Efficacy and Safety of Peppermint Oil in a Randomized, Double-Blind Trial of Patients With Irritable Bowel Syndrome.

BACKGROUND & AIMS: Peppermint oil is frequently used to treat irritable bowel syndrome (IBS), despite a lack of evidence for efficacy from high-quality controlled trials. We studied the efficacy and safety of small-intestinal-release peppermint oil in patients with IBS and explored the effects of targeted ileocolonic-release peppermint oil. METHODS: We performed a double-blind trial of 190 patients with IBS (according to Rome IV criteria) at 4 hospitals in The Netherlands from August 2016 through March 2018; 189 patients were included in the intent-to-treat analysis (mean age, 34.0 years; 77.8% female; 57.7% in primary care), and 178 completed the study. Patients were randomly assigned to groups given 182 mg small-intestinal-release peppermint oil, 182 mg ileocolonic-release peppermint oil, or placebo for 8 weeks. The primary endpoint was abdominal pain response, as defined by the US Food and Drug Administration: at least a 30% decrease in the weekly average of worst daily abdominal pain compared with baseline in at least 4 weeks. The co-primary endpoint was overall relief of IBS symptoms, as defined by the European Medicines Agency. Secondary endpoints included abdominal pain, discomfort, symptom severity, and adverse events. RESULTS: Abdominal pain response did not differ significantly between the peppermint oil and placebo groups: 29 of 62 patients in the small-intestinal-release peppermint oil group had a response (46.8%, P = .170 vs placebo), 26 of 63 patients in the ileocolonic-release peppermint oil group had a response (41.3%, P = .385 vs placebo), and 22 of 64 patients in the placebo group had a response (34.4%). We did not find differences among the groups in overall relief (9.7%, P = .317 and 1.6%, P = .351 vs 4.7% for placebo). The small intestinal peppermint oil did, however, produce greater improvements than placebo in secondary outcomes of abdominal pain (P = .016), discomfort (P = .020), and IBS severity (P = .020). Adverse events, although mild, were more common in both peppermint oil groups (P < .005). CONCLUSIONS: In a randomized trial of patients with IBS, we found that neither small-intestinal-release nor ileocolonic-release peppermint oil (8 weeks) produced statistically significant reductions in abdominal pain response or overall symptom relief, when using US Food and Drug Administration/European Medicines Agency recommended endpoints. The small-intestinal-release peppermint oil did, however, significantly reduce abdominal pain, discomfort, and IBS severity. These findings do not support further development of ileocolonic-release peppermint oil for treatment of IBS. Clinicaltrials.gov, Number: NCT02716285.

Effects of Pharmacogenetic Screening for CYP2D6 Among Elderly Starting Therapy With Nortriptyline or Venlafaxine: A Pragmatic Randomized Controlled Trial (CYSCE Trial).

PURPOSE/BACKGROUND: The duration of untreated depression is a predictor for poor future prognosis, making rapid dose finding essential. Genetic variation of the CYP2D6 isoenzyme can influence the optimal dosage needed for individual patients. The aim of this study was to determine the effectiveness of CYP2D6 pharmacogenetic screening to accelerate drug dosing in older patients with depression initiating nortriptyline or venlafaxine. METHODS/PROCEDURES: In this randomized controlled trial, patients were randomly allocated to one of the study arms. In the intervention arm (DG-I), the specific genotype accompanied by a standardized dosing recommendation based on the patients' genotype and the prescribed drug was directly communicated to the physician of the participant. In both the deviating genotype control arm (DG-C) and the nonrandomized control arm, the physician of the participants was not informed about the genotype and the associated dosing advise. The primary outcome was the time needed to reach adequate drug levels: (1) blood levels within the therapeutic range and (2) no dose adjustments within the previous 3 weeks. FINDINGS/RESULTS: No significant difference was observed in mean time to reach adequate dose or time to adequate dose between DG-I and DG-C. Compared with the nonrandomized control arm group, adequate drug levels were reached significantly faster in the DG-I group (log-rank test; P = 0.004), and there was a similar nonsignificant trend for the DG-C group (log-rank test; P = 0.087). IMPLICATIONS/CONCLUSIONS: The results of this study do not support pharmacogenetic CYP2D6 screening to accelerate dose adjustment for nortriptyline and venlafaxine in older patients with depression.

