Drug-induced Side Effects Research Articles

Pharmacogenomics Can Predict Patient Responses

Pharmacogenomics Can Predict Patient Responses

The low frequency of reported sexual dysfunction in Asian patients with schizophrenia (2001-2009): low occurrence or ignored side effect?

The purpose of the study was to evaluate the frequency of reported sexual dysfunction (SD) in schizophrenia and its associations with sociodemographic and clinical variables in selected Asian countries. A total of 5877 schizophrenia patients in nine Asian countries and territories were examined between 2001 and 2009. The patients' sociodemographic and clinical characteristics, prescription of psychotropic drugs, and drug-induced side effects were recorded using a standardized protocol and data collection. SD was evaluated as "present" or "absent" according to the clinical judgment of experienced psychiatrists. The frequency of reported SD in the whole sample in women and men was 3.0%, 0.8%, and 4.6%, respectively, with variations across study sites. In the multivariate analyses, male sex, more second-generation antipsychotics, benzodiazepines, and antidepressants were independently associated with higher likelihood of reported SD, whereas negative symptoms had an inverse association with reported SD. The results of this study indicate that SD was seldom recorded as a side effect by Asian psychiatrists while treating patients with schizophrenia. It is unclear whether the low prevalence of reported SD compared with Western data is real or whether the results are being insufficiently recognized.

Ka-mi-kae-kyuk-tang oriental herbal cocktail attenuates cyclophosphamide-induced leukopenia side effects in mouse

Ka-mi-kae-kyuk-tang (KMKKT) is an Oriental herbal medicinal cocktail and has been shown to have potent antiangiogenic, anticancer, and antimetastatic activities in preclinical animal models without observable side effects. We previously found that in prostate cancer xenograft experiments, treating tumor-bearing mice with KMKKT alleviated the body weight loss toward the end of the study, suggesting a general health-promoting activity. We investigated whether KMKKT alleviated cancer chemotherapy drug-induced leukopenia and other hematotoxicity in vivo using a mouse model. KMKKT was given once daily orally for 10 days to the mice before they were given cyclophosphamide (CPA) daily injection for 4 days. KMKKT blunted CPA-induced decrease in red blood cells, hemoglobin content, and the total white blood cell/leukocyte counts. Examination of the multiple organ sites involved in hematopoiesis, and lymphocyte differentiation and maturation showed the attenuated changes induced by CPA in each and every type of cells examined. Particularly, some of the cell types are fully restored in the bone marrow and even overstimulated in the Sca-1+, CD117+, or Sca1+/CD117+ and CD34+/CD117+ stem cells, supporting a role of KMKKT to stimulate hematopoietic stem cell (HSC) signaling to compensate for CPA-induced destruction of leukocytes and other cell types. Taken together, KMKKT might be a safe and effective herbal complementary and alternative medicine (CAM) modality to alleviate cancer drug-induced hematological side effects in addition to its anticancer activities. Preclinical investigations with other chemo- and radiation modalities are warranted to support planning translation consideration for human patients.

Sex Differences in Use of Psychotropic Drugs and Drug-Induced Side Effects in Schizophrenia Patients: Findings of the Research on Asia Psychotropic Prescription (REAP) Studies

The aim of this study was to investigate the sex differences in prescribing patterns of psychotropic drugs and drug-induced side effects in schizophrenia patients in Asia using the data of the Research on Asian Psychotropic Prescription Pattern (REAP) surveys. The prescription patterns of 6,441 schizophrenia inpatients in six Asian countries and regions were investigated during the 2001-2009 period. The patients' socio-demographic and clinical characteristics and their prescriptions for psychotropic drugs were recorded using a standardized protocol and data collection procedure. Univariate analyses found the following factors to be significantly associated with the male sex: a younger age, higher doses of antipsychotics, less prominent delusions and hallucinations, more prominent negative symptoms, less likelihood of a prescription for second-generation antipsychotics (SGAs), greater use of antipsychotic polypharmacy, mood stabilizers and depot antipsychotics, more frequent tardive dyskinesia (TD), and less weight gain. In multivariate analyses, fewer prescriptions for SGAs, greater use of mood stabilizers, anticholinergics, antipsychotic polypharmacy and depot antipsychotics, extrapyramidal side effects (EPS) and TD, and less weight gain were independently associated with the male sex. Sex is one of the independent contributors to psychotropic prescription and side effects in Asian schizophrenia patients. Psychopharmacological treatment guidelines for schizophrenia should consider the sexes separately.

