Showing papers in "Journal of Clinical Pharmacy and Therapeutics in 2005"

High prevalence of orthostatic hypotension and its correlation with potentially causative medications among elderly veterans

Abstract: Summary Background: Orthostatic hypotension (OH) is defined as a reduction of systolic blood pressure of at least 20 mmHg, or diastolic blood pressure of at least 10 mmHg from a sitting to a standing position. It is a common physical finding among older adults and associated with significant morbidity and mortality. Use of medications that have the potential to induce OH, particularly concomitant use of several of such medications, is a major factor for the development of OH. Objectives: To describe the prevalence of symptomatic and asymptomatic OH in veterans aged 75 years and older attending a geriatric clinic, and to assess the association between OH and the number of potentially causative medications used. Methods: Charts of all patients who attended a VA geriatric clinic (Michael E. DeBakey VA Medical Center) during the period of 1 June 2002 to 1 June 2003 were reviewed retrospectively for (i) the use of potentially causative medications, i.e. medications that were reported to cause OH in at least 1% of the general population and that were available in the VA formulary, (ii) the presence or absence of OH, and (iii) the presence or absence of symptomatic OH. Patients with primary autonomic dysfunction, Parkinson's disease, and patients who were unable to stand, or who had no assessment for both sitting and standing blood pressure for other reasons were excluded. Results: A total of 505 individual patients attended the clinic during the study period, and 342 patients fit the inclusion criteria. About 189 of these patients (55%) had OH. Among patients with OH, 61 patients (33%) were symptomatic, including 52 patients who had falls. The prevalence of OH in patients receiving zero, one, two, and three or more potentially causative medications was 35, 58, 60 and 65% respectively. Receiving hydrochlorothiazide was associated with the highest prevalence of OH (65%), followed by receiving lisinopril (60%), trazodone (58%), furosemide (56%) and terazosin (54%). Conclusion: The prevalence of OH is very high in older veterans and significantly related to the number of concurrent causative medications used. Providers should be educated to reduce the amount of potentially causative medications in the elderly and better assess patients in which use of such medications is necessary to avoid symptomatic OH.

Counselling quality in community pharmacies: implementation of the pseudo customer methodology in Germany.

Abstract: Summary Objectives: To investigate a new method for evaluating counselling performance of staff in community pharmacies and to assess the quality of patient counselling. Method: Trained pseudo customers, instructed to play their role according to two different self-medication scenarios, visited voluntarily participating community pharmacies in Berlin. After documenting the counselling process, immediately after each visit, outside the pharmacy on an assessment form, the pseudo customer re-entered the pharmacy and gave detailed performance feedback to the counsellor and the pharmacist in charge in order to provide support for improving counselling skills and practice behaviour, when appropriate. This was followed with a written summary of the general performance of all participating pharmacies and additional individual feedback and suggestions for improvement. Educational needs were identified for subsequent performance-based educational strategies such as group-workshops, team-training and on-site team-coaching. Results: Forty-nine community pharmacies in Berlin volunteered to participate in this pilot study. Ninety-eight per cent of the participating pharmacies offered advice. However, in 36% of the cases, advice was only given on request. The different types of scenarios – presentation of a symptom or request for a specific product – made a great difference to the spontaneity of questions and advice. At least one question to check on accuracy of self-diagnosis was asked in 95% of the cases of symptom presentation but in only 47% of the cases of specific product request. Information on appropriate self-medication was provided on at least one item in 74% of pseudo customer visits, but most of the time the information was not sufficient. Communication skills (nonverbal elements, comprehensibility etc.) were very good or good in 54% of the visits. Potential for improvement was mainly in relation to the use of open-ended questions to gain more information and on counselling about appropriate self-medication. Direct feedback was given in 96% of the pharmacies (one person refused to accept feedback and one feedback had to be postponed because of time shortage). All of the participants regarded counselling as an important subject in pharmacy practice. Conclusion: The pseudo customer method was successfully used in this study of German community pharmacies. It was shown that pseudo customer visits and performance feedback following the counselling process, were feasible in daily practice and well accepted by the participants. A training program, focussing on areas in most need of improvement, has been developed. The promising results have led to the Federal Chamber of Pharmacists in Germany adopting this method as part of a continuous quality improvement program in community pharmacies.

Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method.

Abstract: SUMMARY Objective: Intravenous ibuprofen (IBU) has beenfound to be as effective as indomethacin for thetreatment of patent ductus arteriosus (PDA) inpreterm infants and has been associated withfewer adverse effects in comparative phase IIIstudies. The dose regimen used (10–5–5 mg/kg/day) was based on limited pharmacokinetic dataand no phase II study was available to determinethe optimal dose of IBU for this indication. Thepresent study was designed to determine theminimum effective dose regimen (MEDR) of IBU(one course) required to close ductus arteriosus inpreterm infants.Method: A double-blind dose-finding study wasconducted using the continual reassessmentmethod, a Bayesian sequential design. Two dis-tinct target closure rates were initially chosenaccording to postmenstrual age (PMA) at birth:80% in infants with a PMA of 27–29 weeks, and50% in infants with a PMA <27 weeks. Forty neo-nates (20 in each PMA group) with PDA weretreated between days3and5oflife.Fourdifferentdose regimens were tested: loading doses of 5, 10,15or20 mg/kg,followedbytwodoses(1/2loadingdose) at 24-h intervals. Efficacy was evaluated byechocardiography 24 h after the third infusion.Results: IninfantswithaPMAof27–29 weeks,theestimated MEDR was 10–5–5 mg/kg with a finalestimated probability of success of 77% (95%credibility interval: 56–92%). The 15–7AE5–7AE5 mg/kgdoseregimenhadabetterestimatedprobabilityofsuccess(88%,95%credibilityinterval:68–97%),butresultedinmoreminorrenaladverseeffects.Incontrast, in infants with a PMA <27 weeks, theestimated MEDR was 20–10–10 mg/kg with anestimated probability of success of 54AE8% (95%credibility interval: 22–84%), whereas the con-ventionaldoseregimenresultedinalowestimatedprobability of success (30AE6%,95% credibilityinterval: 13–56%). In these infants, compared withthose with a PMA of 27–29 weeks, minor renaladverse effects were more frequent from the 10–5–5 mg/kg/daydoseregimenanddidnotappeartobeclearly dose related.Conclusion: This study confirms that the cur-rently recommended dose regimen (10–5–5 mg/kg) of IBU is associated with a high closurerate (80%) and few adverse effects in prematureinfants with a PMA of 27–29 weeks. The failurerate was much higher below 27 weeks. Ahigher dose regimen (20–10–10 mg/kg) mightachieve a higher closure rate. However, toler-ability and safety of this dose regimen shouldbe assessed in a larger population before con-sidering the use of these doses for ductusarteriosus closure.Keywords: Bayesian design, continual reassess-ment method, dose-ranging study, ductus arte-riosus, ibuprofen, premature neonate.