Biosimilars of low molecular weight heparins: Relevant background information for your drug formulary.

Biosimilars of low molecular weight heparins (LMWHs) are more alike the originator than different branded LMWHs. The latter differ largely in molecular weight, anti-FXa/anti-FIIa ratio and antithrombin binding. The Food and Drug Administration and European Medicines Agency guidelines are sufficient for the clinical use of high quality LMWHs. However, the Food and Drug Administration guideline lacks the results of a phase I clinical trial in the approval process. Most information about biosimilars is available for enoxaparin given that many biosimilars of enoxaparin have received market access. The guidelines of many International Thrombosis Societies for LMWH biosimilars are too stringent, not updated and impractical for formulary uptake discussions. This review gives background information on critical factors for the formulary uptake process of LMWHs with special attention for the use of the System of Objectified Judgment Analysis/Infomatrix model.

Implementation of the WHO-6-step method in the medical curriculum to improve pharmacology knowledge and pharmacotherapy skills.

AIM: The only validated tool for pharmacotherapy education for medical students is the 6-step method of the World Health Organization. It has proven effective in experimental studies with short term interventions. The generalizability of this effect after implementation in a contextual-rich medical curriculum was investigated. METHODS: The pharmacology knowledge and pharmacotherapy skills of cohorts of students, from years before, during and after implementation of a WHO-6-step-based integrated learning programme were tested using a standardized assessment containing 50 items covering knowledge of basic (n = 25) and clinical (n = 24) pharmacology, and pharmacotherapy skills (n = 1 open question). All scores are expressed as a percentage of the maximum score possible per (sub)domain. RESULTS: In total, 1652 students were included between September 2010 and July 2014 (participation rate 89%). The WHO-6-step-based learning programme improved students' knowledge of basic pharmacology (mean score ± SD, 60.6 ± 10.5% vs. 63.4 ± 10.9%, P < 0.01) and clinical or applied pharmacology (63.7 ± 10.4% vs. 67.4 ± 10.3%, P < 0.01), and improved their pharmacotherapy skills (68.8 ± 26.1% vs. 74.6% ± 22.9%, P 0.02). Moreover, satisfaction with education increased (5.7 ± 1.3 vs. 6.3 ± 1.0 on a 10-point scale, P < 0.01) and as did students' confidence in daily practice (from -0.81 ± 0.72 to -0.50 ± 0.79 on a -2 to +2 scale, P < 0.01). CONCLUSIONS: The WHO-6-step method was successfully implemented in a medical curriculum. In this observational study, the integrated learning programme had positive effects on students' knowledge of basic and applied pharmacology, improved their pharmacotherapy skills, and increased satisfaction with education and self-confidence in prescribing. Whether this training method leads to better patient care remains to be established.

Education on prescribing for older patients in the Netherlands: a curriculum mapping.

PURPOSE: Pharmacology and pharmacotherapy education is being increasingly integrated in medical curricula, which might lead to a specific loss of knowledge in these subjects. This, in turn, could lead to harmful prescribing errors, especially in vulnerable older patients. METHODS: Teachers who coordinated education in Dutch medical schools completed a structured interview on (geriatric) pharmacology and pharmacotherapy education. A list of core learning goals was developed. Pharmacology and pharmacotherapy education in general was compared to geriatric pharmacology and pharmacotherapy education. RESULTS: All Dutch medical schools participated. Contact hours for education in pharmacology and pharmacotherapy ranged from 39 to 107 h; ECTSs (representing 28 study hours) ranged from 0 to 3. The various curricula covered, on average, 79% of all learning goals for these subjects: knowledge 85%, skills 76%, and attitudes 66%; the curricula also covered specific geriatric goals: knowledge 87% and skills 65%. All geriatric learning goals were met if a geriatrician was among the coordinators. Half (4 of 8) of the medical schools lacked appropriate assessment procedures. Evaluation was mostly based on students' opinions. Teachers rated students as being moderately well prepared for daily practice. CONCLUSIONS: There are large differences in the quantity and quality of (geriatric) pharmacology and pharmacotherapy education in Dutch medical schools. In general, more time should be devoted to skills and attitude, and the assessment procedures should be optimized with high priority. Other curricula with a problem-based approach might benefit from the points of improvement described in this article.

