Para‐methylthioamphetamine, a new amphetamine designer drug of abuse

A case study is described of a patient who was intoxicated after the intake of socalled herbal stimulants. A visit to a physician after the intoxication prompted to this investigation and the case was examined for its direct cause. An interview with the patient revealed that the source of the herbal stimulants was a socalled 'S5 tablet'. Information provided on the packings of the tablet only indicated the presence of natural alkaloids and vitamines. Toxicological analysis however proved that the 'S5 tablet' contained paramethylthioamphetamine (MTA), mainly. MTA is a relative unknown amphetamine designer drug, which has only been studied as a model compound in some structureactivity relationship studies. The fact that MTA appeared in tablets was therefore completely unexpected. Not only the potential abuse of this new amphetamine designer drug is a serious matter of concern, but also the misleading information provided with the tablet.     

An accelerated stability study of 5‐flucytosine in intravenous solution

The stability of the antimycotic drug flucytosine (5FC) and the extent of 5fluorouracil (5FU) formation in 5FC intravenous solution was studied in an accelerated stability experiment. 5FC intravenous solution (10 mg/ml) was heated at 40, 60, 70, 80 and 90 C for a maximum of 131 days. At appropriate time intervals samples were taken and the concentrations of 5FC and 5FU were determined using a newly developed, stability indicating HPLCUV method. Heating the 5FC intravenous solution at 40, 60, 70, 80 and 90 C lead to 5FC decomposition of respectively 0, 8.9, 14.4, 52.5 and 61.6%. The Arrhenius plot of the 5FC decomposition is described by: Lnk5-FC decomposition = 80.1892 * 1/T 0.2396 and the 5FU formation is described by Lnk5FU formation = 13087 * 1/T + 34.4028. It is concluded that 5FC is very stable in intravenous solution at regular storing temperatures and can therefore be stored at ambient temperatures for several years before the critical limit of 95% 5FC is reached. However, the toxic and teratogen degradation product 5FU may be present in considerable amounts in the product, due to both impurities in the raw material and the formation from 5FC upon sterilisation and storage.     

Peri‐marketing surveillance of lamotrigine in the Netherlands: Doctors'' and patients'' viewpoints

Purpose: Evaluation of daily clinical practice in prescribing lamotrigine in refractory epilepsy patients.Methods: A collaborative, retrospective, perimarketing study was performed in in and outpatients attending one of the three Dutch epilepsy centres. Analysis of both patients' and doctors' information was performed in 520 patients using questionnaires and medical files.Results:After one year of treatment 76% of patients maintained LTG treatment, an intentiontotreat analysis showed >= 50% seizure reduction in 23% of patients; 2050% seizure reduction in 23% of patients. Six percent of patients became at least three months seizure free. In about 20% of patients seizures became less severe and shorter of duration, while in 6% an increase was found.After three months a significant decrease in number of concomitant antiepileptic drugs was found (change from mean 1,8 to 1,5 AEDs) (p=< 0.01). After twelve months the mean number of AEDs was 1,4 per patient. Overall percentage of side effects appeared to be significantly higher if patients' questionnaire data were used. Epilepsy patients considered side effects as an important factor in the choice of medication and in withdrawal of medication. Future developments of new AEDs should take this into account. Conclusion: This perimarketing study gives insight information about longterm daily use of lamotrigine, with emphasis on effectiveness. Patients complained in the questionnaires much more about sideeffects, than was known according to the medical file. Therefore, it seems necessary to perform perimarketing studies more systematically.     