Valproate: a simple chemical with so much to offer.

Abstract: The debate exists amongst clinical pharmacologists as to unlimited supplies of which drug would be most useful when stranded on a deserted island. The tricyclic antidepressants have always rated highly because of their variety of useful therapeutic effects, but valproate also deserves to be high on the list. Of course, it will protect against seizures, if they arise, but it could also be useful for analgesia, preventing migraine and stabilizing the mood particularly if one becomes mentally unbalanced on the island. It might even help to prevent the development of cancer. It would not be an overstatement to suggest that valproate is truly a remarkable drug – a multitude of therapeutic effects from such a simple chemical structure (2-propylpentanoic acid; Fig. 1) – with a remarkable story; it was discovered by chance and is now well-established in the management of a number of neurological conditions and psychiatric disorders. An American chemist (Burton) first synthesized valproate as an organic solvent in 1882 (1). It is a clear, colourless to pale yellow liquid at room and body temperature, and only slightly soluble in water, but highly soluble in organic solvents. The current generic name (valproic acid) was derived from the more descriptive name 2-propylvaleric acid (2). Valproate had been used infrequently as a solvent until its therapeutic properties were serendipitously discovered in 1962 by French researchers, when it was being used as a solvent for other compounds (khelline derivatives) that were being tested for potential anticonvulsant activity (2–4). Eynard and colleagues had encountered difficulty in dissolving some of the derivatives in water or common organic solvents. Valproate was then used to solubilize these compounds and anticonvulsant activity was subsequently observed for the entire test compounds at all doses. Laboratory studies demonstrated anti-seizure activity with valproate (5) and the first clinical trial in epilepsy using the sodium salt of valproic acid was reported in 1964 (6, 7). It was released in France in 1967 (as ‘Depakine’), in Great Britain in 1973 and was approved by the US Food and Drug Administration (FDA) in 1978. It was the only new anticonvulsant drug marketed for many years, beforehand and afterwards. Valproate is currently marketed in over 100 countries and is well established as a first-line and widely used antiepileptic agent, with a very broad spectrum of activity against both generalized and partial seizures in adults and children (4, 8, 9). It is effective against absences and myoclonic, and generalized tonic-clonic seizures. In addition, the drug is useful in the treatment of partial seizures, with or without secondary generalization (2–4, 8, 9). Intravenous valproate has also been shown to be effective against status epilepticus (10). Results from numerous clinical trials suggest that valproate probably has the widest spectrum of anticonvulsant activity of all current antiepileptic drugs in adults and children with epilepsy (4, 8, 9). Received 9 May 2005, Accepted 19 May 2005 Correspondence: Gregory Peterson, Unit for Medication Outcomes Research and Education, School of Pharmacy, University of Tasmania, Locked Bag 26, Hobart TAS 7001, Australia. Tel.: 61 3 62262197; fax: 61 3 62267627; e-mail: g.peterson@utas.edu.au OH H3C H3C

Proposed mechanisms and preventative options of Jarisch–Herxheimer reactions

Abstract: Summary Objective: To review the aetiologies and preventative methods associated with Jarisch–Herxheimer reactions (JHR). Data sources: Ovid Medline® (1966–June Week 1 2004) was utilized to assess biomedical literature; a review of the bibliographies of articles was also performed. Data synthesis: JHR often occurs with the treatment of spirochete infections. However, the mechanism by which the reaction takes place is not clearly defined. Conclusion: Studies suggest with conflicting evidence that the JHR is caused by release of endotoxin-like material from the spirochete as well as cytokine elevation in the body. It appears the type of drug and the rate of spirochete clearance from the body have little effect on the incidence of the reaction. Many pretreatment options have been explored with limited efficacy with the exception of anti-tumour necrosis factor antibodies.

Pharmacoepidemiologic study of potential drug interactions in outpatients of a university hospital in Thailand

Abstract: SUMMARY Background: Drug–drug interaction is a potential cause of adverse drug reactions. The incidence of such drug interactions in university hospitals in Thailand is unknown. Purpose: To estimate the rate of potential drug– drug interactions in outpatients of a typical Thai university hospital, and to identify risk factors for such interactions in Thai patients. Methods: One-year outpatients’ prescription data were retrieved from the hospital computer records. Potential drug interactions were identified using the existing drug-interaction database system. Potential interactions within a specific prescription and involving drugs prescribed 1-, 3- and 7-day earlier were searched for. Possible associations between occurrence of an interaction and a patient’s age and gender and the number of items on the prescription were explored. Results: The overall rate of potential drug interactions was 27AE9% with a maximal value of 57AE8% at the Department of Psychiatry. The rate of the most potentially significant interactions was 2AE6%, being the highest in the Department of Medicine (6AE0%), with isoniazid vs. rifampin as the most common interacting combination. The rate increased with the patient’s age and prescription size (P = 0AE000). The odd’s ratio of having at least one potential drug interaction was 1AE8 (64AE2%) when age increased by 20 years (P = 0AE000) and 2AE8 (165AE7%) when another drug was added (P = 0AE000). The rate of potential drug interactions was the same for both genders. The rate of potential drug interactions detected across prescriptions was higher than within prescriptions and was dependent on the time interval between prescriptions. Conclusions: Potential drug interactions were common in our sample of patients. The rate of such interactions increased with the number of drugs prescribed and the patient’s age.

