Treatment of haemophilia A and B and von Willebrand's disease: summary and conclusions of a systematic review as part of a Swedish health-technology assessment.

In an ongoing health-technology assessment of haemophilia treatment in Sweden, performed by the governmental agency Dental and Pharmaceutical Benefits Agency (TLV; tandvårds-och lakemedelsförmånsverket), the Swedish Council on Health Technology Assessment (SBU; statens beredning för medicinsk utvardering) was called upon to evaluate treatment of haemophilia A and B and von Willebrand's disease (VWD) with clotting factor concentrates. To evaluate the following questions: What are the short-term and long-term effects of different treatment strategies? What methods are available to treat haemophilia patients that have developed inhibitors against factor concentrates? Based on the questions addressed by the project, a systematic database search was conducted in PubMed, NHSEED, Cochrane Library, EMBASE and other relevant databases. The literature search covered all studies in the field published from 1985 up to the spring of 2010. In most instances, the scientific evidence is insufficient for the questions raised in the review. Concentrates of coagulation factors have good haemostatic effects on acute bleeding and surgical intervention in haemophilia A and B and VWD, but conclusions cannot be drawn about possible differences in the effects of different dosing strategies for acute bleeding and surgery. Prophylaxis initiated at a young age can prevent future joint damage in persons with haemophilia. The available treatment options for inhibitors have been insufficiently assessed. The economic consequences of various treatment regimens have been insufficiently analysed. Introduction of national and international registries is important.

Socio-cultural practices of deciduous canine tooth bud removal among Maasai children.

The removal of teeth amongst the Maasai is a traditional practice as part of an initiation or to make space for feeding in an event of diseases locking the jaw. Removal of deciduous canine tooth buds (DCB) among infants below 2 years has been reported in several studies to be common mainly amongst communities in East Africa, Ethiopia and Sudan. The main reason for the practice revolves around the belief that tooth buds or 'maggots' are false teeth, nylon or worms and are responsible for diarrhoea, vomiting, fever and growth retardation in children, amongst other illnesses. The main objective of this study was to assess the socio-cultural factors which contribute to this practice. The main methods of data collected included Focus Group Discussions (FGD) with mothers of children in that age group and Traditional Birth Attendants (TBA). In-depth interviews (IDI)were conducted with key informants versed with Maasai traditions whereas observations were done within the manyattas where participants live. Proceedings at both the FGD and the IDI were recorded on paper and were analysed thematically. The study showed that the removal of canine tooth buds amongst children that started initially with calves--that diseases that cause diarrhoea in calves were brought about by the canine tooth buds that were turning reddish in colour--is deeply rooted and practised in the community despite sensitisation interventions mounted jointly by the University of Nairobi, Kenya Medical Research Institute and the Kenya Medical Training College, among others. This study discovered that canine tooth buds are associated with bad spirits that cause diarrhoea and vomiting and the belief that removing them is a sure way of providing a cure for all children's ailments.

Incorrect use and limited weight reduction of orlistat (Xenical) in clinical practice. A cohort study.

OBJECTIVE: To study the prescribing of the antiobesity drug orlistat in relation to the approved indication and its weight-reducing effect in clinical practice during the first 3 months of treatment. METHODS: Anonymous postal questionnaire survey to prescribers of orlistat concerning a random sample of 1000 of 20,000 prescriptions. PARTICIPANTS: Useful information was obtained for 789 patients. SETTING: Primary and secondary care in Sweden. MAIN OUTCOME MEASURES: Beginning and continued treatment according to the approved indication. Dropout from treatment. Weight loss during treatment. RESULTS: Four percent of the patients were prescribed orlistat despite having a body mass index (BMI) less than 28 kg/m2. Only 24% of the patients had a diet period with a weight loss of 2.5 kg or greater before the start of therapy. Half of the patients with a weight loss of less than 5% after 3 months continued the treatment. Ten percent gained weight or had no weight loss at all while 43% lost less than 5% in weight. At least one-quarter of the patients stopped the treatment within the observation period. CONCLUSION: Orlistat was not prescribed according to the approved indication in the majority of cases. The dropout rate was high and most patients had minor gain from the treatment.

Determination of ketobemidone and its metabolites in plasma and urine using solid-phase extraction and liquid chromatography-mass spectrometry.

The authors developed a sensitive, specific, and rapid liquid chromatography--mass spectrometry (LC-MS) method for determining ketobemidone and its major metabolites in plasma and urine. The method involves a solid-phase extraction, high-performance liquid chromatography (HPLC), and electrospray mass spectrometry. The limit of quantification for ketobemidone and norketobemidone was 3 nmol/L. Recovery rates for ketobemidone and norketobemidone were 84.8% and 81.1%, respectively. Coefficients of variation (CV) ranged from 2.8 % to 9.5%. The method was used to determine ketobemidone and its major metabolites in clinical samples from relevant patient groups.