Cost‐effectiveness analysis of tropisetron vs. chlorpromazine‐dexamethasone in the control of acute emesis induced by highly emetogenic chemotherapy in children

Objective. To perform a costeffectiveness analysis (CEA) between a standard antiemetic regimen chlorpromazine + dexamethasone (CPMDEX) and a 5HT3 receptor antagonist tropisetron (TROP) in the control of acute emesis induced by highly emetogenic chemotherapy in children, considering two analytic perspectives: hospital and patients. Methods. The CEA was performed by constructing a decision tree, for both analytic perspectives, of the possible outcomes of treatment with TROP (single 0.2 mg/kg i.v.) or CPM (515 mg i.v. infusion for 3 doses) plus DEX (2 mg/m2 i.v. bolus i.v. × 2). The patients were stratified by age in two groups (212 and 1317). To estimate the probability of each endpoint at the decision tree we have taken as a base a trial developed in the Department of Pediatrics. Direct medical cost of primary therapy, failure, complications and side effects were included in the cost calculations. Results. From patients' analytic perspective, TROP was more costeffective than CPMDEX for both groups of patients. Discrepancy between both analytic perspectives in 1317 yearold patient's group was resolved in favour of the option chosen from the patients' analytic perspective (TROP). Sensitivity analysis showed the reliability of the results. Conclusions. 1. TROP was more costeffective than CPMDEX. 2. Taking into account the patients' analytic perspective is essential when we compare antiemetics pharmacoeconomically. 3. It seems necessary to increase the effectiveness of TROP in pediatric patients receiving highly emetogenic chemotherapy with strategies such as the addition of a steroid.     

Evaluation of the impact of pharmacist''s advice giving on the outcomes of self‐medication in patients suffering from dyspepsia

The aim of this study was to investigate the outcomes of selfmedication in patients suffering from dyspepsia by comparing changes in the Health related Quality of Life before and after selfmedication of dyspeptic disorders. Another study objective was the quantitative and qualitative analysis of the pharmacist's advicegiving to patients with dyspepsia. Therefore the impact of the counselling by the pharmacist on the patient's health outcomes was surveyed and compared between study and control pharmacies. Moreover, the study analysed the influence of a special training on the services provided by the pharmacies with regard to selfmedication.A beneficial effect of selfmedication on the HRQoL of patients with dyspepsia on a weekly basis has been detected in the study. There is evidence that advicegiving and counselling by the pharmacists in selfmedication have a measurable impact on selfmedication outcomes. Moreover, the study reveals that patients value the information provided by the pharmacist. Pharmacists gathered the relevant and comprehensive information from the patients having dyspeptic symptoms and provided advice concerning OTCdrugs. Moreover, pharmacists frequently discussed the relevance of factors aggravating dyspeptic disorders such as lifestyle, drinking, smoking, and manner of nutrition with the patient. Training programs and treatment guidelines for the pharmacist seem to obtain a positive effect on his performance. The findings of the study substantiate the value of a pharmacistcontrolled selfmedication. The study results suggest that the quality of primary health care in selfmedication would improve if pharmacists' involvement were even more intense.     

Clinical and economic impact of a pharmacist‐intervention to promote sequential intravenous to oral clindamycin conversion

A multicentre, prospective, controlled study compared the clinical efficacy, safety and economic impact of a pharmacist intervention to promote sequential intravenous to oral clindamycin conversion. A total of 473 patients receiving intravenous clindamycin for at least 72 hours were included in the study. Two groups were established: an intervention group (204 patients) in which an informative sheet recommending the sequential treatment was provided, and a control group (269 patients). Clindamycin was prescribed for respiratory infections in 38.9% and for prophylaxis in surgery in 25.4% of the patients (71% were contaminated surgery). No difference between groups regarding sex, infection severity, health status or clinical progress was observed. Both the stepdown treatments after 72 hours of intravenous clindamycin and the change to the oral route later on, were significantly increased with the intervention (p<0.001, p<0.001 respectively). No significant differences between both groups were found in the number of patients with adverse effects associated with the IV therapy, although the incidence tended to be lower in the intervention group (49/204 intervention versus 85/269 control, p=0.07). Compliance with the recommended clindamycin dosing regimen was significantly higher in the intervention group, in which 1.3 days reduction of intravenous therapy provided an average cost savings of PTA5246 (95%CI 25567935) per treatment. A higher reduction of 1.7 days was achieved in those patients candidates for switch therapy on the third day of intravenous clindamycin. A sequential program with clindamycin may provide a costeffective alternative to conventional therapy and the introduction of an information sheet is a costeffective strategy to promote it.     

