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.

Carbamazepine and cigarette smoking induce differentially the metabolism of codeine in man.

The inducibility of codeine metabolism by carbamazepine (CBZ) and cigarette smoking has been investigated. A single oral dose of 25 mg of codeine was given to seven epileptic patients before and after 3 weeks' regular CBZ treatment (400-600 mg per day). Codeine was also given to nine volunteers who were heavy smokers (20 cigarettes per day) and to nine non-smokers as controls. All subjects were found to be extensive metabolizers of codeine by O-demethylation. Urine was collected over 8 h following codeine intake. Codeine and the metabolites were analysed with HPLC. CBZ significantly increased the urinary excretion of the N-demethylated metabolite, norcodeine (NC) which led to a significant decrease in the metabolic ratio (MR) for N-demethylation. The O-demethylation was not significantly altered. The excretion of normorphine, an active metabolite formed through both O- and N-demethylation of codeine increased by almost three-fold after CBZ treatment. Contrary to CBZ treatment, cigarette smoking slightly but significantly induced the glucuronidation of codeine as shown by a decreased MR for glucuronidation in the smokers, while the O- and N-demethylations were not significantly changed as indicated by the similar MRs in smokers and in non-smokers. These results suggest that CBZ and cigarette smoking selectively induce different metabolizing enzymes. The polymorphic O-demethylation is relatively stable to these factors.

Genetic analysis of the CYP2D locus in relation to debrisoquine hydroxylation capacity in Korean, Japanese and Chinese subjects.

The CYP2D6 genotype and the debrisoquine and mephenytoin hydroxylation phenotypes were studied in 63 Oriental subjects including 21 Chinese, 21 Japanese and 21 Koreans. All subjects were extensive metabolizers of debrisoquine. The incidence of the S-mephenytoin poor metabolizer phenotype was 14% in the Chinese, 24% in the Japanese and 24% in the Korean population, respectively, which is similar to previous reports. The CYP2D6 genotype was analysed by Xba I and Eco RI RFLP, and by allele-specific PCR analysis for the presence of several allelic variants of the CYP2D locus. No CYP2D6A or CYP2D6B alleles, two of the most common defect alleles among Caucasians, were found among the Oriental subjects. The frequency of the CYP2D6D allele was similar to that in Caucasian populations and consistent with the low incidence of the poor metabolizer phenotype in all three Oriental populations. The CYP2D6L2-allele with duplication of an active CYP2D6L gene was identified in one Korean and one Chinese allele in association with high CYP2D6 activity. The CYP2D6Ch alleles CYP2D6Ch1 and Ch2, identified by RFLP and PCR for the -1338C-->T and 188C-->T mutations, were the most frequent allelic variants in all three populations studied, and were related to a decreased CYP2D6 activity as previously shown in Chinese. In conclusion, the present pilot study revealed major similarities in the polymorphic CYP2D locus between Korean, Japanese and Chinese populations.

Quinidine inhibition of debrisoquine S(+)-4- and 7-hydroxylations in Chinese of different CYP2D6 genotypes.