A comparison of medical and pharmacy students' knowledge and skills of pharmacology and pharmacotherapy.

AIM: Pharmacotherapy might be improved if future pharmacists and physicians receive a joint educational programme in pharmacology and pharmacotherapeutics. This study investigated whether there are differences in the pharmacology and pharmacotherapy knowledge and skills of pharmacy and medical students after their undergraduate training. Differences could serve as a starting point from which to develop joint interdisciplinary educational programmes for better prescribing. METHODS: In a cross-sectional design, the knowledge and skills of advanced pharmacy and medical students were assessed, using a standardized test with three domains (basic pharmacology knowledge, clinical or applied pharmacology knowledge and pharmacotherapy skills) and eight subdomains (pharmacodynamics, pharmacokinetics, interactions and side-effects, Anatomical Therapeutic Chemical Classification groups, prescribing, prescribing for special groups, drug information, regulations and laws, prescription writing). RESULTS: Four hundred and fifty-one medical and 151 pharmacy students were included between August 2010 and July 2012. The response rate was 81%. Pharmacy students had better knowledge of basic pharmacology than medical students (77.0% vs. 68.2% correct answers; P < 0.001, δ = 0.88), whereas medical students had better skills than pharmacy students in writing prescriptions (68.6% vs. 50.7%; P < 0.001, δ = 0.57). The two groups of students had similar knowledge of applied pharmacology (73.8% vs. 72.2%, P = 0.124, δ = 0.15). CONCLUSIONS: Pharmacy students have better knowledge of basic pharmacology, but not of the application of pharmacology knowledge, than medical students, whereas medical students are better at writing prescriptions. Professional differences in knowledge and skills therefore might well stem from their undergraduate education. Knowledge of these differences could be harnessed to develop a joint interdisciplinary education for both students and professionals.

Medication review and reconciliation with cooperation between pharmacist and general practitioner and the benefit for the patient: a systematic review.

This article systematically reviews the literature on the impact of collaboration between pharmacists and general practitioners and describes its effect on patients' health. A systematic literature search provided 1041 articles. After first review of title and abstract, 152 articles remained. After review of the full text, 83 articles were included. All included articles are presented according to the following variables: (i) reference; (ii) design and setting of the study; (iii) inclusion criteria for patients; (iv) description of the intervention; (v) whether a patient interview was performed to involve patients' experiences with their medicine-taking behaviour; (vi) outcome; (vii) whether healthcare professionals received additional training; and (viii) whether healthcare professionals received financial reimbursement. Many different interventions are described where pharmacists and general practitioners work together to improve patients' health. Only nine studies reported hard outcomes, such as hospital (re)admissions; however, these studies had different results, not all of which were statistically significant. Randomized controlled trials should be able to describe hard outcomes, but large patient groups will be needed to perform such studies. Patient involvement is important for long-term success.

Geriatric pharmacology and pharmacotherapy education for health professionals and students: a systematic review.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The rate of medication errors is high, and these errors can cause adverse drug reactions. Elderly individuals are most vulnerable to adverse drug reactions. One cause of medication errors is the lack of drug knowledge on the part of different health professionals. Medical curricula have changed in recent years, resulting in less education in the basic sciences, such as pharmacology. WHAT THIS STUDY ADDS: Our study shows that little curricular time is devoted to geriatric pharmacology and that educational programmes in geriatric pharmacology have not been thoroughly evaluated. While interest in pharmacology education has increased recently, this is not the case for geriatric pharmacology education. Education on geriatric pharmacology should have more attention in the curricula of health professionals, given the often complex pharmacotherapy in elderly patients. Educational topics should be related to the known risk factors of medication errors, such as polypharmacy, dose adjustments in organ dysfunction and psychopharmacotherapeutics. AIMS: Given the reported high rates of medication errors, especially in elderly patients, we hypothesized that current curricula do not devote enough time to the teaching of geriatric pharmacology. This review explores the quantity and nature of geriatric pharmacology education in undergraduate and postgraduate curricula for health professionals. METHODS: Pubmed, Embase and PsycINFO databases were searched (from 1 January 2000 to 11 January 2011), using the terms 'pharmacology' and 'education' in combination. Articles describing content or evaluation of pharmacology education for health professionals were included. Education in general and geriatric pharmacology was compared. RESULTS: Articles on general pharmacology education (252) and geriatric pharmacology education (39) were included. The number of publications on education in general pharmacology, but not geriatric pharmacology, has increased over the last 10 years. Articles on undergraduate and postgraduate education for 12 different health disciplines were identified. A median of 24 h (from 15 min to 4956 h) devoted to pharmacology education and 2 h (1-935 h) devoted to geriatric pharmacology were reported. Of the articles on education in geriatric pharmacology, 61.5% evaluated the teaching provided, mostly student satisfaction with the course. The strength of findings was low. Similar educational interventions were not identified, and evaluation studies were not replicated. CONCLUSIONS: Recently, interest in pharmacology education has increased, possibly because of the high rate of medication errors and the recognized importance of evidence-based medical education. Nevertheless, courses on geriatric pharmacology have not been evaluated thoroughly and none can be recommended for use in training programmes. Suggestions for improvements in education in general and geriatric pharmacology are given.