Prevention of heterotopic ossification after total hip replacement with NSAIDs

Introduction: non steroidal antiinflammatory drugs ((NSAIDs) and prophylactic radiotherapy can prevent ectopic bone formation around the hip after total hip arthroplasty. Methods: We retrieved from Medline, Embase and the Cochrane Register (clinical)) trials and other relevant literature on the prevention of heterotopic ossification (HO) from 19902002 for further review.Results: Review of these clinical trials shows that HO is effectively prevented by a postoperative NSAID treatment with indomethacin for at least seven days. The best evidence is available for indomethacin, although naproxen, diclofenac and ibuprofen are also well documented. Short term use of ibuprofen is not effective. If NSAIDs are contraindicated, preoperative or postoperative radiotherapy is a very effective therapeutic option to prevent HO. Discussion and conclusion: Because of the potential of serious gastrointestinal side effects of NSAIDs and their interaction with anticoagulant drugs, rofecoxib and other COX2 specific NSAIDs may be a safer option for the treatment of HO. However, randomised controlled studies are needed to confirm the results of the rofecoxib study.     

Experience with a recently introduced drug information service in an Israeli hospital pharmacy

In July 1996, the Pharmacy Department of the Barzilai Medical Center in Ashkelon, Israel, initiated a prospective study aimed at justifying and evaluating the drug information service provided by the pharmacy team to the medical staff. The information is provided via telephone, with written consultations or bibliographies provided on request. All telephone queries and responses are computer recorded, so that the responses to requests can be evaluated. A standard form was prepared to evaluate this service. A total of 293 consultations took place during a oneyear period, yielding 528 different questions. The questions were received from different departments, including internal diseases (32.4%), surgery (31.2%), pediatrics (16.7%), obstetrics (10.9%), and psychiatry, oncology and hematology (together 6.8%). The pharmacy team provided this service to physicians and surgeons(51.2%), nurses (41.9%), and other medical professionals (6.9%). The types of drugs most frequently inquired about were antiinfectives, antihypertensives,TPN & infusion preparations and anticoagulant drugs. Requested data included information regarding administration/dosage (34.1%), indications (14.6%), and interactions (13.9%), with very few questions about the availability of products (4.7%), equivalency (2.1%) and cost (1.5%). The time devoted to this service justified an additional quartertime employee. This study proved to be a quality assurance tool in the assessment of the educational and functional requirements of the hospital's medical health team.     

Oral bioavailability of phenobarbital: a comparison of a solution in myvacet 9‐08, a suspension, and a tablet

Purpose: A threeway crossover study with seven healthy male volunteers was conducted to determine the relative bioavailability of phenobarbital after single dose administration of 100 mg of phenobarbital as oral solution in Myvacet 908, and as a suspension, compared with a 100 mg phenobarbital tablet. Materials and methods: At 4week intervals each subject received the solution in Myvacet 908, the suspension and the tablet in randomized order. Blood samples were collected for 48 h after each dose for analysis of phenobarbital. From the individual serum concentrationversustime curves C _maxand T _max were determined and AUC₀₄₈ was calculated. Results: All three oral dosage forms of phenobarbital are bioequivalent. No significant diffences in T _maxwere observed. Conclusion: The oral solution in Myvacet 908, and the suspension of phenobarbital proved to be bioequivalent to a tablet.     

Genotyping of the arylamine N‐acetyltransferase polymorphism in the prediction of idiosyncratic reactions to trimethoprim‐sulfamethoxazole in infants.