Morphine and alternative opioids in cancer pain: the EAPC recommendations.

An expert working group of the European Association for Palliative Care has revised and updated its guidelines on the use of morphine in the management of cancer pain. The revised recommendations presented here give guidance on the use of morphine and the alternative strong opioid analgesics which have been introduced in many parts of the world in recent years. Practical strategies for dealing with difficult situations are described presenting a consensus view where supporting evidence is lacking. The strength of the evidence on which each recommendation is based is indicated.

Pharmacokinetic interaction between single oral doses of diltiazem and sirolimus in healthy volunteers.

AIM AND BACKGROUND: The pharmacokinetic interaction between sirolimus, a macrolide immunosuppressant metabolized by CYP3A4, and the calcium channel blocker diltiazem was studied in 18 healthy subjects. Several clinically important interactions have previously been reported for other immunosuppressive drugs that are metabolized by the same enzyme and for calcium antagonists. METHODS: Healthy subjects who were 20 to 43 years old participated in an open, three-period, randomized, crossover study of the pharmacokinetics of a single 10-mg oral dose of sirolimus, a single oral 120-mg dose of diltiazem, and the two drugs given together. The three study periods were separated by a 21-day washout phase. RESULTS: The geometric mean (90% confidence interval) whole blood sirolimus area under the plasma concentration time-curve increased 60% (35%-90%), from 736 to 1178 ng x h/mL, and maximum concentration increased 43% (14%-81%), from 67 to 96 ng/mL, with diltiazem coadministration, whereas the mean elimination half-life of sirolimus decreased slightly, from 79 to 67 hours. Apparent oral clearance and volume of distribution of sirolimus decreased with 38% and 45%, respectively, when sirolimus was given with diltiazem. The plasma maximum concentration and area under the plasma concentration-time curve of diltiazem, desacetyldiltiazem, and desmethyldiltiazem were unchanged after coadministration of sirolimus, and no potentiation of the effects of diltiazem on diastolic or systolic blood pressure or on the electrocardiographic parameters was seen. CONCLUSIONS: Single-dose diltiazem coadministration leads to higher sirolimus exposure, presumably by inhibition of the first-pass metabolism of sirolimus. Because of the pronounced intersubject variability in the extent of the sirolimus-diltiazem interaction, whole blood sirolimus concentrations should be monitored closely in patients treated with the two drugs.

Pharmacokinetics and safety of single oral doses of sirolimus (rapamycin) in healthy male volunteers.

A phase I study was conducted to determine the pharmacokinetics, safety, and tolerability of sirolimus, a new immunosuppressive drug, in 45 healthy men between 19 and 36 years of age. Nine subjects in each group were randomly assigned to receive single oral doses of either sirolimus (n = 6) or placebo (n = 3) in group I (0.3 mg/m2), group II (1 mg/m2), group III (3 mg/m2), group IV (5 mg/m2) and group V (8 mg/m2). No serious adverse events occurred during the study. Twenty-eight of the 45 volunteers (62%) reported an adverse event; 19 of 30 (63%) were in the sirolimus group and 9 of 15 (60%) were in the placebo group (ns). Asthenia was the most common adverse event, occurring in 7 of 30 (23%) in the sirolimus group compared with 6 of 15 (40%) in the placebo group (ns). Absorption occurred within 1 hour in all volunteers. Whole blood peak concentration and area under the concentration-time curve increased proportionally with dose. Mean (+/- SD) whole blood terminal disposition half-life (t1/2), apparent oral dose clearance (Cl/F), and volume of distribution (Vss/F) were 82 +/- 12 hours, 278 +/- 117 mL/h x kg and 23 +/- 10 L/kg, respectively. Distribution of sirolimus into formed blood elements was extensive, with a mean whole blood-to-plasma ratio of 36. Single oral doses of sirolimus (0.3 to 8 mg/m2) solution were well tolerated in healthy male volunteers.

Inhibition of cytochrome P450 2D6 modifies codeine abuse liability.

