Drug Side Research Articles

AMINO ACID TRANSPORTERS IN DRUG DISCOVERY

Administered drugs interact with membrane transporters of epithelia, Blood Brain Barrier and other districts influencing their delivery and efficacy. Drugs can also be used as inhibitors of transporters involved in human pathology. Drug-transporter interactions are responsible of off-target effects contributing to toxicity. High Throughput Screening technologies increased the potential applications in therapy or in predicting side effects. These strategies will be helpful in reducing animal experimentation. The identification of transporters important for drug absorption, delivery and side effect production and the best technologies for studying interactions are the main goals in this field. Amino acid transporters are not yet considered in human therapy in spite of their involvement in several pathologies. The function of the amino acid transporters EAAT1, ASCT2, GLYT2, GLYT1, B0AT1, LAT1 and LAT2 is so far well characterized. Some structural data on these transporters have also been obtained by bioinformatics. Interactions of these proteins with several drugs have been well defined at the molecular level. Large scale and, in some cases, high throughput screening of pharmacological compounds make these transporters of particular interest and potential application in human health.

Driving under the influence (DUID): Prevalence of drugs in oral fluid

Abstract Nowadays, detection of drugs of abuse is a usual practice in the legal field due to its incidence in several proceedings. Saliva is a matrix of increasing utility as it is a non-invasive sample that has been tested in international projects such as ROSITA and DRUID. Objectives: the study focused on the study of prevalence of drugs of abuse in a sample population of drivers of motor vehicles.3468 oral fluid samples came from local police activities, during the years 2007 until June 2010 in Barcelona (Spain). Methods: drivers suspected of driving under the influence of drugs had to comply with an analytical road side drug testing. A commercial kit immunoassay based was used (Cozart® DDS 801). Kits with positive results to any drug, 24.59%, were submitted to the Catalonia Institute of Legal Medicine, with an additional saliva sample ( as indicated by Cozart® DDS 801 provider) for confirmation by gas- chromatography mass- spectrometry (GC/MS). Drugs detected by the test Cozart® included:9 tetrahydrocannabinol, cocaine, opiates, methamphetamines amphetamines Results: after confirmation results showed a cannabis prevalence in 2064 samples (59.5%), cocaine in 1952 samples (56.2%) opiates in 258 (7.4%) amphetamines in 69 samples (1.9%) and methamphetamines in 57 (1.6%). No quantitative analysis was achieved. Conclusions: Results show that cannabis is the most prevalent in the study, followed by cocaine. Data are valuable in order to initiate sanctionary proceedings in Spanish legislation and also as signs of recreational drugs consumption which provide information to both epidemiology and public health.

Dissociative Identity Disorder Presenting as a Suicide Attempt or Drug Overdose: A Case Report

The major feature of dissociative identity disorder is the existence of at least two different identities that alternately control a person's behavior. Dissociative identity disorder is known as a rare disorder due to underdiagnosis and misdiagnosis. One of the presenting symptoms in dissociative identity is a suicide attempt. In this case, dissociative identity disorder and overdose drug intake, which emerges during the treatment of depression with fluoxetine, is identified. With regard to this complex case, the is- sues of overdose drug intake, suicide attempt, depression, antidepressant-associated suicide or side effects in dissociative disorder and their relations with each other will be discussed.