Colonic necrosis in a young patient receiving oral kayexalate in sorbitol: Case report and literature review

Kayexalate (sodium polystyrene sulfonate) is a cation-exchange resin used to treat patients with hyperkalemia. Concomitant administration of kayexalate and sorbitol may induce gastrointestinal injury, which is potentially lethal. However, this well-documented complication is often underrecognized both clinically and pathologically. We propose a typical case along with colonoscopic photos and microscopic pictures. Additionally, we also present a review of the literature on this rare drug-induced side effect.

In Silico Modeling of Changes to Ventricular Myocyte Action Potential Morphology Caused by Pharmacological Agents

Changes in electrocardiogram morphology associated with ventricular arrhythmias are one of the largest causes of the removal or restriction of marketed pharmacological agents and can be difficult to predict during drug development. Since changes to ECG morphology are the consequence of cellular-level alterations in the action potential, fresh insights can be gained by using computational models of cardiac action potentials and simulating drug-induced side effects. Although most pro-arrhythmic drugs block the rapid delayed rectifier current encoded by the gene commonly referred to as HERG, many drugs are non selective. With this in mind we analyzed mathematical models of ventricular action potentials to develop methods to predict non-specific, potentially pro-arrhythmic effects of new pharmacological agents. Through simulations, we generated predictions of changes in action potential duration (APD) caused by different concentrations of hypothetical drugs that specifically blocked with a defined affinity individual ion transport pathways (channels, pumps, or transporters). These relationships were empirically fit to the Hill equation. We then generated predictions of changes in APD caused by hypothetical drugs that blocked multiple pathways with different affinities. Based on linear transformations of the Hill equation fits and minimum least squares, our “reverse engineering” algorithm predicted the pathways that were most likely to be affected by a particular drug based on the APD versus [drug] relationship. Simulations were performed with the ten Tusscher model of the human ventricular myocyte in which hypothetical drugs blocked the rapid delayed rectifier current along with one of six other currents. When the results were fed to the algorithm in a blinded fashion, the program successfully identified the drug targets. The results show promise for the development of methods to determine potential channel candidates when the cause of APD disturbance is unknown.

Toxicological characterization of N-methyl-N-nitrosourea-induced cataract in rats by LC/MS-based metabonomic analysis

Cataract is one of the most serious drug-induced side effects that can terminate the development of drug candidates, and pharmaceutical companies consider it important to evaluate cataract-inducing potential in the early phases. Metabonomics is expected to be a powerful approach for the safety evaluation of drug candidates. In this study, we conducted a toxicological characterization of N-methyl-N-nitrosourea (MNU)-induced cataract in rats by LC/MS-based metabonomic analysis. MNU was intraperitoneally administered once to 15-day old rats at 70 mg kg(-1) . After that, animals were kept for 3 weeks waiting for cataract formation. Lens samples for metabonomic analysis were collected on 7, 14 and 21 days after MNU administration. Comprehensive analyses of lens metabolites were conducted using an LC/MS system, and multivariate data for each sample were compared by principal component analysis (PCA) to find any changes in lens metabolites. Lens opacity was confirmed by ophthalmoscopy 14 days after dosing, and even by gross observation 21 days after dosing. PCA of the lens samples for the control and MNU-treated groups revealed that the metabolite profiles of lens differed from each other, and several lens metabolites, such as lots of α-amino acids and gluthathione, decreased after MNU treatment. In conclusion, metabonomic analysis enabled us to identify new marker candidates for cataract and provided a better understanding of the mechanism related to MNU-induced cataract. It was considered that metabonomics is a useful approach for the characterization of drug-induced toxicity.