No involvement of the adenosine A2A receptor in tardive dyskinesia in Russian psychiatric inpatients from Siberia.

BACKGROUND: The adenosine A2A receptor forms a heteromeric complex with the striatal dopamine D2 receptor. We examined whether a specific polymorphism in adenosine A2A receptor (2592 C/Tins) is associated with tardive dyskinesia. METHODS: Tardive dyskinesia was assessed cross-sectionally in 146 Caucasian psychiatric inpatients from Siberia. RESULTS: Between-group comparisons of genotypic or allelic frequencies showed no statistically significant difference. Logistic regression analysis with the occurrence of tardive dyskinesia as dependent variable showed no significant association with age, duration of illness, gender, and genotype. CONCLUSION: The interaction between the A2A and D2 receptors seems not involved in the development of tardive dyskinesia.

Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon.

Coumarin oral anticoagulant drugs have proven to be effective for the prevention of thromboembolic events. World-wide, warfarin is the most prescribed drug. In Europe, acenocoumarol and phenprocoumon are also administered. Yet it has been proven that variant alleles of the VKORC1 and CYP2C9 genotypes influence the pharmacokinetics and pharmacodynamics of these drugs. The combination of these two variant genotypes is a major cause of the inter-individual differences in coumarin anticoagulant drug dosage. Individuals who test positive for both variant genotypes are at increased risk of major bleeding. The impact of the CYP2C9 and VKORC1 genotype is most significant during the initial period of coumarin anticoagulant therapy. The effect of VKORC1 allelic variants is relatively similar for all three VKAs. The CYP2C9 polymorphism is associated with delayed stabilisation for coumarin anticoagulants. The effects of CYP2C9 polymorphisms on the pharmacokinetics and anticoagulant response are least pronounced in the case of phenprocoumon. In the long term, patients using phenprocoumon have more often international normalised ratio (INR) values in the therapeutic range, requiring fewer monitoring visits. This leads us to conclude that in the absence of pharmacogenetic testing, phenprocoumon seems preferable for use in long-term therapeutic anticoagulation. Pharmacogenetic testing before initiating coumarin oral anticoagulants may add to the safety of all coumarin anticoagulants especially in the elderly receiving multiple drugs.

Pharmacological aspects of neonatal antidepressant withdrawal.

UNLABELLED: Depression is common in reproductive age women, and continued pharmacologic treatment of depression during pregnancy may be necessary to prevent relapse, which could be harmful for both the fetus and the mother. Although data on drug safety are imperfect and incomplete, the benefits of antidepressant therapy during pregnancy generally outweigh the risks. Neonates who are exposed to antidepressant medications during gestation are at increased risk to have neonatal withdrawal syndrome, although the exact incidence of this complication is unknown because the definition of the syndrome is not clear and withdrawal reactions are probably underreported. Tricyclic antidepressant withdrawal syndrome is most likely related to muscarinergic activity and individual drug half-lives, and selective serotonin reuptake inhibitor withdrawal may be due to a decrease in available synaptic serotonin in the face of down-regulated serotonin receptors, the secondary effects of other neurotransmitters, and biological or cognitive sensitivity. Other factors that influence neonatal toxicity or withdrawal include the normal physiologic changes of pregnancy, the altered activity of CYP450 enzymes during pregnancy, drug-drug transporter (PgP and OCT3) interaction, and the presence of genetic polymorphisms in genes influencing drug metabolism. Further research is necessary. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to explain the importance of antidepressant therapy during pregnancy and postpartum, summarize the important neonatal effects of antidepressants, and describe the potential teratogenic effects of antidepressants.