Pronounced differences in the CYP2D6 gene between Chinese and Caucasians have previously been described. There was a low frequency of detrimental mutations in the Chinese CYP2D6 gene causing the poor metabolizer (PM) phenotype. In contrast to Caucasians where the Xba I 44 kb allele is almost always associated with the PM phenotype, Chinese with the 44/44 kb RFLP pattern are extensive metabolizers (EM). In order to evaluate whether the debrisoquine hydroxylation seen in subjects with this haplotype is catalysed by a functionally similar enzyme to CYP2D6 or is catalysed by another type of P450 isozyme, product selectivity of the 4-hydroxylation was studied in 27 Chinese. The inhibition of CYP2D6 by quinidine was also investigated. In the 26 Chinese EM the S(+)-4-hydroxy enantiomer was found to be the major urinary metabolite of debrisoquine with an enantiomeric excess of 96.8-100%, which is similar to that in Caucasians. A correlation between the amount of S(+)-4-hydroxy and the minor 7-hydroxy metabolites excreted in urine (r = 0.72; p < 0.001) was seen. The amount of these two metabolites excreted was less in Chinese EM of debrisoquine with the 44/44 kb RFLP pattern, than in those with the wild type 29/29 kb pattern (p < 0.01). The stereoselectivity was very high in both groups. All Chinese homozygous for the 44 kb fragment (n = 5) were transformed to apparent PM after a single 100 mg dose of quinidine similarly to five Caucasian EM. Both the S(+)-4- and 7-hydroxylations of debrisoquine were inhibited by quinidine in both populations. This study shows that the cytochrome P450 catalysing the 4- and 7-hydroxylations of debrisoquine in Chinese EM has the same properties (product stereoselectivity and inhibition by quinidine) as the CYP2D6 in Caucasian EM.

Morphine kinetics in cancer patients.

Oral and intravenous morphine kinetics were studied in seven patients with cancer who needed continuous treatment with morphine because of severe chronic pain. Single oral (20 to 30 mg) and intravenous (4 mg) doses were given on separate days, followed by repetitive blood sampling for morphine analysis by gas chromatography. Volume of distribution ranged from 0.95 to 3.75 l/kg and serum clearance from 5.0 to 16.1 ml/min/kg. Oral morphine in doses that were more than five times the intravenous dose gave concentrations (at 10 and 120 min after dose) between 38 and 112 ng/ml. During the 0.25- to 8-hr period after the oral dose serum concentrations were higher than after the intravenous dose. There was a variation in oral bioavailability of 15% to 64% and an interindividual variation in terminal half-life from 58 to 465 min. These data warrant careful adjustment of the oral dose under close supervision of the patient at the onset of therapy.

Amitriptyline metabolism: association with debrisoquin hydroxylation in nonsmokers.

Eleven healthy nonsmokers with wide variation in the ability to hydroxylate debrisoquin (D) were given single oral doses of amitriptyline and nortriptyline on different occasions. The urinary D/4-hydroxy-D ratio correlated significantly (P less than 0.01) with all three parameters of amitriptyline disposition measured (total plasma clearance, clearance by demethylation, and clearance by pathways other than demethylation), with rs = -0.89, -0.78, and -0.83, respectively. In contrast, we failed to demonstrate such correlations in a previous sample of smokers. Our data suggest that there may be a common regulation of the hydroxylation of D and the oxidative metabolism of amitriptyline in nonsmokers. It is hypothesized that an additional demethylase/hydroxylase is induced in smokers that is not involved in D hydroxylation.

Polymorphic oxidation of sparteine and debrisoquine: related pharmacogenetic entities.

Thirty-eight healthy subjects were given single oral doses of debrisoquine and sparteine in a crossover study. The close correlation between urinary metabolic ratios of the two drugs (rs = 0.91; P less than 0.001) demonstrates that the polymorphic N-oxidation of sparteine and 4-hydroxylation of debrisoquine are related pharmacogenetic entities; the metabolism of the two drugs is regulated by identical or closely related genetic factors.

Polymorphic debrisoquin hydroxylation in 757 Swedish subjects.

The metabolic ratios (MRs) between debrisoquin and 4-hydroxydebrisoquin in urine after a single oral dose of 10 mg debrisoquin were bimodally distributed in 757 healthy, white Swedish volunteers. Forty-one subjects (5.4%) had an MR greater than 12.6 and were classified as slow debrisoquin hydroxylators. The MR was reproducible in urine stored at +8 degrees C for 1 week and at -20 degrees C over a period of 5 years. Collection intervals of 6 or 12 hours gave the same MR. Intraindividual repeatability of the debrisoquin phenotyping test was established in 37 subjects examined twice at least 2 weeks apart. The calculated frequency of the single allele that is believed to control deficient debrisoquin hydroxylation is similar among white Swedish people, as among other white groups examined so far; however, it is significantly different from the frequency in certain Oriental groups. Detailed comparisons of the prevalence of slow debrisoquin hydroxylation in different ethnic groups are not possible due to shortcomings in current epidemiologic techniques used (small materials, the location of the antimode distinguishing rapid and slow hydroxylators unknown, and family studies missing).