Herbal Cocktail Ka-Mi-Kae-Kyuk-Tang Stimulates Mouse Bone Marrow Stem Cell Hematopoiesis and Janus-Activated Kinase 2/Signal Transducer and Activator of Transcription 5 Pathway

Ka-mi-kae-kyuk-tang (KMKKT) is an Oriental herbal medicinal cocktail. Our collaborative team has shown that it has potent anti-angiogenic, anti-cancer and anti-metastatic activities in vivo without observable side effects. We have documented evidence for KMKKT to alleviate drug-induced hematotoxicity in vivo. In the present study, we investigated the mechanistic and signaling events through which KMKKT enhances hematopoiesis, using hematopoietic stem cells (HSCs) isolated from the bone marrow of 8-12 week-old C57BL/6 mice. Our results show that KMKKT significantly increased the expression of the hematopoietic cytokines interleukin (IL)-3, stem cell factor (SCF), granulocyte-macrophage-colony stimulating factor (GM-CSF), thrombopoietin (TPO) and erythropoietin (EPO) at the level of mRNA and secretion in HSCs. KMKKT also increased the expression of c-Kit, a cytokine receptor expressed in HSCs. In addition, KMKKT enhanced phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5), and increased the binding activity of STAT5 to gamma interferon activated sites (GAS) that mediate JAK2 downstream signaling. Furthermore, we found that KMKKT significantly enhanced the growth rate of colony-forming unit granulocyte erythrocyte monocyte macrophages (CFU-GEMM) and burst forming unit erythroid (BFU-E) of mouse HSCs (mHSCs) stimulated by IL-3/EPO. Overall, our results demonstrated that KMKKT alleviated drug-induced side effects through enhanced hematopoiesis, at least in part through cytokine-mediated JAK2/STAT5 signaling.

Assessing general side effects in clinical trials: reference data from the general population

Side effects in clinical trials are frequently assessed in an unstructured fashion, using ascertainment strategies with unclear quality criteria. To improve the assessment and interpretation of general side effects, a structured approach is presented and validated (General Assessment of Side Effects, GASE). Base rates and reference data of the general population as well as quality criteria of this new side effect ascertainment method are provided. We developed a screener assessing the most common subjective side effects of clinical trials (according to FDA statistics and others). The screener was evaluated in a general population survey including 2512 participants, 1276 of them taking drugs. We present reference data of the general population that help to interpret and compare future results of clinical trials assessing general side effects. Highest scores for side effects were reported from users of psychopharmacological drugs, medium scores of people taking antihypertensives, and lower scores of people taking lipid-lowering drugs, pain killers, and antidiabetics. If people take multiple drugs, more side effects are reported compared to single-class drugs. This confirms GASE's validity to assess side effects. We suggest that a structured, patient-based approach to assess general side effects could improve the detection of drug-induced side effects. The problem of clinical studies being underpowered to detect side effects could be reduced by using more reliable approaches. Our plea is for side effect ascertainment with sophisticated approaches for expected side effects, systematic screening for general side effects, and open question methods for spontaneous reports.

Predictors of relapse in Chinese schizophrenia patients: a prospective, multi-center study

Relapse prevention is the main goal of maintenance treatment in schizophrenia. This study aimed to determine the rate and the socio-demographic and clinical predictors of relapse in Chinese schizophrenia patients following treatment of the acute phase of the illness. In a multi-center, randomized, controlled, longitudinal study, 404 patients with schizophrenia who were clinically stabilized following an acute episode were randomly assigned to either the maintenance (i.e., initial optimal therapeutic doses continued throughout the study) or the dose-reduction group (i.e., initial optimal therapeutic doses continued for 4 or 26 weeks followed by a 50% dose reduction that was maintained until the end of the study). Participants were interviewed at entry using standardized assessment instruments, and followed up for 12-26 months. In univariate analyses, relapse was significantly associated with the membership of the dose-reduction group, poor medication adherence, and having a diagnosis of the paranoid type of schizophrenia. In Cox proportional-hazards regression analysis the membership of the dose-reduction group, poorer medication adherence, more severe drug-induced side effects and prominent paranoid symptoms independently predicted a higher risk of relapse. The study confirmed the importance of maintenance medication in preventing relapse in Chinese schizophrenia patients underscoring the risk of relapse associated with lack of treatment adherence, severe side effects and the patients' paranoid attitude. Socio-demographic characteristics were not associated with relapse in Chinese schizophrenia patients. Potential residual confounding caused by unmeasured variables should be fully considered in future studies.