The pathogenesis of hypersensitivity to trimethoprimsulfamethoxazole (TMPSMX) is supposed to be associated with the slow acetylation phenotype. This pharmacogenetic defect is associated with the mutations of the arylamine Nacetyltransferase (NAT2) encoding gene. The aim of the study was to compare the usefulness of the acetylation phenotype and NAT2 coding genotype in the prediction of idiosyncratic reaction to Cotrimoxazole in infants. The study was carried out in the group of 20 infants, aged 212 months (mean age 6.3 months) treated with Cotrimoxazole, administered at 100 mg/kg b.w./24 h doses. In seven children (35%) no adverse effects of the treatment have been observed, whereas in 13 (65%) children various adverse effects occurred as a result of the therapy, such as rash (4 children), granulocytopenia with anemization (5 children) or liver impairment (4 children). The acetylation phenotype of each child was determined on the basis of urine of Nacetyl isoniazid/isoniazid ratio, after ingestion of isoniazid as a model drug. Furthermore we used polymerase chain reaction (PCR) followed by the analysis of restriction fragments length polymorphism (RFLP) technique to identify the known mutant alleles of the NAT2 gene. It has been presumed that the genotype determining fast acetylation contains at least one of wildtype allele. No correlation has been found between the observed adverse effects of Cotrimoxazole and age, gender and acetylation phenotype. However, it has been demonstrated that the risk of adverse effects of Cotrimoxazole is considerably higher in children with mutations of the NAT2 encoding gene. The comparison of the results from PCRRFLP genotyping with phenotyping suggested that in infants, the NAT2 genotype rather than phenotype provides the basis for the detection of hypersensitivity to TMPSMX.     

Physico‐chemical stability of docetaxel premix solution and docetaxel infusion solutions in PVC bags and polyolefine containers

We assessed the physical and chemical stability of docetaxel infusion solutions. Stability of the antineoplastic drug was determined 1.) after reconstitution of the injection concentrate and 2.) after further dilution in two commonly used vehiclesolutions, 0.9% sodium chloride and 5% dextrose, in PVC bags and polyolefine containers. Chemical stability was measured by using a stabilityindicating HPLC assay with ultraviolet detection. Physical stability was determined by visual inspection. The stability tests revealed that reconstituted docetaxel solutions (= premix solutions) are physicochemically stable (at a level 95% docetaxel) for a minimum of four weeks, independent of the storage temperature (refrigerated, room temperature). Diluted infusion solutions (docetaxel concentration 0.3 mg/ml and 0.9 mg/ml), with either vehiclesolution, proved physicochemically stable (at a level 95% docetaxel) for a minimum of four weeks, when prepared in polyolefine containers and stored at room temperature. However, diluted infusion solutions exhibited limited physical stability in PVC bags, because docetaxel precipitation occured irregularly, though not before day 5 of storage. In addition, timedependent DEHPleaching from PVC infusion bags by docetaxel infusion solutions must be considered.     

Determination and pharmacokinetics of dextromoramide in methadone maintenance therapy.

To study the pharmacokinetics of dextromoramide in longterm opiate addicts on methadone maintenance therapy (MMT) a reversephase HPLC technique was developed to monitor dextromoramide and methadone concentrations in plasma simultaneously. After liquidliquid extraction from plasma, dextromoramide and methadone were determined using a Supelcosil LCABZ column and a mobile phase of KH2phosphate buffer (25 mM, pH 2.5) mixed with acetonitrile (80:20, v/v) and UV detection at 206 nm. The method was found to be sufficiently sensitive, specific and reproducible to apply in six subjects on MMT for many years, receiving orally administered dextromoramide as adjuvant. Pharmacokinetic data sets for dextromoramide in each subject were conducted and analysed further, indicating short elimination halflife values (71 min, range 31152 min). Contrary to previous studies, in all subjects tested the pharmacokinetics of dextromoramide are best described using an onecompartment model.     