Myocarditis, pericarditis and cardiomyopathy in patients treated with clozapine

Abstract: Clozapine is known to cause cardiac side-effects, including myocarditis, pericarditis and cardiomyopathy. Prompted by a case of clozapine-related pericarditis in our hospital we undertook a review of the literature for reports of myocarditis, pericarditis and cardiomyopathy occurring in patients treated with clozapine. This is the first comprehensive review of the literature on this topic.

The quality of sulphadoxine-pyrimethamine and amodiaquine products in the Kenyan retail sector.

Abstract: Summary Background and objective: Malaria is a disease of major public health importance in Kenya killing 26 000 children under 5 years of age annually. This paper seeks to assess the quality of sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ) products available over-the-counter to communities in Kenya as most malaria fevers are self-medicated using drugs from the informal retail sector. Methods: A retail audit of 880 retail outlets was carried in 2002 in four districts in Kenya, in which antimalarial drug stocks and their primary wholesale sources were noted. In addition, the expiry dates on audited products and the basic storage conditions were recorded on a proforma. The most commonly stocked SP and AQ products were then sampled from the top 10 wholesalers in each district and samples subjected to standard United States Pharmacopoeia (USP) tests of content and dissolution. Results and discussion: SP and AQ were the most frequently stocked antimalarial drugs, accounting for approximately 75% of all the antimalarial drugs stocked in the four districts. Of 116 SP and AQ samples analysed, 47 (40·5%) did not meet the USP specifications for content and/or dissolution. Overall, approximately 45·3% of SP and 33·0% of AQ samples were found to be sub-standard. Of the sub-standard SP products, 55·2% were suspensions while 61·1% of the substandard AQ products were tablets. Most SP failures were because of the pyrimethamine component. Conclusion: There is a need to strengthen post-marketing surveillance systems to protect patients from being treated with sub-standard and counterfeit antimalarial drugs in Kenya.

Differences in the single-oral-dose pharmacokinetics and urinary excretion of paracetamol and its conjugates between Hong Kong Chinese and Caucasian subjects

Abstract: Summary Background and Objectives: The present study was conducted to determine if ethnic differences exist for single oral dose pharmacokinetics of paracetamol and its conjugates between Hong Kong Chinese and Caucasian subjects. Methods: Twenty healthy Chinese (n = 11) and Caucasian (n = 9) subjects, aged 21–44 years, 11 male and nine female, were given oral paracetamol syrup 20 mg/kg, following an overnight fast. Paracetamol and its metabolites (glucuronide, sulphate, cysteine and mercapturic acid conjugates) were measured in serial plasma samples (0·25, 0·5, 0·75, 1·0, 1·5, 2, 3,…,12, 24 h) and urine collections (0–24 h) by high-performance liquid chromatography. Results: In Chinese subjects, the (mean range) peak plasma concentration of paracetamol was 23·8 μg/mL (17·9–32·3) and time to attain this peak 0·66 h (0·5–0·75). This was lower (P < 0·015) at 18·7 μg/mL (14·4–22·9) and achieved later (P < 0·033) at 1·06 h (0·5–2·0) in Caucasians. In Chinese subjects, plasma levels of glucuronide were lower, sulphate higher and cysteine conjugates significantly lower than in Caucasians (P < 0·05). Chinese subjects excreted 6% more sulphate and 5% less glucuronide. They also excreted significantly less mercapturic acid conjugates (P < 0·001). Discussion and Conclusion: Chinese subjects show more rapid absorption of paracetamol, a tendency to produce less glucuronide but more sulphate conjugates and reduced production of cysteine and mercapturic acid conjugates. The latter may help to protect against hepatotoxicity following paracetamol overdose.

Ketoconazole increases plasma concentrations of antimalarial mefloquine in healthy human volunteers

Abstract: Summary Background: Antimalarial mefloquine has a structure related to quinine. The major metabolite of quinine is 3-hydroxyquinine formed by cytochrome P450 3A4 (CYP3A4). Ketoconazole, a potent inhibitor of CYP3A4, is known to markedly increase plasma concentrations of various co-administered drugs including quinine. Objective: To assess the effect of ketoconazole on plasma concentrations of mefloquine in healthy Thai male volunteers. Methods: In an open, randomized two-phase crossover study separated by a 1-month period, eight healthy Thai male volunteers received a single oral dose of 500 mg mefloquine alone or co-administration with 400 mg/day ketoconazole orally for 10 days. Serial blood samples were collected at specific time points for a 56-day period. Plasma mefloquine and mefloquine carboxylic metabolite concentrations during 56 days were measured by a modified and validated high-performance liquid chromatographic method with UV detection. Results: Co-administration with ketoconazole markedly increased the mean values of mefloquine AUC0−t, t1/2, and Cmax when compared with mefloquine alone by 79% (P < 0·001), 39% (P < 0·05) and 64% (P < 0·001) respectively. The AUC0−t , and Cmax of mefloquine carboxylic acid metabolite were decreased by 28% (P < 0·05) and 31% (P < 0·05), respectively when compared with mefloquine alone. Conclusions: Co-administration with ketoconazole increased plasma mefloquine concentrations in healthy human volunteers. One of possible mechanisms of the increase in plasma mefloquine concentrations may be the result of the inhibition of CYP3A4 by ketoconazole. In case of mefloquine is co-administered with ketoconazole, drug–drug interactions should be recognized and the dose of mefloquine should be adjusted to maximize the therapeutic efficacy and to reduce the cost of therapy.