Amitriptyline metabolism: relationship to polymorphic debrisoquine hydroxylation.

Amitriptyline AT demethylation to nortriptyline NT was determined in nine healthy subjects who had been phenotyped with respect to debrisoquine D hydroxylation capacity. AT demethylation was calculated from the ratio between the plasma AUCs of NT after single oral doses of AT and NT. Plasma clearance of AT by demethylation did not correlate with the ratio between D and 4-hydroxy-D in urine (rs = -0.55).

E- and Z-10-hydroxylation of nortriptyline: relationship to polymorphic debrisoquine hydroxylation.

Eight healthy subjects [who were phenotyped with a debrisoquine (D) hydroxylation test] were selected to cover a wide range in the ratio between D and 4-hydroxydebrisoquine (4-OH-D) in the urine. After a single oral dose of nortriptyline (NT) the metabolic clearance by 10-hydroxylation in the E-position, but not in the Z-position, correlated closely to the metabolic ratio D/4-OH-D (rs = -0.88, p less than 0.01). This indicates that common enzymatic mechanisms are involved in the hydroxylation of D and the E- but not the Z-10-hydroxylation of NT. Slow hydroxylators of NT and D excreted less 10-hydroxynortriptyline in urine and had lower plasma clearance of NT than the rapid hydroxylators. The strong correlation (r = 0.96) between the total plasma clearance of NT and the metabolic clearance by E-10-hydroxylation shows that this metabolic reaction is important in the disposition of the drug.

Importance of genetic factors in the regulation of diazepam metabolism: relationship to S-mephenytoin, but not debrisoquin, hydroxylation phenotype.

Single oral 10 mg doses of diazepam and demethyldiazepam were given on different occasions to 16 healthy subjects. The subjects included four poor hydroxylators of debrisoquin and three poor hydroxylators of mephenytoin. There was a correlation between the total plasma clearance of diazepam and demethyldiazepam (rs = 0.83; p less than 0.01). There was no relationship between benzodiazepine disposition and debrisoquin hydroxylation. Poor hydroxylators of mephenytoin had less than half the plasma clearance of both diazepam (p = 0.0008) and demethyldiazepam (p = 0.0001) compared with extensive hydroxylators of mephenytoin. The plasma half-lives were longer in poor hydroxylators than they were in extensive hydroxylators of mephenytoin for both diazepam (88.3 +/- SD 17.2 and 40.8 +/- 14.0 hours; p = 0.0002) and demethyldiazepam (127.8 +/- 23.0 and 59.0 +/- 16.8 hours; p = 0.0001). There was no significant difference in volume of distribution of the benzodiazepines between the phenotypes. This study shows that the metabolism of both diazepam (mainly demethylation) and demethyldiazepam (mainly hydroxylation) is related to the mephenytoin, but not to the debrisoquin, hydroxylation phenotype.

Theophylline metabolism in relation to antipyrine, debrisoquine, and sparteine metabolism.