Cost-effectiveness of periconceptional supplementation of folic acid

Background: Supplementation of folic acid prior to and in the beginning of pregnancy may prevent neural tube defects (NTDs) in newborns – such as spina bifida – and possibly other congenital malformations.Objective: To estimate cost effectiveness of periconceptional supplementation of folic acid using pharmacoeconomic model calculation.Method: Probabilities for NTDs, risk reductions through periconceptional supplementation of folic acid and lifetime costs of care for children with spina bifida were estimated using Dutch registrations and international literature.Main outcome measure: Cost effectiveness was expressed in net costs per discounted lifeyear gained. Cost effectiveness was calculated in the baseline and in sensitivity analysis.Results: Estimated cost effectiveness of periconceptional supplementation of folic acid amounts to NLG 3900(D1800) in the base case. In sensitivity analysis cost effectiveness mostly remains below NLG 10.000(D4500).Conclusion: Periconceptional supplementation of folic acid shows a favorable cost effectiveness. From pharmacoeconomic point of view this justifies further stimulation of folicacid supplementation prior to pregnancy. This can be done through targeted education by healthcare workers, such as pharmacists.     

Elevated plasma levels of clozapine after concomitant use of fluvoxamine

Selective serotonin reuptake inhibitors can be added to clozapine therapy in order to treat remaining negative symptoms and obsessive compulsive symptoms. The present case report describes a 44yearold man exhibiting extremely elevated plasma levels of clozapine after the addition of fluvoxamine, up to 4160 mcg/l. The elevated plasma levels of clozapine, which were discovered 6 months after the SSRI was added, is likely to be caused by a drugdrug interaction. Clozapine is a substrate of CYP 1A2 and is predominantly metabolised in the liver. Of the SSRIs, fluvoxamine is one of the most potent inhibitors of the isoenzyme CYP 1A2. This case serves to emphasise the need for continuous attention to drugdrug interactions, especially when they might be easily overlooked due to the lack of clear symptoms.     

Failure of “antigastrin” (SC-15 396) to inhibit gastric acid and pepsin secretion in anaesthetized gastric fistula cats

Summary 1. The effect of antigastrin (SC-15 396) on gastric acid and pepsin secretion produced by the gastrin-analogue tetrapeptide amide Try. Met. Asp. Phe-NH₂ and by electrical stimulation of the vagus was investigated in anaesthetized gastric fistula cats.2. Antigastrin failed to inhibit both acid and pepsin response stimulated by either the tetrapeptide or vagus excitation.3. It was concluded that the ineffectiveness of antigastrin in cats is due to a species difference between rats and dogs on the one hand and cats on the other, and that antigastrin is not a specific gastrin antagonist.Supported by the Deutsche Forschungsgemeinschaft and by the Alfred Teufel-Stiftung.     

Leading ordinary lives: a qualitative study of younger women''s perceived functions of antidepressants

Background: While the overall consumption of psychotropic medicines such as tranquillisers and hypnotics has declined, the consumption of the newer antidepressants – selective serotonin reuptake inhibitors (SSRIs) has increased drastically since their introduction. In order to understand the mechanisms underlying the use, it is important to gain insight into the users' perceptions about their medicine and use.Objective: To analyse younger women's perceived functions of SSRIs in their everyday lives. Methods: 12 in depth interviews and 6 re interviews were conducted with a community based sample of 21 to 34 year old women taking SSRIs. The women were recruited through Danish pharmacies.Results: Prior to taking SSRIs the women struggled with their emotional problems, often in great frustration and distress. While taking SSRIs the women experienced that the medicine functioned both at a psychological and a social level. They believed that the medicine gave them resources to behave actively in a way that was not previously possible. They felt that the medicine use enabled them to concentrate on daily life activities other than dealing solely with their emotional problems. The women found that the medicine gave them back a sense of 'normality'.Conclusion: The main finding in this paper is that the perceived functions of SSRIs were related to social meanings and goals in everyday life.     