Oral codeine preparations, widely used for analgesia and cough suppression, are abused by some individuals for their mood-altering properties. The enzymatic O-demethylation of codeine is catalyzed by cytochrome P450 2D6 (CYP2D6), leading to the production of metabolites (morphine, morphine-6-glucuronide) that are pharmacologically more potent than codeine. A placebo-controlled, single-blind study was conducted to characterize the subjective effects of codeine associated with abuse liability and to determine the importance of metabolic O-demethylation to codeine abuse liability. Twelve non-drug-dependent subjects received oral administration of placebo and codeine 60, 120, and 180 mg, and a favorite dose (FD) was determined for each subject. The FD was readministered after pretreatment with placebo, 50 mg of quinidine (a specific, selective CYP2D6 inhibitor) once, or 50 mg of quinidine given four times a day for 4 days. Single-dose quinidine pretreatment significantly decreased the recovery of O-demethylated metabolites in plasma (p < 0.01) and resulted in a decrease in the positive (e.g., "high," p < 0.05) and negative (e.g., nausea, p < 0.05) subjective effects of codeine in both the FD120 and FD180 groups. Short-term quinidine pretreatment inhibited codeine O-demethylation more than did single-dose quinidine pretreatment (p < 0.01), and it decreased positive codeine effects in the FD120 group (N = 7), but unexpectedly not in the FD180 group (N = 5). These results suggest that the O-demethylated metabolites contribute substantially to the subjective effects and abuse liability of codeine.

Tacrolimus whole blood concentrations correlate closely to side-effects in renal transplant recipients.

AIMS: To evaluate the relationship between tacrolimus whole blood concentrations and side-effects and rejections in 14 renal transplant recipients. METHODS: Tacrolimus was measured by MEIA in whole blood in samples collected repeatedly during the first year after transplantation. Retrospectively, tacrolimus trough concentrations on the days with adverse events (n=172) or rejection (n=28) were related to the total distribution of the concentration values (n=656). RESULTS: Side-effects (one or more) were noted in connection with 76% of tacrolimus concentrations above 30 ng ml-1, with 41% of concentrations within the interval of 20-30 ng ml-1, with 26% of the concentrations within the interval of 10-20 ng ml-1 and with only 5.3% on the concentrations lower than 10 ng ml-1. No relation to the tacrolimus concentration was seen for rejection episodes. CONCLUSIONS: We conclude that therapeutic drug monitoring may be helpful in the management of tacrolimus therapy and that tacrolimus whole blood trough concentrations (MEIA) should preferably be kept below 20 ng ml-1 to avoid side-effects, such as nephro-and neurotoxicity and infections. The lower limit of the therapeutic range has yet to be defined.

A simple HPLC method for simultaneous determination of mycophenolic acid and mycophenolic acid glucuronide in plasma.

A reversed-phase high-performance liquid chromatographic method for the simultaneous determination of mycophenolic acid and its metabolite, mycophenolic acid glucuronide, is presented herein. Sample purification is limited to protein precipitation with acetonitrile. The analytes were separated on a C18 column with a mobile phase containing 30% acetonitrile and a 40 mm phosphoric acid buffer at pH 2.1 and measured with UV-detection at 215 nm.

Effect of codeine on oro-cecal transit time in Chinese healthy volunteers in comparison with Caucasian subjects.

OBJECTIVES: To evaluate the effect of codeine on oro-cecal transit time (OCTT) in Chinese subjects. METHODS: OCTT was measured with the hydrogen breath test in 12 Chinese healthy volunteers on two occasions: after placebo and after a single oral dose of codeine 50 mg. Codeine and its metabolites in urine were measured by HPLC. The Results of this study were compared with those previously obtained from Caucasian subjects. RESULTS AND CONCLUSION: The mean OCTT increased significantly after a single oral dose of codeine 50 mg [2.6 (1.2) h] compared with placebo [1.9 (0.6) h] in the Chinese subjects (P = 0.05). The increase in OCTT after codeine was similar in the Caucasian [0.9 (0.8) h] and in the Chinese subjects [0.7 (0.9) h]. However, the Chinese subjects had a significantly longer OCTT after placebo [1.9 (0.6) h] compared with the Caucasian subjects [1.3 (0.6) h, P < 0.05], possibly due to different environmental factors.

Near fatal intoxication with controlled-release morphine tablets in a depressed woman.

BACKGROUND: A 46-year-old woman suffering from a reactive depression was admitted to the emergency room in coma and with severe respiratory failure. She later developed cardiovascular instability and general convulsions. Two days following admission the patient had no respiratory effort but was able to communicate in writing that she had ingested a large amount of controlled-release morphine tablets. Following treatment with naloxone she was successfully weaned from the respirator the next day. METHODS: Sampling for determination of plasma and urine concentrations of morphine and its metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) was started 60 h after the presumed time of intake and continued up to 8 days after admission. RESULTS: The initial plasma concentrations of morphine, M3G and M6G were 2160, 13100 and 2330 nM, respectively, compatible with a lethal dose in an opioid-naive patient. The urinary recovery of morphine, M3G and M6G corresponded to 6.8 mmol, equivalent to an oral intake of at least 2500 mg. CONCLUSION: The plasma concentrations of morphine and morphine metabolites documented in this case, indicative of considerable absorption of drug, demonstrate that prolonged observation is necessary following intoxications with controlled-release morphine tablets. This case also highlights the importance of continuous follow-up of oral morphine therapy, so that unused drug is not left unaccounted for in the patient's home.