Improving the outcomes of anticoagulation in rural Australia: an evaluation of pharmacist‐assisted monitoring of warfarin therapy

Abstract: Summary Objective: The aim of this project was to assess whether rural pharmacist involvement in the management of patients receiving warfarin has the potential to lead to safer and more effective anticoagulation, and is valued and welcomed by patients and their general practitioners (GPs). Methods: A convenience sample of rural pharmacists was trained in the use of the CoaguChek S International Normalized Ratio (INR) monitor and then conducted pharmacy-based testing for approximately 3 months. Two types of testing were performed in the pharmacy: (i) comparison testing was defined as pharmacy-based tests taken within 4 h of conventional laboratory testing or (ii) additional testing, which was a pharmacy-based test with no direct comparison laboratory test taken. Pharmacists, GPs and patients completed anonymous satisfaction surveys after the completion of the pharmacy-based testing. Results: Pharmacists from 16 rural pharmacies were trained to use the CoaguChek S monitor. During the trial period, 518 INR tests were performed in the pharmacies on 137 different patients. A total of 120 tests were evaluated against results from laboratory testing. The pharmacy-based INR values were significantly correlated with the laboratory INR values (mean of 2·32 ± 0·77 and 2·32 ± 0·59 respectively; r = 0·88, P < 0·0001). A total of 398 additional pharmacy-based tests were conducted in the pharmacy and 8·5% of the additional tests resulted in a subsequent dosage change. The monitoring was well received by pharmacists, GPs and patients. Conclusions: The results of the trial were very positive. The CoaguChek S monitor in pharmacy-based testing performed accurately compared with conventional laboratory testing. Further research needs to be conducted on the impact of community pharmacy-conducted INR monitoring on patient care and outcomes.

Patient valuation of pharmacist services for self care with OTC medications.

Abstract: Summary Background and Objectives: The objectives of this study were to determine whether patients would be willing to pay for pharmacist self-care services on proper use of over-the-counter medications. In addition, we examined whether patients’ willingness to pay was associated with community pharmacy setting and patients’ socio-economic factors. Methods: A self-administered questionnaire was handed out to patrons of community pharmacies in Arkansas, USA. The questionnaire contained question items related to patients’ willingness to pay, community pharmacy setting, prescription drug insurance and socio-economic information. Patients’ willingness to pay was measured using the checklist method. Results and Discussion: A total of 262 questionnaires were completed. More than twice as many patients (51%) are now willing to pay for pharmacist services for patient self care than a decade ago. They were willing to pay about $5 for a 5-min consultation. Willingness to pay was significantly associated with community pharmacy setting (chi-square, P = 0·030). Grocery/chain pharmacy patrons were more willing to pay than independent pharmacy patrons. Conclusion: This increased patient willingness to pay, along with growing self-care markets, provides pharmacists with opportunities to develop self-care clinics or services.

Reduced oral itraconazole bioavailability by antacid suspension.

Abstract: Summary Aims: To investigate the effects of antacid suspension on oral absorption of itraconazole. Methods: A randomized, open-labelled, two-period, crossover study with a 1-week washout period was conducted in 12 healthy Thai male volunteers. The participants were allocated in either treatment A or B in the first period. In treatment A, the volunteers were orally administered with 200 mg of itraconazole alone. In treatment B, the volunteers were administered orally with 200 mg of itraconazole co-administered with antacid suspension. Serial serum samples were collected over the period of 24 h and subsequently analysed by using a validated high-pressure liquid chromatographic method with ultraviolet detection. Pharmacokinetic parameters were determined by non-compartmental analysis. Results: Time to reach maximal concentration (Tmax), maximal concentration (Cmax) and area under the curve (AUC0--∞) were markedly decreased in antacid-treated group. Tmax for treatment A was 3·0 ± 0·4 and 5·1 ± 2·7 h for treatment B. Cmax and AUC0--∞ of treatments A and B were 146·3 ± 70·5 vs. 43·6 ± 16·9 (ng/mL) and 1928·5 ± 1114·6 vs. 654·8 ± 452·2 (ng·h/mL) respectively. 90% Confidence interval (90% CI) of Cmax and AUC0--∞ were 24·1–42·1 and 16·2–65·9 respectively. Conclusions: Rate and extent of itraconazole oral absorption were markedly decreased by concurrent use of antacid suspension. Hence, co-administration of itraconazole and antacid suspension should be avoided.

Achieving a sustained reduction in benzodiazepine use through implementation of an area-wide multi-strategic approach.

Abstract: Summary Objective: This study aimed to evaluate the impact, in a regional setting, of a multi-strategic partnership approach for reducing benzodiazepine use in the management of insomnia, as recommended in Australia's National Policy on Quality Use of Medicines. Method: The setting was a rural region of South Australia, covering approximately 2000 km2, with a population of over 20 000. The study involved participatory action research, with qualitative and quantitative evaluations. The intervention involved a multi-strategic approach, including provision of treatment guidelines, provision of consumer information, a local media campaign and education and training of health professionals. The quantitative evaluation involved a single region before/after study with 2 years of follow-up using pharmacy-based dispensing data for benzodiazepines and antidepressants, gathered for the months of November to April in 1998/99 (‘before’ period) through to 2000/01 (‘after’ period). The data were analysed using non-parametric statistics. Results: There was a 19% reduction in benzodiazepine dispensing 2 years after the intervention compared with a 6% reduction nationally. Dispensing of antidepressants increased by 33%, compared with a 28% increase nationally. Conclusion: It was concluded that the multi-strategic approach to the management of sleep disorders proved successful in promoting the use of non-drug alternatives, achieving sustained reduction in benzodiazepine consumption in a rural community, without therapeutic substitution of antidepressants. Implications: The study demonstrated that a sustainable reduction in prescribing of benzodiazepines can be achieved through the implementation of a multi-strategic approach involving local consumers, health professionals, a Division of General Practice, a government department, aged-care facilities and the local media.

Clinical factors associated with hyperkalemia in patients with congestive heart failure.