Vasopressin stimulates release of β-lipotropin and β-endorphin in conscious rats as measured by radioimmunoassay of unextracted plasma

Summary Using a newly developed radioimmunoassay to determine the -endorphin-like immunoreactivity (-EI) in unextracted plasma, the effect of vasopressin injections on plasma -EI was investigated in conscious rats. Arginine vasopressin caused a dose-dependent increase of plasma -EI from 34.5±7.8 fmol ml^–1 (n=6) in vehicle-treated animals to 205.0±36.1 fmol ml^–1 (n=7) after injection of the highest vasopressin dose employed (486 ng/100 g b.w.). In view of the appreciable cross-reactivity of -lipotropin (-LPH) in the radioimmunoassay used, plasma was extracted and subjected to gel chromatography on a Sephadex G-50 column. On average, about 70% of the -EI co-eluted with human -LPH and about 30% with human -endorphin in plasma extracts obtained from both control and vasopressin-treated rats. No peripheral conversion of human -LPH occurred under the experimental conditions, since after i.v. bolus injection of human -LPH 97% of the -EI comigrated with human -LPH during gel filtration. A similar blood pressure increase to that induced by the vasopressin injections, when elicited by noradrenaline or angiotensin II i.v., was not followed by an elevation of plasma -EI.These data indicate that vasopressin stimulates -lipotropin and -endorphin release into the systemic circulation in vivo.     

Quantification of communication processes, is it possible?

The PAS^® system (ProblemAnalysisSolutionsystem) is developed to quantify oral communication processes during counselling in pharmacy practice. The pharmacist translates the patients' drugrelated questions into a Pcode, the analysis of the question into an Acode and finally the given solution upon the question into a Scode. The PAS^® system has been developed for two goals. First, for the registation of drugrelated questions from patients which gives the pharmacist insight in the most common issues addressed by patients. Second, it might help the pharmacist to structure the communication with the patient during the consultation. Fortyone pharmacists participated in the evaluation of the PAS^® system. The validation of the PAS^® system consisted of two phases: the external validation and the internal validation. Kappa values were calculated as a measure of agreement in the coding by the pharmacists. The kappavalue of the external validation for the P , A and Scodes for the total set of questions indicate a moderate to poor agreement. This means that pharmacists categorize drugrelated questions from patients in a different way. Therefore we conclude that the PAS system is less reliable for research purpose. The kappavalue of the internal validation for the Pcode varies from 0.42 to 0.91. For the Acode it varies from 0.07 to 0.35 and for the Scode from zero to 0.68. Internal reproducibility is good for Pcode but not for the Acode and Scode This implies that the pharmacist can use the Pcodes for registration of patients' questions in his own pharmacy. Moreover, the usage of the PAS^® system during counselling in pharmacy practice can structure the consultation.     

Distribution of pharmaceuticals ? a Norwegian logistic perspective

There is a general concern about rising costs of pharmaceutical expences. One political measure is a more efficient distribution system, which can take the form of new channels for retailing. In Norway mailorder pharmacy (MOP) has been brought to the agenda due to the recently proposed law regulating pharmacies (Apoteklov), market developments abroad, demand for selfmedication, the increase in OTCproducts and advances in information technology. Mailorder pharmacy involves direct delivery of medications through postal mail to patients or those responsible for dispensing medication. With reference to the USA, mailorder pharmacy has filled a niche in the market and several other countries are following. We are convinced that it is possible to maintain a high level of service quality in the sense of safety, councelling and compliance, and that there is a potential to develop a model for this distribution form in Norway. We believe that the actors in the Norwegian pharmaceutical market are better served in taking a more active role in this area and where possible initiating pilot projects in mailorder distribution. The pharmacists will continue to play an important role as a retail outlet and should, with their influence over patients, their knowledge and experience, contribute towards developing MOP to be a safe and complementary sales outlet. Developing such a solution demands the right balance between performance and quality on the one hand and efficiency on the other; two criteria, which we believe, do not contradict each other.     

Recommended structure for reporting economic evaluation on pharmaceuticals in Belgium

Pharmacoeconomic evaluations become more important for the reimbursement of pharmaceuticals, and will be obligatory for new pharmaceutical drugs for which an added therapeutic value is claimed and a price premium is proposed by the manufacturer. Therefore, it is important to guide purchasers and providers of pharmaceutical care in their efforts related to the evaluation process. Standard Report Format can support the quality, transparency and exhaustiveness of the data submitted. A multidisciplinary task force developed a Standard Report Format for pharmacoeconomic evaluations in Belgium.