Theophylline plasma clearance (Clp) and clearance to its metabolites ( Clm ), as well as antipyrine saliva clearance ( Clsal ) and its Clm were compared in a crossover study in 25 healthy subjects. They were selected with regard to smoking status (nine smokers, 16 nonsmokers) and oxidation phenotype of debrisoquine and sparteine (six poor metabolizers [PMs] and 19 extensive metabolizers [EMs]). Clm of theophylline (1,3-dimethyluric acid, 1-methyluric acid, and 3-methylxanthine) correlated (r greater than or equal to 0.92) to each other and to total theophylline Clp (r greater than or equal to 0.97). Smokers had higher Clm to all metabolites, particularly by the N-demethylation pathways. After correction for the effect of smoking, there was no difference between EMs and PMs with regard to theophylline Clp or Clm . Antipyrine clearances by EMs and PMs ( Clsal and Clm of 4-OH-antipyrine, 3-OH- methylantipyrine , or norantipyrine) also did not differ. Antipyrine Clsal and Clm correlated to theophylline Clp (r between 0.50 and 0.69). It is concluded that theophylline metabolism (N-demethylations and C-oxidation) is not under the same genetic control as sparteine and debrisoquine oxidations, and that there may be a partial overlap in factors that regulate the metabolism of theophylline and antipyrine.

Nortriptyline formation after single oral and intramuscular doses of amitriptyline.

Oral (50 mg) and intramuscular (25 mg) amitriptyline (AT) was given to six normal subjects and the area under the plasma concentration-time curve (AUC) for nortriptyline (NT) formed was calculated. There was no difference between the AUCs (corrected for dose) after the two routes of administration. The ratio between the AUCs (corrected for dose) after the two routes of administration. The ratio between AUCoral and AUCim averaged 0.95 (range 0.69 to 1.13). After intramuscular AT maximum NT plasma concentration was reached after 24 to 48 hr, whereas it was 8 to 24 after oral dosing.

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.

Cyclosporine plasma levels in renal transplant patients. Association with renal toxicity and allograft rejection.

In 69 renal allograft recipients the highest-tolerated dose was given with respect to clinical events but without respect to the CsA plasma level (CsA-PL). The CsA dose was gradually decreased during the first 6-12 months after transplantation, and in some patients even later. The CsA dose after 12 months was 5-8 mg/kg/day and after 18 months 4-6 mg/kg/day, resulting in CsA-PL of 85-140 ng/ml and less than 50-110 ng/ml, respectively. CsA side-effects were usually seen in patients with high CsA-PL, but they were also encountered at levels normally seen in patients without toxicity. In the individual patient, acute CsA nephrotoxicity was associated with a significant rise in CsA-PL. In patients with acute nephrotoxicity a reduction of the CsA dose (mean 24%) was necessary to regain satisfactory renal function. All patients with several consecutive CsA-PL above 1000 ng/ml had hepatotoxicity or nephrotoxicity, or both, associated with severe morbidity and mortality. No difference was found between CsA-PL during acute rejection and during good renal function. The percentage of CsA determinations resulting in plasma levels below 50 ng/ml (the limit of detection) increased with the time of therapy and constituted 22% of all CsA-PL after 6 months of therapy. No rejections were seen later than 5 months after transplantation despite the low CsA-PL in many long-term treated patients. Treatment with high doses of methylprednisolone increased CsA-PL by 223%. Trimethoprimsulphamethoxazole in CsA-treated patients caused increases in serum creatinine levels. Monitoring of trough CsA plasma levels is recommended as a complement to clinical judgment. To avoid most nephrotoxicity and hepatotoxicity we have decided to keep the CsA-PL below 500 ng/ml during the first month, below 250 ng/ml the second month after transplantation, and below 200 ng/ml the third month after transplantation--and in long-term treated patients we now keep the CsA-PL between less than 50 and 150 ng/ml.

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.

High-dose morphine and methadone in cancer patients. Clinical pharmacokinetic considerations of oral treatment.