Effect of chlorzoxazone in patients with downbeat nystagmus

Downbeat nystagmus (DBN) is the most frequent form of acquired persisting fixation nystagmus with different symptoms such as unsteadiness of gait, postural instability, and blurred vision with reduced visual acuity (VA) and oscillopsia. However, different symptomatic therapeutic principles are required, such as 3,4-diaminopyridine and 4-aminopyridine, that effectively suppress DBN. Chlorzoxazone (CHZ) is a nonselective activator of small conductance calcium-activated potassium (SK) channels that modifies the activity of cerebellar Purkinje cells. We evaluated the effects of this agent on DBN in an observational proof-of-concept pilot study. Ten patients received CHZ 500 mg 3 times a day for 1 or 2 weeks. Slow-phase velocity of DBN, VA, postural sway, and the drug's side effects were evaluated. Recordings were conducted at baseline, 90 minutes after first administration, and after 1 or 2 weeks. Mean slow-phase velocity significantly decreased from a baseline of 2.74°/s ± 2.00 to 2.29°/s ± 2.12 (mean ± SD) 90 minutes after first administration and to 2.04°/s ± 2.24 (p < 0.001; post hoc both p = 0.024) after long-term treatment. VA significantly increased and postural sway in posturography showed a tendency to decrease on medication. Fifty percent of patients did not report any side effects. The most common reported side effect was abdominal discomfort and dizziness. The treatment with the SK-channel activator CHZ is a potentially new therapeutic agent for the symptomatic treatment of DBN. This study provides Class IV evidence that CHZ 500 mg 3 times a day may improve eye movements and visual fixation in patients with DBN.

Genotype-Based Ancestral Background Consistently Predicts Efficacy and Side Effects across Treatments in CATIE and STAR*D

Only a subset of patients will typically respond to any given prescribed drug. The time it takes clinicians to declare a treatment ineffective leaves the patient in an impaired state and at unnecessary risk for adverse drug effects. Thus, diagnostic tests robustly predicting the most effective and safe medication for each patient prior to starting pharmacotherapy would have tremendous clinical value. In this article, we evaluated the use of genetic markers to estimate ancestry as a predictive component of such diagnostic tests. We first estimated each patient’s unique mosaic of ancestral backgrounds using genome-wide SNP data collected in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) (n = 765) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) (n = 1892). Next, we performed multiple regression analyses to estimate the predictive power of these ancestral dimensions. For 136/89 treatment-outcome combinations tested in CATIE/STAR*D, results indicated 1.67/1.84 times higher median test statistics than expected under the null hypothesis assuming no predictive power (p<0.01, both samples). Thus, ancestry showed robust and pervasive correlations with drug efficacy and side effects in both CATIE and STAR*D. Comparison of the marginal predictive power of MDS ancestral dimensions and self-reported race indicated significant improvements to model fit with the inclusion of MDS dimensions, but mixed evidence for self-reported race. Knowledge of each patient’s unique mosaic of ancestral backgrounds provides a potent immediate starting point for developing algorithms identifying the most effective and safe medication for a wide variety of drug-treatment response combinations. As relatively few new psychiatric drugs are currently under development, such personalized medicine offers a promising approach toward optimizing pharmacotherapy for psychiatric conditions.

Cardiovascular Effects of Anti-Diabetic Medications in Type 2 Diabetes Mellitus

Over the past several years, there have been a significant number of new agents developed for the treatment of type 2 diabetes. Our goal in this article is to review the cardiovascular effects (risks and benefits) of these oral and non-insulin injectable agents. We review six major categories of diabetic therapies: biguanides, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, GLP-1 agonists, and DPP-IV inhibitors. In order to achieve a personalized regimen that aims for optimal outcomes, we must take into consideration each drug's side effects, patients' cardiovascular risk factors, and their individual health profile.

Do randomized clinical trials with inadequate blinding report enhanced placebo effects for intervention groups and nocebo effects for placebo groups? A protocol for a meta-epidemiological study of PDE-5 inhibitors