A Novel Ileocolonic Release Peppermint Oil Capsule for Treatment of Irritable Bowel Syndrome: A Phase I Study in Healthy Volunteers.

INTRODUCTION: Peppermint oil (PO) has been shown to reduce abdominal pain in patients with irritable bowel syndrome (IBS). PO is assumed to induce intestinal smooth muscle relaxation and desensitization of nociceptive nerve afferents. To increase colonic PO concentration, an ileocolonic release peppermint oil (IC-PO) capsule has been developed. The aim of this study was to compare pharmacokinetic parameters of the currently available small intestinal release PO (SI-PO) and the novel IC-PO. METHODS: In this randomized, double-blind, crossover study, subjects received 182 mg of either SI-PO or IC-PO in a crossover design with a washout period of more than 14 days. Blood samples were collected to determine menthol glucuronide concentrations. RESULTS: Eight healthy volunteers (50% female, median age 22) were included. The time to reach the maximum concentration (Tmax) of IC-PO was significantly longer compared to SI-PO with a median (IQR) of 360 (360-405) versus 180 (120-180) min. The lag time (Tlag) was significantly longer with a median (IQR) of 225 (204-284) for IC-PO compared to 37 (6-65) min for SI-PO. The areas under the menthol glucuronide plasma concentration-time curves were significantly smaller with a median (IQR) of 2331 µg h/L (2006-2510) for IC-PO compared to 2623 µg h/L (2471-2920) for SI-PO. No significant differences were found in peak concentrations and elimination half-lives. CONCLUSION: IC-PO has a significantly delayed peak menthol glucuronide concentration and Tlag, both pointing to the release of PO in the more distal part of the intestine. This may enhance therapeutic efficacy as it results in increased exposure of colonic mucosal afferents to the PO. A randomized controlled trial investigating the efficacy of SI and IC-PO in IBS is currently ongoing. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02291445, EudraCT database 2014-004195-32.

Incidence and nature of medication errors in neonatal intensive care with strategies to improve safety: a review of the current literature.

Neonates are highly vulnerable to medication errors because of their extensive exposure to medications in the neonatal intensive care unit (NICU), the general lack of evidence on pharmacotherapeutic interventions in neonates and the lack of neonate-specific formulations. We searched PubMed and EMBASE to identify relevant original studies published in the English language. Eleven studies were identified on the frequency of medication errors in the NICU. The highest rate was 5.5 medication errors per 100 prescriptions; however, medication error rates varied widely between studies, partly due to differences in the definition of an error and the rigor of the method used to identify medication errors. Furthermore, studies were difficult to compare because medication error rates were calculated differently. Most studies did not assess the potential clinical impact of the errors. The majority of studies identified dose errors as the most common type of error. Computerised physician order entry and interventions by clinical pharmacists (e.g. the participation of pharmacists in ward rounds and review of patients' prescriptions prior to dispensing) were the most common interventions suggested to improve medication safety in the NICU. However, only very limited data were available on evaluation of the effects of such interventions in NICUs. More research is needed to determine the frequency and types of medication errors in NICUs and to develop evidence-based interventions to improve medication safety in the NICU setting. Some of these research efforts need to be directed to the establishment of clear definitions of medication errors and agreement on the methods that should be used to measure medication error rates and their potential clinical impact.

Direct medical costs of serious gastrointestinal ulcers among users of NSAIDs.