Several clinical studies have shown oral morphine and methadone to be effective in the treatment of intractable pain in patients with malignant disease. Recent pharmacokinetic studies have confirmed the rationale for regular administration of oral morphine and methadone but have revealed marked interindividual differences in the kinetics and metabolism which must be considered when titrating the oral dose according to the individual patient's need. Oral absorption of morphine in patients with malignant diseases is rapid, with peak plasma concentrations occurring at 20 to 90 minutes. Predose steady-state concentrations bear a constant relationship to dose, but vary considerably between individuals. The oral bioavailability is approximately 40% with marked patient-to-patient variations as a result of differences in presystemic elimination. The reported values for the volume of distribution range from 1.0 to 4.7 L/kg. Plasma protein binding is about 30%. The elimination half-life varies between 0.7 and 7.8 hours. Plasma clearance is approximately 19 ml/min/kg (5 to 34 ml/min/kg) and mostly accounted for by metabolic clearance. Studies in a few patients with malignant diseases treated regularly with daily doses of oral morphine ranging from 20 to 750mg indicate a linear relationship between the dose and trough concentration of morphine. Long term treatment with 10- to 20-fold increase of the oral dose over a period of 6 to 8 months does not seem to change the kinetics of oral morphine. The plasma concentrations of the main metabolite, morphine-3-glucuronide (M3G), exceed those of the parent drug by approximately 10-fold after intravenous administration and by 20-fold after oral administration. The relationship between the area under the plasma concentration-time curve (AUC) of morphine and the AUC of morphine-3-glucuronide remains constant during the development of tolerance upon long term treatment with increasing doses. Renal disease causes a significant increase in the mean plasma concentrations of morphine for 15 minutes after its administration, while mean values of terminal half-life and total body clearance are within the normal range. However, the glucuronidated polar metabolite morphine-3-glucuronide rises rapidly to high concentrations which persist for several days. Chronic liver disease causes an increase in the bioavailability of oral morphine but no, or only a slight reduction in the intravenous clearance. The elimination half-life and volume of distribution are within the normal range.(ABSTRACT TRUNCATED AT 400 WORDS)

Morphine pharmacokinetics and metabolism in humans. Enterohepatic cycling and relative contribution of metabolites to active opioid concentrations.

Morphine, morphine-6-glucuronide (M6G), morphine-3-glucuronide (M3G) and normorphine were analysed with high performance liquid chromatography in plasma and urine, collected over 72 h after administration of single intravenous 5 mg and oral 20 mg doses of morphine to 7 healthy volunteers. Systemic plasma clearance of morphine was on average 21.1 +/- 3.4 ml/min/kg (1.27 +/- 0.20 L/h/kg), volume of distribution was 2.9 +/- 0.8 L/kg and oral bioavailability was 29.2 +/- 7.2%. Clearance of morphine to form M3G and M6G comprised 57.3% and 10.4%, respectively, and renal clearance comprised 10.9% of total systemic plasma clearance; hence, more than one-fifth of a dose (20.8%) remained as unidentified residual clearance. On the basis of the area under the plasma concentration-time curves determined after oral and intravenous administration, the ratios of M6G:morphine were 3.6 +/- 1.2 and 0.7 +/- 0.3, respectively. The corresponding figures for M3G:morphine were 29.9 +/- 6.8 and 7.7 +/- 1.4. Differences in metabolic ratios between the parenteral and oral routes could be attributed solely to differences in morphine concentrations as evidenced both by plasma concentrations and amounts excreted in urine. An oral:parenteral potency ratio of 1:3 may, thus, be due to differences in circulating amounts of morphine since the proportions of an administered dose found as M6G and M3G after administration by both routes were equal. A major finding was a slowly declining terminal phase of morphine and metabolites that was evident both in plasma and in urinary excretion versus time curves, where the half-lives of morphine, M3G and M6G were 15.1 +/- 6.5 h, 11.2 +/- 2.7 h and 12.9 +/- 4.5 h, respectively. The terminal half-life of normorphine was 23.9 +/- 10.1 h after oral administration. Comparison of oral with intravenous excretion curves showed that a greater part of morphine and metabolites were excreted during the slowly declining phase after the oral dose than the intravenous dose, which is highly suggestive of enterohepatic cycling. The renal clearance of M6G and morphine was seen to exceed creatinine clearance, possibly due to an active secretion process.