Drug-induced acute pancreatitis related to medications commonly used in gastroenterology

Background With the growing number of pharmacological agents available nowadays, the gastrointestinal drug-induced side effects become more common than ever. However, drug-induced pancreatitis belongs to rather seldom reported adverse drug reactions, probably because of the difficulty in proving the relationship between an inflammation of the pancreas and the pharmacotherapy with a certain drug. Aim The aim of this review is to draw attention to an infrequent but real problem of drug-induced acute pancreatitis associated with medications commonly used in the treatment of gastrointestinal disorders. Methodology For the purpose of that the PubMed database was searched using the keywords “drug-induced pancreatitis”, “drug-associated pancreatitis”, “acute pancreatitis”, “pancreatitis” in various combinations and relevant literature was reviewed. Results A substantial number of drugs commonly prescribed for gastrointestinal disorders are known to cause acute pancreatitis. Case reports and review articles published so far draw attention to medications already known to cause drug-induced pancreatic damage as well as implicate new drugs. Generally, the etiopathological mechanisms involved in drug-induced pancreatitis remain unclear. It is difficult to establish or rule out definitely such unwanted event, especially in patients taking numerous medications prescribed for multiple comorbidities. Conclusion Pharmacological agents are among etiologic factors that should be considered in all patients presenting with signs and symptoms consistent with acute pancreatitis. The diagnosis of drug-induced AP is often difficult to established. Therefore a high index of suspicion and thorough drug history are crucial for making the final diagnosis.

Multimodal analgesia in children

Acute and chronic pain management in children is increasingly characterized by either a multimodal or a preventive analgesia approach, in which smaller doses of opioid and nonopioid analgesics, such as nonsteroidal anti-inflammatory drugs, local anaesthetics, N-methyl-D-aspartate antagonists, alpha(2)-adrenergic agonists, and voltage-gated calcium channel alpha-2 delta-proteins, are combined alone and in combination with opioids to maximize pain control and minimize drug-induced adverse side effects. A multimodal approach uses nonpharmacological complementary and alternative medicine therapies too. These include distraction, guided imagery, hypnosis, relaxation techniques, biofeedback, transcutaneous electrical nerve stimulation, and acupuncture. Using the neurophysiology of pain as a blueprint, the molecular targets and strategies used in multimodal pain management are described. Finally, weight-based dosage guidelines for commonly used opioid and nonopioid analgesics are provided to facilitate therapy.

A qualitative study of the ramifications of rash from epidermal growth factor receptor (EGFR) inhibitors

Over 50% of cancer patients who are treated with epidermal growth factor receptor (EGFR) inhibitors develop a papulopustular rash that involves the face, neck, and upper torso. However, because relatively few previous reports have focused on the full ramifications of this drug-induced side effect, this qualitative study was undertaken. Fifteen patients who had either an active or previous rash from these agents participated in scripted interviews. All interviews were transcribed and examined by means of a qualitative methodologic approach. Four major themes emerged: (1) actual physical discomfort was associated with the rash; (2) patients were concerned about their appearance; (3) despite initial denial, patients did suffer social isolation; and (4) high medical morbidity was associated with the rash. Patients voiced concerns such as: (1) 'Especially when I try to sleep, I can feel the itch and burn all over…'; (2) 'My face looks so bad that if I go to see my friends and they say, 'What happened to you.' I am self conscious about that'; (3) 'I just told them they would be better off just calling me, don't come visit…'; and (4) 'I went to the hospital for my face…they made a bandage to put all over [my] face…. [I] just had a little nose hole, a mouth hole and holes for…eyes.'. Rash from EGFR inhibitors can have a major negative impact upon cancer patients.

Russian observational study of the efficacy and tolerability of depakine chrono as first-linemonotherapy for focal epilepsy

Objective: to evaluate the efficacy and tolerability of sustained-release sodium valproate sodium as first-line monotherapy in patients with newly or recently diagnosed focal epilepsy. Subjects and methods. This was an open-label, prospective, observational study performed in the real treatment setting. It covered 1580 patients (children older than 6 years and adults) with focal epilepsy. The patients received sustained-release sodium valproate in an average daily dose of 1268 mg for 6 months. Therapeutic effectiveness was evaluated from remission rates when the study was completed. Moreover, the proportion of patients who continued to take the drug following 6 months was estimated. The total efficiency of the therapy was evaluated by the Clinical Global Impression Scale (CGI). Results. At 6 months of the study, 1478 (93.5%) patients continued to take the drug, 1167 (73.9%) of the 1580 patients achieved remission (they were seizure-free). The drug proved to be effective in all types of epileptic seizures of different etiology and different localization of an epileptic focus. In complex partial seizures and secondary generalized seizures, the efficiency of sustained-release sodium valproate was somewhat higher than that in simple partial seizures [71.1% (477/672), 74% (853/1153), and 68.4% (476/697), respectively]. During treatment, 67.9% (1072/1580) of the patients showed an evident and significant improvement without side effects. The drug was well tolerated. Drug-induced side effects were observed in 139 (8.8 %) of the 1580 patients; these were mild and moderate and led to drug discontinuation in only 10 (0.6%) of the 1580patients. The most adverse events were weight gain in 1.8% (29/1580) of the patients, alopecia in 1.8% (28/1580), and tremor in 1.5% (25/1580). Conclusion. The study indicates that the use of sustained-release sodium valproate is an effective and well tolerable first-line drug for the treatment of focal epilepsy in children and adults.