BACKGROUND: The occurrence and prevention of gastrointestinal ulcers during use of NSAIDs has become a major healthcare issue. OBJECTIVE: To determine the direct medical costs of serious NSAID-related ulcer complications. METHOD: An observational cost-of-illness study was conducted in a large general hospital serving a population of 152,989 persons. From November 2001 to December 2003 all consecutive patients hospitalised with serious NSAID-related ulcer complications were identified. Serious NSAID-related ulcer complications were defined as ulcerations of the stomach or proximal duodenum causing perforation, obstruction or bleeding that occurred during the use of NSAIDs, necessitating hospitalisation of the patient. Data were retrieved with respect to days hospitalised and the number and type of diagnostic and therapeutic interventions. The main outcome measure was estimated mean direct medical costs of resources used. RESULTS: A total of 104 patients were hospitalised with serious NSAID-related ulcer complications (incidence 31.4 per 100,000 persons per year). Most patients were elderly (mean 70.4 years, SD 16.7). In-hospital mortality was 10.6%. Mean direct medical costs were euro 8375 (95% CI 7067, 10 393). On the basis of these results, we estimated that approximately 5105 people are hospitalised with serious NSAID-related ulcer complications in The Netherlands each year, of whom 541 die in hospital. The total annual direct medical costs for serious NSAID-related ulcer complications in The Netherlands were estimated to be euro 42,754 375 (95% CI 36 077 035, 53 056 265). CONCLUSIONS: Serious NSAID-related ulcer complications have a mortality rate of 10.6% in The Netherlands and the annual direct medical costs to the country of such complications are approximately euro 42,750 000.

Cost considerations in the treatment of colorectal cancer.

Colorectal cancer is among the most common malignancies in developed countries. Screening can reduce mortality significantly, although the most appropriate method is still under debate. Observational studies have revealed that lifestyle measures may also be beneficial for prevention of colorectal cancer. Surgery is still the most effective treatment modality for colorectal cancer. The survival benefits of chemotherapy are only modest. For nearly 5 decades, 5-fluorouracil (5-FU) has been the main cytotoxic agent for treatment of colorectal cancer. In the last decade, the new cytotoxic agents raltitrexed, irinotecan and oxaliplatin have been introduced, next to the oral 5-FU analogues capecitabine and tegafur in combination with uracil (UFT). Moreover, the immunotherapeutics bevacizumab and cetuximab have become approved for treatment of metastatic colorectal cancer. The economic implications of colorectal cancer treatment are substantial. The costs of treatment are mainly attributable to the early and terminal stage of the disease (i.e. surgery, hospitalisation, chemo- and immunotherapy and supportive care). The introduction of new chemo- and immunotherapeutics has caused a continuing increase of treatment expenditures. Therefore, comparative costs and cost effectiveness are important for assessing the value of new treatment regimens. The available study results suggest that addition of irinotecan or oxaliplatin to 5-FU/folinic acid dosage regimens is cost effective. Also, capecitabine is calculated to be cost effective when compared with 5-FU/folinic acid. For UFT, no comparative studies of cost effectiveness were found. Since raltitrexed and 5-FU/folinic acid have shown equal efficacy in terms of survival, cost-effectiveness analysis is considered not to be applicable and cost-minimisation analysis may be sufficient. At present, pharmacoeconomic analyses of combination treatment with the immunotherapeutics bevacizumab or cetuximab are not available, except for recent cost-effectiveness considerations by the UK National Institute for Health and Clinical Excellence with negative recommendations for both agents in the treatment of metastatic colorectal cancer. Given the high treatment costs, substantial toxicity and relatively limited efficacy of the fast changing chemo- and immunotherapeutic combinations for colorectal cancer, examination of cost-effectiveness studies should be conducted on a routine basis along with determination of clinical benefits.

A simple method for quantification of allopurinol and oxipurinol in human serum by high-performance liquid chromatography with UV-detection.