Abstract: Summary Background: Patients with congestive heart failure (CHF) are at risk for hyperkalemia because of coexisting comorbidities and use of multiple medications that impair potassium (K) excretion such as angiotensin converting enzyme (ACE) inhibitors. Objective: To identify clinical factors associated with hyperkalemia on initial presentation in patients hospitalized for CHF. Design: A case–control study. Setting: Two university-affiliated tertiary-care hospitals. Subjects: Using ICD-9 code for CHF, CHF admissions with hyperkalemia on presentation (cases) were identified from a population of 938 non-dialysis-dependent CHF patients. CHF admissions with normokalemia on presentation were used as controls. Hyperkalemia was defined as serum K ≥ 5·6 mmol/L, and normokalemia as serum K ≥ 3·5 and ≤5·5. Methods: Data were collected on demographic characteristics, clinical variables, comorbidity and medication use. Factors associated with hyperkalemia on initial presentation were examined. Results: Mean age did not differ between cases [76 years, standard deviation (SD) = 12] and controls (75 years, SD = 12) (P = 0·824). Mean potassium levels for cases and controls were 6·2 mmol/L (range 5·6 to 8·2) and 4·3 mmol/L respectively (P < 0·001). On multivariate analysis, diabetes mellitus [odds ratio (OR) = 2·42, 95% confidence interval (CI) = 1·04–5·59], creatinine clearance <40 mL/min (OR = 8·36, CI = 2·73–25·56), use of spironolactone (OR = 4·18, CI = 1·27–13·79), and use of ACE inhibitors (OR = 2·55, CI = 1·06–6·13) were independently associated with hyperkalemia. Conclusions: In CHF patients, hyperkalemia on presentation is independently associated with diabetes, creatinine clearance <40 mL/min, use of spironolactone, and use of ACE inhibitors. Recommendations for use of spironolactone and ACE inhibitors in CHF, and the intensity of serum K monitoring need to be clarified to account for patients at higher risk for hyperkalemia.

The efficacy of three desensitizing agents in treatment of dentine hypersensitivity

Abstract: Summary Purpose: The purpose of this study was to evaluate the efficacy of three desensitizing agents vs. placebo. Materials and methods: One hundred and six hypersensitive teeth of 26 patients were included in this study, and the baseline hypersensitivity level of all teeth was established as ‘moderate’ by using Visual Analogue Scale (VAS). The teeth were divided into four groups: to the first group 5% potassium nitrate bio-adhesive gel, to the second 2% sodium fluoride bio-adhesive gel and to the third one step adhesive system Prompt L-Pop were applied as desensitizing agents. Group 4 was the control group in which a desensitizer-free bio-adhesive gel was used as placebo. Post treatment and eighth week control measurements were recorded on VAS. Results: It was observed that the efficacy of three desensitizing agents did not differ from each other (P > 0·05) and except for placebo all reduced moderate dentin hypersensitivity effectively (P < 0·05). Clinical relevance: Five per cent potassium nitrate, 2% sodium fluoride bio-adhesive gels and one-step bonding agent Prompt L-Pop were effective in reducing moderate dentine hypersensitivity.

Health-related quality of life in hypertension: impact of a pharmacy intervention programme.

Abstract: Summary Background and objective: In a previous study, we observed that a pharmacy-based intervention programme decreased the blood pressure of hypertensive patients. The objective of the present study was to assess the effect of this pharmacy programme on the health-related quality of life (HRQOL) of individuals treated for hypertension. Methods: In a quasi-experimental cohort pilot study, we recruited 91 participants from nine pharmacies in the Quebec City area. We offered the intervention programme over a 9-month period to participants enrolled at four of the pharmacies. The other participants were not exposed to pharmaceutical services other than those usually given by their pharmacists. We used the SF-36 to evaluate HRQOL. Covariance analysis was used to test for significant differences of HRQOL scores between participants exposed and not exposed to the programme. Results and discussion: When compared with the non-exposed participants, those receiving the intervention and with high income had an improvement in vitality score (P = 0·05). On the contrary, low-income exposed participants did not show this benefit and had a decline in mental health score (P = 0·01). Improvement in vitality is likely due to increased physical activity and to a reduction in systolic blood pressure in the high-income exposed group. The negative effect of the programme on the mental health of those exposed in the low-income group might be due to the fact that the programme was not effective in reducing blood pressure and may therefore have caused anxiety. Conclusion: Pharmacists’ interventions can have both a positive and negative impact on the HRQOL of individuals, treated with antihypertensive agents, depending on income level.

Amantadine for traumatic brain injury: does it improve cognition and reduce agitation?

Abstract: Summary Objective: To review the available literature pertaining to amantadine as therapy for improving cognition and reducing agitation following a non-penetrating traumatic brain injury (TBI). Data sources: Clinical literature was accessed through MEDLINE (from 1966 to February 2004) and bibliographic searches. Key search terms included ‘amantadine’, ‘traumatic brain injury’, ‘cognition’, and ‘agitation’. Data synthesis: Amantadine is primarily used for treatment and prophylaxis of influenza A. Its ability to improve mentation and motor function in patients with head injury remains questionable. An evaluation of five clinical trials, two case reports, and one case series is conducted focusing on the use of amantadine following TBI. Patients in clinical trials were assessed using a variety of neuropsychological tools aimed at, among other things, assessing cognition and agitation. Although individual patient results varied, the majority of patients studied showed improved neuropsychological test scores. Similar observations are noted in the case reports and case series. Improvement in cognition and reduced agitation seems to occur with post-injury amantadine therapy. Conclusions: Amantadine is a reasonable option for improving cognition and reducing agitation following a TBI but confirmatory evidence of the efficacy the drug is necessary.

Dose evaluation for long-term magnesium treatment in aneurysmal subarachnoid haemorrhage

Abstract: BACKGROUND: Magnesium is a neuroprotective agent that might prevent or reverse delayed cerebral ischaemia after aneurysmal subarachnoid haemorrhage (SAH). We are presently running a randomized, placebo-controlled, double blind trial with magnesium sulphate (64 mmol/day intravenously). We studied whether this treatment regime resulted in our target serum magnesium levels of 1.0-2.0 mmol/L. METHODS: Magnesium sulphate was administered intravenously as soon as possible after admission and continued until 14 days after occlusion of the aneurysm. Serum magnesium measurements were done at baseline and at least every 2 days during administration of trial medication. For comparison we used the serum magnesium levels of the placebo-treated patients. RESULTS: Magnesium therapy was begun in 94 patients. The mean magnesium level in the treatment period was 1.47 +/- 0.32 mmol/L. In 81 patients serum magnesium stayed within target levels during the entire treatment period. One patient had a serum magnesium level below 1.0 mmol/L (0.91 mmol/L) in a single measurement and 10 patients had serum magnesium levels above 2.0 mmol/L at one or more measurements. In six patients magnesium therapy was discontinued: in three because of nausea, headache, or both in combination with serum magnesium levels above 2.0 mmol/L and in the other three because of hypotension, phlebitis and renal failure. CONCLUSIONS: With an intravenous dosage schedule of 64 mmol magnesium sulphate a day, serum magnesium levels of 1.0-2.0 mmol/L can easily be maintained without severe side effects for an extended period in a vast majority of patients with SAH.