Hyperlipidemia in renal transplant recipients treated with sirolimus (rapamycin).

BACKGROUND: Sirolimus is an interesting immunosuppressive drug that does not seem to cause nephrotoxicity, neurotoxicity, or diabetogenicity, as commonly seen in patients treated with cyclosporine or tacrolimus. In this report, we describe a possible association between sirolimus and observed hyperlipidemia. METHODS: Serum levels of triglycerides and cholesterol were analyzed in 11 patients who participated in a pilot study evaluating the effect of oral sirolimus or placebo combined with cyclosporine and corticosteroids on the occurrence of acute renal transplant rejection. RESULTS: In four of nine patients given sirolimus, significantly increased serum triglyceride levels were seen, with peak levels occurring 2-4 months after transplantation and ranging between 11.7 and 42.0 mmol/L (reference value <2.2 mmol/L). In two patients given placebo, the serum triglyceride levels remained below 5.0 mmol/L. After reduction or discontinuation of sirolimus, the serum triglyceride levels decreased within 1-2 months and after 1-8 months levels had returned to their pretransplant values. A significant increase in serum cholesterol levels was seen in one of nine patients given sirolimus. CONCLUSION: It seems that long-term treatment with sirolimus in combination with cyclosporine and corticosteroids may increase the risk of hypertriglyceridemia.

Quantification of the O- and N-demethylated and the glucuronidated metabolites of codeine relative to the debrisoquine metabolic ratio in urine in ultrarapid, rapid, and poor debrisoquine hydroxylators.

The O-demethylation of codeine is polymorphic and catalyzed by CYP2D6. The metabolites of codeine formed through O- and N-demethylation as well as glucuronidation were quantified in the ultrarapid metabolizers of debrisoquine and compared with the normal extensive (EM) and poor metabolizers (PM). The urinary codeine and its seven metabolites were detected after 25 mg codeine in 24 healthy Caucasian subjects with low debrisoquine metabolic ratios (MR, < or = 0.11) and a group of 132 subjects tested earlier with codeine and debrisoquine including 114 EMs (MR < 12.6) and 18 PMs (MR > 12.6). Whereas the O-demethylated metabolites accounted for < 0.4% of the total recovery on average in the PMs and 1.7% to 8.7% in the EMs, they accounted for 15.3% in the 24 subjects with ultrarapid metabolism of debrisoquine. This study suggests that the ultrarapid debrisoquine hydroxylators may develop increased O-demethylated metabolite-dependent effects or side-effects of codeine.

Indices and graphical approaches for the detection of interindividual and interethnic variations in codeine metabolism.

AIMS: To evaluate the use of different graphical methods and statistical tests in the detection of interindividual and interethnic variations in codeine metabolism. Various urinary metabolic ratios (MR) for codeine O-demethylation were also compared for their ability to determine phenotype. METHODS: Frequency histograms, normal test variable (NTV) plots and admixture analysis were used to examine the distributions of the urinary MRs for codeine O-demethylation, N-demethylation and glucuronidation in 132 Caucasian and 222 Chinese subjects. RESULTS: In the Caucasian population, apparent bimodality was shown in both a frequency histogram and NTV plot of the log MR of codeine O-demethylation (codeine/(morphine (M) + M-3 and M-6-glucuronide (M3G and M6G) + normorphine (NM)). Admixture analysis confirmed the co-segregation of codeine O-demethylation and debrisoquine hydroxylation. The antimode for the codeine O-demethylation MR between extensive and poor metabolisers was located between 5.5 and 8.3. A simplified MR for codeine O-demethylation (codeine/M3G) demonstrated a similar correlation with the debrisoquine MR to the more complex MR, allowing a simplification of the analytical method for phenotyping. The Chinese population had significantly higher median MRs for codeine N-demethylation, O-demethylation and glucuronidation, which was shown clearly in the frequency histograms, but not in the NTV plots. CONCLUSION: A histogram seems preferable over a NTV plot for assigning phenotype using the codeine O-demethylation MR, because it is clear and simple. Interethnic difference in the metabolism of codeine are also better visualised from the histograms.