BackgroundPatients’ expectations of treatment effects may contribute to positive (placebo) and negative (nocebo) outcomes. The effect of patient expectations may be pronounced in subjectively assessed conditions, such as male erectile dysfunction. The aim of this project is to examine the magnitude of expectancy in trials of phosphodiesterase-5 inhibitors. We hypothesize that randomized controlled trials with inadequate blinding will report enhanced placebo effects for intervention groups and nocebo effects for placebo groups, compared with adequately blinded studies.Methods/designWe will quantify the magnitude of expectancy by comparing the effect estimates of trials with inadequate and adequate blinding. Blinding will be assessed using four domains from the Cochrane ‘risk-of-bias’ tool: allocation concealment; blinding of patient; caregiver; and outcome assessor. Our secondary aim is to identify factors that can modify expectations, such as prior experience with the intervention and drug side effects.We will perform an electronic search using a combination of controlled vocabulary and free text words in the following databases: MEDLINE, EMBASE, CENTRAL, and a clinical trials register. We will include randomized controlled trials, with either parallel or crossover design, that compare one phosphodiesterase-5 inhibitor with a placebo. The study’s primary aim should be to investigate the efficacy of phosphodiesterase-5 inhibitors for treating male erectile dysfunction. Screening will take place at two levels: abstracts and titles, followed by full text reports. Two reviewers will independently extract data on the primary outcome and assess risk of bias.We will meta-analyze treatment effects, if appropriate, to assess the magnitude of enhanced placebo effects and nocebo effects in intervention and placebo groups, respectively. We will explore possible mediators of placebo and nocebo effects with subgroup and meta-regression analyses.DiscussionTreatments may confer significant costs and risk of adverse effects; it is important, therefore, to determine whether the effects of treatments are larger than expectancy alone. If treatment expectations can be used in a non-deceptive way to produce clinically advantageous outcomes, then it may be possible to incorporate such mechanisms into evidence-based healthcare decision-making.

The fidelity mechanism of DNA synthesis

Accurate DNA synthesis is vital to maintain genome stability and ensure propagation of species. Synthetic errors have far reaching consequences. Therefore, DNA synthesis is remarkably accurate. The high fidelity is mainly achieved through three steps: ① nucleotide selection, which is based on hydrogen, base pair shape, or some other elements; ② 3'→5' exonuclease proofreading, which removes mis-incorporated nucleotides in cis or trans; ③ repair process, which could correct mismatched nucleotides escaping from proofreading, such as mismatch repair, excission repair, homologous recombination repair, and translesion DNA synthesis. Because all polymerases are suitable targets for anticancer or antiviral drugs, their fidelity is involved in drug resistance and side effects. Understanding the molecular basis of synthesis fidelity is of vital importance. In this review, the fidelity mechanisms of DNA synthesis will be discussed in detail. Furthermore, their application perspective was discussed.

Worry vs. knowledge about treatment-associated hypoglycaemia and weight gain in type 2 diabetic patients on metformin and/or sulphonylurea

Background and aims:Hypoglycaemia and body weight gain are side effects of certain glucose-lowering drugs, e.g. sulphonylurea (SU) compounds. Type 2 diabetes mellitus (T2DM) is often treated with multiple oral antidiabetic drugs complicating patient insight into drug safety and side effects. We aimed to elucidate the extent of patient worry about hypoglycaemia and body weight gain contra their knowledge about these two phenomena being actual side effects of SU.Methods:We used an observational, cross-sectional approach and included 492 patients with T2DM: 331 (67%) on metformin alone (MET), 52 (11%) on SU in monotherapy (SU), and 109 (22%) on metformin in combination with SU (MET + SU). All participants filled in a questionnaire enquiring about the patient’s knowledge and worry about side effects such as hypoglycaemia and weight gain in addition to the importance of their treatment not eliciting these two side effects.Results:Nineteen (MET), 29 (SU) and 38% (MET + SU) of the patients in the three groups agreed (fully or partially) with the statement ‘treatment with my diabetes medicine increases the risk of episodes with low blood sugar’. Significantly (p < 0.001) larger proportions of the three groups (68, 75 and 68%) felt it important that their glucose-lowering medication did not increase the risk of hypoglycaemia. Similar discrepancies for weight gain were observed.Limitations:The present study has several limitations: patients consisted of a non-randomised cohort, data were patient-reported and only patients with internet access could participate.Conclusion:A considerable proportion of patients with T2DM treated with SU are not aware of the risks of hypoglycaemia and weight gain associated with the treatment. This information gap exists despite the fact that to most patients treated with SU it is important that their antidiabetic treatment does not cause hypoglycaemia and/or weight gain, suggesting that these patients might be insufficiently informed about side effects.