Oral Glutamine Attenuates Cyclophosphamide-Induced Oxidative Stress in the Bladder but Does Not Prevent Hemorrhagic Cystitis in Rats

Cyclophosphamide (CP) is widely used in the treatment of cancer and non-malignant disease states such as rheumatoid arthritis. Hemorrhagic cystitis is a major dose-limiting side effect of CP. The incidence of this side effect is related to the dosage and can be as high as 75%. Elimination of the side effects of CP can lead to better tolerance of the drug, and a more efficient therapy can be achieved for patients in need of CP treatment. Several studies have demonstrated that oxidative stress and neutrophil infiltration play important roles in CP-induced bladder damage. Glutamine is utilized under clinical conditions for preventing chemotherapeutic drug-induced side effects, based on its ability to attenuate oxidative stress. The aim of the study is to verify whether glutamine prevents CP-induced oxidative stress and bladder damage using a rat model. Adult male rats were administered 150mg/kg body weight of CP intraperitoneally. Glutamine pretreated rats were administered 1g/kg body weight of glutamine orally 2h before the administration of CP. Vehicle/glutamine-treated rats served as controls. All the rats were killed 16h after the dose of CP/vehicle. The urinary bladders were removed and used for light microscopic and biochemical studies. The markers of oxidative stress including malondialdehyde content, protein carbonyl content, protein thiol, and myeloperoxidase activity, a marker of neutrophil infiltration, were measured in bladder homogenates. CP treatment induced hemorrhagic cystitis in the rats. Pretreatment with glutamine significantly reduced CP-induced lipid peroxidation (p < 0.01), protein oxidation (p < 0.01), and increase in myeloperoxidase activity (p < 0.05). However, it did not prevent CP-induced bladder damage. The results of the present study show that glutamine pretreatment does not attenuate CP-induced hemorrhagic cystitis, although it prevents CP-induced oxidative stress and neutrophil infiltration significantly. It is therefore necessary to clarify the utility of glutamine as a chemoprotective agent before it is recommended in the market as a nutrient supplement.

Interferon Alfa-associated Anterior Ischemic Optic Neuropathy

To report a possible association between interferon alfa therapy and anterior ischemic optic neuropathy (AION). Database study and review of the literature. Thirty-six case reports from spontaneous reporting systems and the literature. Case reports from a review of the literature were combined with spontaneous reports from the National Registry of Drug-Induced Ocular Side Effects, the World Health Organization, and the Food and Drug Administration looking for reports on interferon therapy associated with optic neuropathy. Data from the spontaneous reports include the type of interferon, age, gender, adverse drug reaction (ADR), dosage, duration of therapy until onset of ADR, concomitant drugs, systemic disease, and dechallenge and rechallenge data. Thirty-six case reports of AION are described in association with interferon alfa therapy. The average age of subjects was 54.5 years; 26 were male and 10 were female. The median duration of therapy to onset of AION was 4.5 months, with 50% of subjects having some form of permanent vision loss. Anterior ischemic optic neuropathy was bilateral in 67% of subjects. There are 3 positive rechallenge case reports. Interferon alfa's association with AION can be classified as "possible" using the World Health Organization classification system. If optic neuropathy is suspected, rapid cessation of interferon therapy may portend a better prognosis because multiple case reports indicate visual defects may be permanent if this possible ADR remains unrecognized.

