-analysis

ObjectiveTo assess the impact of adjunctive antibiotic therapy on uncomplicated skin abscesses.DesignSystematic review and network meta-analysis.Data sourcesMedline, Embase, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov.Study selectionA BMJ Rapid...