A Computational Approach to Finding Novel Targets for Existing Drugs

Repositioning existing drugs for new therapeutic uses is an efficient approach to drug discovery. We have developed a computational drug repositioning pipeline to perform large-scale molecular docking of small molecule drugs against protein drug targets, in order to map the drug-target interaction space and find novel interactions. Our method emphasizes removing false positive interaction predictions using criteria from known interaction docking, consensus scoring, and specificity. In all, our database contains 252 human protein drug targets that we classify as reliable-for-docking as well as 4621 approved and experimental small molecule drugs from DrugBank. These were cross-docked, then filtered through stringent scoring criteria to select top drug-target interactions. In particular, we used MAPK14 and the kinase inhibitor BIM-8 as examples where our stringent thresholds enriched the predicted drug-target interactions with known interactions up to 20 times compared to standard score thresholds. We validated nilotinib as a potent MAPK14 inhibitor in vitro (IC50 40 nM), suggesting a potential use for this drug in treating inflammatory diseases. The published literature indicated experimental evidence for 31 of the top predicted interactions, highlighting the promising nature of our approach. Novel interactions discovered may lead to the drug being repositioned as a therapeutic treatment for its off-target's associated disease, added insight into the drug's mechanism of action, and added insight into the drug's side effects.

Investigating gene expression profile of non-small cell lung cancer

Abstract Lung cancer is mainly a lifestyle-associated disease with poor prognosis and the lowest five year survival rate of all types of cancer. Lung cancers are divided into two main groups: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Surgical treatment is generally indicated in cases of early stage NSCLC, and those patients treated with radical and aggressive surgery have a somewhat better survival rate. The main problems with lung cancer treatment are due to late diagnosis, rapidly developing drug resistance and side effects of the treatment that are experienced by almost all patients. The next step for distinguishing histologically complicated lung cancers and determining optimal treatment strategies is gene expression analysis. Supported by gene expression data, it is possible to prognosticate the course of the disease.

Pneumocystis carinii Pneumonia Prophylaxis

Pneumocystis pneumonia (PCP) can be life threatening for children receiving chemotherapy and immunosuppressive medication, including high-dose steroids. Although there are no current guidelines for prophylaxis in pediatric oncology patients, ongoing studies are evaluating the efficacy, side effects, ease of administration, and compliance of drugs used for PCP prophylaxis. Drugs currently being prescribed in practice include Bactrim, pentamidine, dapsone, and atovaquone. Bactrim remains superior for preventing PCP, but alternatives are being analyzed and investigated for those unable to tolerate Bactrim because of drug allergy or side effects. Educating patients and families about the importance of PCP prophylaxis and compliance should be a priority for all health care providers caring for children receiving immunosuppressive medications, including chemotherapy.

Cholesterol Superlattice Modulates Drug Release from Liposomes

Combretastatin A4 disodium phosphate (CA4P) is an anticancer drug currently under Phase II clinical trials. CA4P disrupts tumor blood vessels, causing extensive tumor necrosis. Liposomal CA4P, as opposed to free CA4P, can reduce the drug's side effects and achieve targeted delivery. Previously we have shown that liposomal CA4P significantly delayed tumor growth in mice (Pattillo et al. (2009) Pharmaceutical Research 26, 1093-1100). However, the overall efficacy of the liposomal CA4P was still low. One of the strategies to improve this efficacy is to optimize the liposomal formulation. In this study, we have developed a new fluorescence assay and used it to examine the effect of cholesterol content on the release of entrapped CA4P from unilamellar vesicles (∼180 nm) composed of cholesterol and POPC. We have used small cholesterol increments (0.5 mol%) over a wide range of cholesterol mole fractions (∼19-52 mol%). We found that, at 24oC, the initial rate of CA4P release varies with cholesterol content in an alternating manner, showing a local maximum at 20.0, 22.2, 25.0, 32.8, 40.0 and 50.0 mol%. These cholesterol mole fractions are in excellent agreement with the theoretically predicted cholesterol critical mole fractions (Cr) for maximal superlattice formation. Similar results were obtained at 37oC. The faster release of CA4P at Cr can be explained in terms of the sterol superlattice model. At any given cholesterol mole fraction, sterol superlattice regions always coexist with non-superlattice regions. At Cr, the interfacial areas between superlattice and non-superlattice domains reach a local maximum (Venegas et al. (2007) J. Phys. Chem. B., 111, 5180-5192). Since the interfacial areas have more void space and volume fluctuations, CA4P can leak out more easily at Cr. These results may help to optimize the liposomal CA4P formulation to achieve higher efficacy for cancer treatment.