OBJECTIVES: Allopurinol is a uric acid lowering drug used in the treatment of gout and the prevention of tumor lysis syndrome. Allopurinol and its active metabolite oxipurinol inhibit xanthine oxidase, which forms uric acid from xanthine and hypoxanthine. Therapeutic drug monitoring is an important option for evaluation and optimization of allopurinol treatment in case of renal impairment, interaction with uricosuric drugs or to verify patient adherence. In this study we developed and validated a simple quantitative assay using reverse phased high-performance liquid chromatography (HPLC) with UV-detection as a method for quantification of allopurinol and oxipurinol in human serum in the presence of different frequently used drugs. METHODS: The HPLC-UV method uses a mobile phase consisting of sodium acetate (0.02 M; pH 4.5), at a flow rate of 1.0 mL/min. Allopurinol and oxipurinol are detected by UV-absorption at 254 nm with a retention time of 9.9 min for oxipurinol and 12.3 min for allopurinol. Aciclovir is used as internal standard. RESULTS: Validation showed for allopurinol lower and upper limits of quantification of 0.5 and 10mg/L and for oxipurinol 1 and 40 mg/L, respectively. The assay was linear over the concentration range of 0.5-10mg/L (allopurinol) and 1-40 mg/L (oxipurinol). Intra- and inter-day precision showed coefficients of variation <15% over the complete concentration range; accuracy was within 5% for allopurinol and oxipurinol. Endogenous purine-like compounds were separated from allopurinol, oxipurinol and aciclovir with a resolution factor >1.5. Exogenous purine-like compounds and co-medication frequently used by gout patients did not hinder the analysis due to the dichloromethane washing step or to low UV-absorpion at 253 nm. Serum levels of 66 patients prescribed allopurinol 300 mg/day were determined using this HPLC-UV method. Measured serum allopurinol and oxipurinol concentrations in clinical practice showed large variability with a range of <0.5-4.3 mg/L for allopurinol and <1.0-39.2 mg/L for oxipurinol, respectively. CONCLUSION: We developed an easy-to-operate and validated HPLC-UV method for the quantification of allopurinol and oxipurinol in human serum. This method was proven to be valid for samples of gout patients frequently using concomitant medications.

Biochemical effectiveness of allopurinol and allopurinol-probenecid in previously benzbromarone-treated gout patients.

In 2003, the uricosuric drug benzbromarone was withdrawn from the market. The first alternative drug of choice was the xanthine oxidase inhibitor allopurinol. The purpose was to (1) investigate the efficacy of allopurinol (standard dosage) compared with previous treatment with benzbromarone; and (2) investigate the combination therapy allopurinol-probenecid as an effective alternative treatment compared with previous benzbromarone treatment. A prospective, open study was carried out in a cohort of 51 gout patients who discontinued benzbromarone therapy because of market withdrawal. Patients were given 200-300 mg allopurinol (stage 1). When allopurinol failed to attain the target serum urate (sUr) levels

Tyrosine Kinase Inhibitors and Proton Pump Inhibitors: An Evaluation of Treatment Options.

Tyrosine kinase inhibitors (TKIs) have rapidly become an established factor in oncology, and have been shown to be effective in a wide variety of solid and hematologic malignancies. Use of the oral administration route of TKIs offers flexibility and is convenient for the patient; however, despite these advantages, the oral route of administration also causes a highly relevant new problem. Acid-inhibitory drugs, such as proton pump inhibitors (PPIs), increase the intragastric pH, which may subsequently decrease TKI solubility, bioavailability, and treatment efficacy. Clear and practical advice on how to manage PPI use during TKI therapy is currently not available in the literature. Since PPIs are extensively used during TKI therapy, prescribers are presented with a big dilemma as to whether or not to continue the combined treatment, resulting in patients possibly being deprived of optimal therapy. When all pharmacological characteristics and data of either TKIs and PPIs are considered, practical and safe advice on how to manage this drug combination can be given.

Estradiol gel: review of the pharmacology, pharmacokinetics, efficacy, and safety in menopausal women.

OBJECTIVE: To review the pharmacology, pharmacokinetics, safety, and efficacy of a gel containing estradiol that is applied to the skin. DESIGN: MEDLINE and EMBASE searches were conducted from 1966 to March 2005. Additional references were identified from bibliographies from selected studies in addition to approved product information. RESULTS: Estradiol gel is indicated for the relief of moderate to severe vasomotor symptoms in menopausal women, and moderate to severe symptoms of vulvar and vaginal atrophy. Women who are intolerant of the oral route, have had previous hypersensitivity skin reactions, or have had difficulties with adhesive patches are ideal candidates for estradiol gel. CONCLUSIONS: Estradiol gel can effectively reduce menopause symptoms with minimal side effects. Long-term safety data of estradiol gel are required.