Measuring the appropriateness of prescribing in primary care: are current measures complete?

Abstract: Background and objectives: Appropriateness of prescribing is often assessed by standard instruments. We wished to establish whether judgements of appropriateness that included patients’ perspectives and contextual factors could lead to different conclusions when compared with commonly used instruments. To explore the predictive accuracy of these instruments. Methods: The design was interviews of patients, audio recordings of the consultation and interviews of the doctors, in varied primary care practices in England. Participants were patients who were likely to discuss a medication issue. The outcome measures were judgements of appropriateness made by the researchers and by two instruments: the Prescribing Appropriateness Index and the Medication Appropriateness Index. Implications for the predictive accuracy of the measures was also investigated. Results: From 35 cases there was agreement between the judges and the instruments in 22 cases, 16 were appropriate and 6 inappropriate. Of 10 cases classified as inappropriate by the instruments the judges thought four were appropriate. Of 18 cases classified as appropriate by the instruments, two were considered inappropriate by the judges. In seven cases the prescribing decisions could not be classified by the instruments because the decision was to not prescribe. Conclusions: Current measures of appropriateness of prescribing depend predominantly on pharmacological criteria, and so do not represent cases that would be judged appropriate when including the patient's views and contextual factors. If most prescribing is appropriate then use of these measures may lead to more false negatives than real negatives. The instruments should be renamed as measures of ‘pharmacological appropriateness’ and are useful where the incidence of this type of inappropriate prescribing is relatively high. [ABSTRACT FROM AUTHOR]

Long-term tolerability of tramadol LP, a new once-daily formulation, in patients with osteoarthritis or low back pain.

Abstract: Introduction Tramadol hydrochloride is a centrally acting analgesic, which possesses opioid agonist properties and activates monoaminergic spinal inhibition of pain. An oral, once a day, sustained release formulation of tramadol is thought to be advantageous compared with immediate release preparations as it prevents plasma peaks associated with increased side-effects of the drug. It may also improve compliance. The purpose of the study was to assess the long-term safety of a new sustained-release formulation of tramadol (tramadol LP) in patients with knee or hip osteoarthritis and in patients with refractory low back pain. Study design The design was a phase III, open, multicentre, international, tolerability study with tramadol LP at a dose titrated by the patient between 100 and 400 mg once daily, according to the intensity of pain. The treatment was administered for a continuous period of 4 weeks followed by an intermittent intake of 5 months in 204 patients. The safety criteria for evaluation were recording of adverse events, laboratory tests, electrocardiogram, radiography, global tolerability assessed by the patient and the investigators. Results Long-term use of tramadol LP was reasonably well tolerated. Most of the reported adverse events were expected and occurred within the first month of treatment. Roughly half of the patients (49%) reported adverse events, of which 66% were related to treatment. Gastrointestinal events (nausea and vomiting) were the most frequent. Serious adverse events were reported in 6.4% of patients, from which only two cases were related to treatment. There was no sign of tolerance development and the percentage of patients presenting withdrawal symptoms after the end of treatment was low (6%). Conclusion Long-term treatment with tramadol LP once daily is generally safe in patients with osteoarthritis or refractory low back pain.

Self-medication with chloroquine in a rural district of Tanzania: a therapeutic challenge for any future malaria treatment policy change in the country.

Abstract: Summary Background: Malaria continues to be a leading cause of morbidity and mortality in children aged 5 years or younger in Tanzania. Children who develop mild disease can rapidly progress to severe malaria (cerebral malaria with convulsions) and even death, because of mismanagement, delays and inappropriate drug therapy in the remote areas where primary health care facilities are inaccessible or unavailable. The threat is particularly severe in those who are unable to take oral medications. Objective: To identify treatment strategies adopted by mothers or guardians of children under five for malaria. Method: A cross-sectional descriptive study using a questionnaire and blood sampling was carried in Kibaha district primary health care facilities. Over 500 mothers/guardians of sick children aged up to 5 years who visited the public facilities seeking care were interviewed in order to assess what management they offered to their sick children in their homes prior to coming to the public health facilities. Results: Seventy-four per cent of the mothers/guardians stated that they had given some medication to their children prior to visiting the public health facilities: mostly analgesics (asprin, paracetamol) and chloroquine. Eighty-five per cent of the sick children given chloroquine had whole blood chloroquine levels above 500 nmol/L and 33% of the sick children with whole blood chloroquine levels above 1000 nmol/L had malaria parasites in their blood. Of the sick children given chloroquine at the health facilities, 63% had no malaria parasites in their blood. Conclusion: There is a need to educate both rural communities, and health care providers about rational prescribing, dispensing and use of antimalarials.

Effect of MKC-733, a 5-HT3 receptor partial agonist, on bowel motility and symptoms in subjects with constipation: an exploratory study

Abstract: Summary Background: MKC-733, a 5-HT3 receptor partial agonist, is a novel enteroprokinetic compound. Objective: The aim of this study was to explore the effects of MKC-733 on bowel motility and symptoms in a small group of subjects with constipation. Tolerability was also examined. Methods: The study was conducted in a single-blind and dose-escalation manner on 14 male and female subjects with constipation aged 22–67 years. After a 1 week run-in period, subjects were treated with placebo (b.i.d.) for 1 week, and 0·2 and 0·5 mg of MKC-733 (b.i.d.) for 2 weeks sequentially. Geometric mean and per cent elimination of surrogate markers of bowel motility were measured by a radio-opaque marker technique at the end of each treatment period. They were analysed on the whole group and subgroups with low (n = 6) and high (n = 8) bowel motility based upon the geometric mean value after placebo treatment. Subjects kept diaries of their bowel habits and gastrointestinal symptoms. Results: Percent elimination increased after treatment with 0·5 mg MKC-733 compared with placebo treatment in the whole group (70·4 ± 33·5% vs. 47·1 ± 36·6%, mean ± SD, P < 0·05). In the low bowel motility group, both geometric mean and percent elimination increased after treatment with 0·5 mg MKC-733 compared with placebo (7·1 ± 0·9 vs. 5·9 ± 0·5, P < 0·05; 60·0 ± 35·8% vs. 13·3 ± 19·4%, P < 0·05). Stool frequency increased after the first-week treatment with MKC-733 compared with placebo (P < 0·05). Numbers of sensation of incomplete evacuation and gastrointestinal symptoms decreased to half and less after the treatment with MKC-733. No serious adverse effect was noted. Conclusion: Multiple doses of 0·5 mg MKC-733 improve bowel motility, which was clearly demonstrated in the subjects with decreased bowel motility. MKC-733 at the doses studied might be effective in increasing stool frequency and reduce gastrointestinal symptoms related to constipation. MKC-733 was well tolerated. Further studies will be needed to clarify efficacy and safety of MKC-733 on a larger population.