Current situation of tongue diagnosis in psychiatric diagnosis

This paper overviewed the studies of the current situation of tongue diagnosis in psychiatric diseases (schizophrenia,depression,nervous disorders,sleep disorders and psychotropic drug-induced side-effects),summed up the importance of tongue diagnosis for the diagnosis and prognosis of mental illnesses. Key words: Tongue diagnosis; Mental illness

Attenuation of neuropathy-induced allodynia following intraplantar injection of pregabalin

Pregabalin exhibits potent anticonvulsant, analgesic, and anxiolytic activity in animal models. However, few studies have evaluated pregabalin's potential peripheral effects on neuropathic pain. The aim of this study was to evaluate the peripheral analgesic effects of pregabalin in a rat model of neuropathic pain. Male Sprague-Dawley rats were prepared by ligating the left L5 and L6 spinal nerves to produce neuropathic pain. Sixty rats with neuropathic pain were randomly assigned to six groups. Normal saline (control) and pregabalin (10, 20, 30, and 50 mg.kg(-1)) were administered to the plantar surface of the affected left hind paw. Pregabalin (50 mg.kg(-1)) was administered into the unaffected contralateral paw in order to determine its systemic effect. Responses to mechanical, cold, and heat stimulation were recorded at 15, 30, 60, 90, 120, 150, and 180 min after drug administration. Rotarod performance was measured to detect drug-induced side effects, including sedation and reduced motor coordination. Saline injected into the affected paw and a pregabalin dose of 50 mg.kg(-1) injected into the contralateral paw showed no differences for mechanical, cold, and heat allodynia. Administration of pregabalin to the affected left hind paw in the dose range of 10-50 mg.kg(-1) resulted in a dose-dependent increase in thresholds to mechanical, cold, and heat stimulation. Peripherally administered pregabalin attenuates mechanical, cold, and heat allodynia in a rat model of neuropathic pain.

Management of refractory complex partial seizures: current state of the art

Diagnosis of complex partial epilepsy is based on the clinical history, and laboratory tests, including EEG and neuroimaging studies, corroborate the diagnosis. The goal of epilepsy management is to make the patient completely seizure-free without drug-induced side effects, even in the patient with refractory complex partial seizures. Frequently this can be accomplished by choice of the optimal antiepileptic drug (AED) or a combination of drugs, the use of strategies to maximize the effectiveness of drug treatment, or by surgical removal of the seizure focus. Currently there are five "classical" first-line AEDs and 11 new AEDs available in the US and in many other countries for the treatment of localization-related epilepsy. The current state of the evidence is that no AED is clearly superior to other AEDs in the management of refractory complex partial seizures. Therefore the choice of which drug to use in an individual patient has to be based on other considerations, including the potential adverse reactions that may occur in that patient. There are a number of strategies for optimal use of AEDs in the management of refractory complex partial seizures. These include verification of the diagnosis of epilepsy and classification of specific seizure types, use of monotherapy if possible but polytherapy if necessary, starting with a low dose and raising it slowly but, until complete seizure control is achieved, pushing to the maximum tolerated dose, changing timing of dosing to reduce toxicity, using pharmacokinetic principles to fine-tune AED doses, adjusting dose for drug-drug interactions, and never giving up in the pursuit of better seizure control. Resection of the seizure focus can be curative in the majority of patients with seizures localized to one mesial temporal lobe. Success rates for resection of extratemporal seizure foci are lower. Vagus nerve stimulation (VNS) devices result in a significant reduction of seizure frequency in many patients, but patients rarely become completely seizure-free as a result of VNS device implantation. Management of refractory complex partial seizures continues to improve with the identification of new drugs and the development of new approaches to their control and cure.

Adverse effects of drugs on small intestine and colon

The small and large intestine are one of the most common sites for the adverse action of drugs, accounting for 20-40% of all drug side effects. The most important factor in the diagnosis of drug-induced intestinal side effect is awareness. The mechanisms of damage are invariably complex, but may be due to topical effects, a known pharmacologic action of the drug on motility (for instance cholinergic/anti-cholinergic effect) and/or secretion, immune suppression and in the case of cytotoxic drug treatment a combination of many actions. The diagnosis of damage may be simple and widely recognised (NSAID-induced enteropathy resulting in bleeding, protein loss and rarely perforation and diaphragm disease), or at other times ignored (tricyclic antidepressants increasing constipation) or life threatening (docetaxene). Some associations require further research (statin and anti-retroviral associated irritable bowel symptoms). Diagnosis is traditionally made by symptom improvement on discontinuation of the drug. More lately capsule enteroscopy is used to aid diagnosis.