Genetic Studies of Drug Response and Side Effects in the STAR∗D Study, Part 1

Genetic Studies of Drug Response and Side Effects in the STAR∗D Study, Part 1

Discussing side effects of over-the-counter medicines: impact of adding percentage data

Discussing side effects with patients continues to be a difficult area of practice. Questions arise as to how many should be mentioned and which ones. The way such information is presented can affect drug-taking decisions. This study examined how over-the-counter (OTC) medicine users are influenced by numerical risk estimates of side effects. As part of a larger study on patient decision-making, 30 participants aged over 50 years were asked to consider three OTC headache medicines. They responded to one of two headache scenarios, one with symptoms described as mild but common and the other severe but rare. Participants made their selection based on drug efficacy and side effects, at first not linked to occurrence rates and then with this information provided. Average age was 66.6 years and the majority were female. Most were currently using some form of drug therapy. Drug choices differed in relation to mild versus severe headache scenarios. A stronger preference for drug X (50% effective and two side effects) was evident when the headaches were mild, shifting to a more effective agent (but with more side effects) when more severe. Addition of occurrence rates to the side effects had the greatest effect within the severe headache scenario, where more participants opted for the most effective agent (drug Z at 100% effective but six side effects) upon seeing the numbers. Overall, however, most kept the same drug in spite of the numerical information. Inclusion of numerical data for side effects did not negatively influence potential OTC medicine users. For most, effectiveness and side effects were the concern before receiving the percentages, while effectiveness became more important when the frequency data seemed to instil a sense of reassurance.

Drug information resources at community pharmacies in Amman, Jordan

The aim of this study was to investigate the drug information resources available in community pharmacies in Amman, Jordan. A total of 156 private community (retail) pharmacies in different parts of Amman, the capital of Jordan, were recruited by personal contact. Pharmacists at the sample pharmacies completed a self-administered questionnaire that consisted of two sections. The first section elicited the drug information resources available in their pharmacies. The second section presented five mock medicines information scenarios and asked respondents to identify the most suitable information resource to be used from a given list. Answers then were coded and entered into SPSS for Windows for statistical analysis. All pharmacies had at least one reference book, but most were outdated. The Monthly Index of Medical Specialties (MIMS) was the most commonly found (n = 101; 64.7%), and 40.4% (n = 63) had internet access. Only 19.2% (n = 30) of the respondents reported getting medicines information directly from pharmaceutical companies, usually through pharmaceutical representatives. Most pharmacists could identify appropriate information resources for drug dosing and side effects but did not fare well for medicine identification, drug interactions and primary research evidence. The quality of drug information resources in private community pharmacies in Amman is far from optimal. This will affect the quality of information provided to patients and prescribers and have an adverse effect on the role that pharmacists can play in the health system in Jordan.

Short-duration furazolidone therapy in combination with amoxicillin, bismuth subcitrate, and omeprazole for eradication of Helicobacter pylori

Background/Aim:Resistance to metronidazole is one of the most common reasons for Helicobacter pylori treatment failure with the classic triple therapy. The clarithromycin-based regimen is not cost-effective for use in developing countries. Though furazolidone is a great substitute it has many side effects. Decreasing the duration of treatment with furazolidone to 1 week may help decrease the drug's side effects.Aim:To study the efficacy and side effects of furazolidone when given for 1 week in combination with bismuth subcitrate, amoxicillin, and omeprazole.Patients and Methods:One hundred and seventy-seven patients with duodenal ulcer were randomly divided into two groups. Group I received omeprazole 2 Χ 20 mg + amoxicillin 2 Χ 1 g + bismuth subcitrate 4 Χ 120 mg for 2 weeks, with furazolidone 2 Χ 200 mg in the first week only. Group II received the same regimen, except that 1 week of furazolidone was followed by 1 week of metronidazole in the second week. Control endoscopy was performed after 6 weeks. Three biopsies from the antrum and three from the corpus were taken for urease testing and histology. Eradication was concluded if all tests were negative for H pylori.Results:One hundred and fifty-seven patients completed the study. Two subjects from group I and three from group II did not tolerate the regimen and were excluded from the analysis. No serious complication was detected in any patient. The eradication rates by per-protocol (PP) analysis and intention-to-treat (ITT) analysis were 89% and 79.3% in group I and 86.6% and 74.4% in group II, respectively.Conclusion:One week of furazolidone in combination with 2 weeks of amoxicillin, omeprazole, and bismuth subcitrate is a safe and cost-effective regimen for the eradication of H pylori. Adding metronidazole to the above regimen does not increase the eradication rate.