Grapefruit juice-nifedipine interaction: possible involvement of several mechanisms.

Abstract: Summary Objective: To develop a model based on mean residence time for better understanding the effect of grapefruit juice on the metabolism of nifedipine (NIF). Material and methods: Sixteen healthy volunteers from an urban population were included. For each trial, the subjects drank water, fresh grapefruit juice or bottled grapefruit juice. Thirty minutes later, the subjects took a 10 mg capsule of NIF, orally. Plasma concentration of NIF was measured and the kinetic parameters were calculated with a non-compartmental model. Results: Grapefruit juice increased the bioavailability of NIF, but did not significantly reduce the drug's metabolism as shown by the approximately constant metabolite to parent drug AUC ratio (P = 0·948). There was no significant increase in the amount of non-metabolized drug absorbed during first-pass: 0·12 and 0·16 (P = 0·470) without and with grapefruit juices respectively. There was an increase in the relative bioavailability (P = 0·039) and the apparent volume of distribution (Vdm) (P =0·025) of dehydronifedipine with grapefruit co-administration. A second peak was also observed in the NIF plasma-concentration profile when the drug is co-administered with grapefruit juice. Therefore, the most likely explanation for the double peak phenomenon is a delay in gastric emptying (+32 min with grapefruit juice) caused by the pH of grapefruit juice. Conclusion: This study shows that grapefruit juice interferes with the metabolism of NIF by inhibiting NIF metabolism and slowing down the rate of gastric emptying. This study also confirms that the metabolic inhibition is not a first pass effect, but is a secondary oxidative step.

TGF-beta1 mRNA expression in liver biopsy specimens and TGF-beta1 serum levels in patients with chronic hepatitis C before and after antiviral therapy.

Abstract: Summary Background and objective: Transforming growth factor (TGF)-β1 is the best-characterized profibrogenic cytokine. TGF-β1 increases the production of extracellular matrix proteins and their receptors and inhibits the synthesis of matrix degrading proteolytic enzymes. We undertook this study to simultaneously evaluate the effect of interferon α 2b plus ribavirin therapy on TGF-β1 daily serum levels and on mRNA TGF-β1 expression in liver biopsy specimens from 60 patients with chronic hepatitis C. Methods: Serum levels of TGF-β1 were measured by ELISA. The levels of the RNAs in liver biopsy specimens were measured by quantitative reverse transcriptase polymerase chain reaction. After treatment, patients were divided into two groups: 34 responders [undetectable hepatitis C virus (HCV)-RNA, normal ALT levels, decrease in histology activity index compared with pretreatment liver biposy] and 26 non-responders (detectable HCV-RNA, elevated ALT levels, no decrease in the histology activity index). Results and discussion: In patients with hepatitis C, the ‘responders’ to the antiviral treatment showed significant decreases in both mean daily serum TGF-β1 levels and mRNA TGF-β1 expression in the liver biopsy specimens. The ‘non-responders’ serum TGF-β1 concentrations did not change significantly, but the mRNA TGF-β1 expression did. Conclusion: Both serum TGF-β1 concentration and mRNA TGF-beta1 expression in liver biopsy specimens may be useful as prognostic markers in patients with hepatitis C undergoing antiviral therapy.

A literature search on pharmacokinetic drug interactions of statins and analysis of how such interactions are reflected in package inserts in Japan

Abstract: Summary Background and objectives: Statins (HMG-CoA reductase inhibitors) are one of the most widely prescribed classes of drugs throughout the world, because of their excellent cholesterol-lowering effect and overall safety profile except for rare but fatal rhabdomyolysis arising either directly or indirectly by pharmacokinetic interactions with certain other drugs. As package inserts in pharmaceuticals are the primary source of information for health care providers, we carried out a literature search to examine how crucial information was provided in package inserts of five statins approved in Japan (simvastatin, atorvastatin, fluvastatin, pravastatin and pitavastatin). Methods: A MEDLINE search from 1996 to June 2004 was carried out to identify studies on clinical pharmacokinetic drug interactions for the five statins. We mainly collected information on area under plasma concentration (AUC) following co-administration of statins with other drugs. The current package inserts used in Japan were obtained from the website of the Pharmaceutical and Medical Device Agency whereas USA package inserts were obtained from the Food and Drug Administration website. Results: The majority of package inserts listed the drugs that interacted with statins with most describing the risk of rhabdomyolysis because of the possibility of increases in blood concentration. However, quantitative information such as change in AUC was provided in only a few cases. Instructions for dosage adjustment are seldom provided in the Japanese package inserts. USA package inserts list almost identical drug interactions as the Japanese package inserts, although they contain more quantitative data, especially for typical cytochrome P450 (CYP) inhibitors. Conclusion: All pharmacokinetic drug interactions including relevant quantitative data for potential effectors and details on mechanisms of interaction need to be given in package inserts as soon as the information becomes available, to ensure safe and proper use of the drugs concerned. Including such information in the package insert will be an extremely valuable aid for health care providers.

Advice-giving on self-medication: perspectives of community pharmacists and consumers in Singapore

Abstract: Summary Background: In Singapore, community pharmacists provide an advice-giving service to consumers who seek self-medication for minor ailments management. This service has not been studied formally from the perspectives of pharmacists and consumers. Objectives: The study aimed to identify (i) the approach taken by pharmacists in providing advice for self-medication and (ii) consumers’ behaviour in self-treatment and their perception of the advice-giving role of the community pharmacist. Method: The pharmacists and consumers were surveyed independently using two structured questionnaires. Results and discussion: All community pharmacists who participated in the survey were confident in providing advice on self-medication. However, none of them recorded the consultations and only 17·5% of them had documented their general physician referrals. Most consumers (66·3%) would self-medicate and only consult a professional when the desired outcome was not achieved. Less than 10% of consumers would approach the pharmacists as the first option for advice. More than half of the pharmacists felt that the advice they rendered deserved a fee whereas only 28·4% of the consumers were willing to pay. Both parties thought the fee should not be more than S$5 (US$3). Conclusion: Generally, there is congruence in the perspectives on self-medication between the advice-giving pharmacist and the consumer. The consumers still lack awareness that pharmacists can help them to self-medicate more safely and effectively. Therefore, more effort in public education is warranted. The current state of poor documentation of the advisory function of community pharmacists should be improved.

Prevalence of over-the-counter drug-related overdoses at Accident and Emergency departments in Northern Ireland--a retrospective evaluation.

Abstract: Background and objectives: One major concern associated with misuse/abuse of over-the-counter (OTC) products is the potential for over-dosage. The aim of this research study was to evaluate, over a 3-month period, OTC medicine-related overdoses (those involving OTC drugs only and OTC drugs in combination with other drugs) that led to patients presenting at the Accident and Emergency (A & E) departments in four Belfast hospitals. Methods: A data collection sheet was designed to capture the information required from the A & E records in each hospital. A retrospective week-by-week data collection, reviewing A & E records, took place over a 3-month period (starting on 1 December 2002). All data related to cases presenting at the A & E departments because of drug overdoses (either accidental or deliberate according to Read Clinical Classification) were included in the study. Data were coded and entered into a custom designed SPSS((c)) database for analysis, using Chi square and Fisher exact tests. Results: OTC drug-related overdoses comprised 40.1% of all overdoses, of which 24.0% were OTC-only overdoses. Those who overdosed on OTC drugs (solely or combined with other drugs) were mainly female (62.3%) and in the age category 31-50 years (44.9%; P

The chemical and pharmaceutical equivalence of sulphadoxine/pyrimethamine tablets sold on the Tanzanian market.

Abstract: Summary This study investigated chemical and pharmaceutical equivalence of 11 brands of pyrimethamine–sulphadoxine combination tablets sold on the Tanzanian market. Physical and chemical tests were performed for all the 11 brands. These tests included hardness test, friability, disintegration, dissolution, weight uniformity and assay for the active components. All the brands passed all the quality specifications of the United States Pharmacopoeia (USP) and British Pharmacopoeia (BP) in terms of hardness, friability, disintegration, assay and dissolution test, except for three brands that failed the hardness, disintegration or friability tests. One brand failed both the hardness and disintegration test; one failed the hardness test, whereas another one failed the friability test. The percentage content of pyrimethamine in the brands was in the range of 91·04–100·20% whereas that of sulphadoxine ranged from 91·53% to 99·88%. There were no major differences between the different brands of tablets containing pyrimethamine and sulphadoxine and the innovator product (Fansidar®), and all brands were physically and chemically equivalent. The results indicate that the post-market surveillance and registration process in Tanzania is having an impact on product quality as there was no brand which could be considered of very poor quality. Impurity profiling of all the locally produced brands indicated that they all contained the same sulphadoxine impurity, which was absent in the innovator product, suggesting a common source of generic raw material.

Efficacy and tolerability of frovatriptan in acute migraine treatment: systematic review of randomized controlled trials.

Abstract: Summary Objective: To evaluate the efficacy and tolerability of frovatriptan in acute migraine treatment. Methods: Systematic review and meta-analysis of randomized controlled trials. Clinical trials of frovatriptan were systematically identified through electronic searches and historical searches up until February 2005. Studies were included if they were (i) double-blind, randomized, placebo controlled trials that evaluated frovatriptan 2·5 mg in acute migraine treatment and (ii) reporting the efficacy data in terms of pain-free, headache response, headache recurrence, or relief of migraine-associated symptoms. Two authors extracted data independently. Disagreements were resolved through discussion. The efficacy was estimated using risk ratio (RR), risk difference, and number needed to treat together with 95% confidence intervals. Results: Five trials involving a total of 2866 patients were included. Frovatriptan 2·5 mg was more effective than placebo in rendering patient pain-free (RR 3·70, 95% CI 2·59–5·29, P < 0·0001 at 2 h and 2·67, 95% CI 2·21–3·22, P < 0·0001 at 4 h post-dose). It was also superior to placebo in reducing headache severity. The pooled RR was 1·66 (95% CI 1·48–1·88, P < 0·0001) and 1·83 (95% CI 1·66–2·00, P < 0·0001), respectively, at 2 and 4 h after treatment. In those whose headache was relieved at 4 h, the risk of headache recurrence within 24 h was reduced by 26% with frovatriptan (RR 0·74, 95% CI 0·59–0·93, P = 0·009). Frovatriptan was also superior to placebo in improving symptoms associated with migraine. At 2 h after dosing, frovatriptan reduced the risk of nausea by 14% (95% CI 6–20%, P = 0·0005), photophobia 17% (95% CI 12–22%, P < 0·0001), and phonophobia 14% (95% CI 17–20%, P < 0·0001). The corresponding numbers at 4 h after dosing were 37% (95% CI 30–43%, P < 0·0001), 34% (95% CI 29–39%, P < 0·0001) and 30% (95% CI 23–36%, P < 0·0001), respectively. Frovatriptan caused more adverse events than did placebo (RR 1·31, 95% CI 1·07–1·62, P = 0·01). Conclusion: The available evidence suggests that frovatriptan is more effective but may cause more adverse events than placebo in the treatment of acute moderate to severe migraine. It is effective in providing pain relief and reducing the risk of recurrence. However, its effectiveness relative to other more established agents needs to be better defined by appropriate head to head trials.