A side effect resource to capture phenotypic effects of drugs

The molecular understanding of phenotypes caused by drugs in humans is essential for elucidating mechanisms of action and for developing personalized medicines. Side effects of drugs (also known as adverse drug reactions) are an important source of human phenotypic information, but so far research on this topic has been hampered by insufficient accessibility of data. Consequently, we have developed a public, computer-readable side effect resource (SIDER) that connects 888 drugs to 1450 side effect terms. It contains information on frequency in patients for one-third of the drug–side effect pairs. For 199 drugs, the side effect frequency of placebo administration could also be extracted. We illustrate the potential of SIDER with a number of analyses. The resource is freely available for academic research at http://sideeffects.embl.de.

Vernakalant hydrochloride for the treatment of atrial fibrillation

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. Rhythm control strategy for AF is limited by drug toxicity and side effects, and recent trials have shown that this strategy is not superior to a rate control one. New antiarrhythmic drugs, free of undesired effects, would enhance rhythm control, with the possibility of sinus rhythm restoration and maintenance. A promising find in the search for new antiarrhythmic therapies is atrial-tissue specific ion channels. The findings that the ultrarapid delayed rectifier (IKur) and the inwardly rectifying, acetylcholine-regulated current (IK-Ach) exist in atrial but not ventricular tissue increase the probability that atrioselective drugs without ventricular proarrhythmic toxicity can be developed for treatment of patients with AF. There are also other potential targets for atrial-selective therapy: transient outward current (Ito), rapidly and slowly activating delayed rectifier currents (IKr and IKs), atrial sodium current (INa) and atrially expressed connexins. New drugs under development with promising atrial-selectivity include: tertiapin, NIP-142, NIP-141, JTV-519, AVE0118, AVE1231, DPO-1, AZD7009 and many others. Among such new agents, vernakalant hydrochloride is currently in an advanced phase of development and has already been evaluated in clinical trials. In this overview, we describe the history and current state of developmental process of the drug, as well as its mechanism of action and influence on electrophysiological parameters. Vernakalant seems to be effective in terminating recent-onset AF, but is not efficacious in long-lasting AF and atrial flutter. The drug may be relatively free of proarrhythmic effects, and exerts a protective effect on ventricular tissue and ventricular repolarization. It is expected that the intravenous formulation will soon be approved for the pharmacological termination of recent-onset AF.

Cultural interpretations of the efficacy and side effects of antimalarials in Tanzania

This paper examines the cultural interpretations and the perceived efficacy and side effects of antimalarials in Tanzania. Interviews with 56 mothers of children diagnosed with malaria revealed that they were nostalgic about chloroquine, a banned antimalarial. Additional findings indicated that a majority of the mothers had an overall negative disposition toward sulfadoxine-pyrimethamine (SP), the first-line antimalarial. Mothers considered the persistence of fever as the primary undesirable side effect of SP, while also mentioning a range of other side effects. Mothers who could not afford an alternative to SP, rationalized the drug's side effects as indicative of disease egress. It is argued that ethnographic studies of cultural perceptions of malaria and antimalarials provide useful perspectives on how people negotiate the identity of a febrile illness, and how they understand and interpret the efficacy of existing antimalarials. In acknowledging the intra-cultural variability in perceptions of malaria and antimalarials, health policy makers must be cautious when implementing a ‘one drug fits all’ approach to malaria control.