Bleeding-related hospitalization in patients with von Willebrand disease and the impact of prophylaxis: Results from national registers in Sweden compared with normal controls and participants in the von Willebrand Disease Prophylaxis Network.

INTRODUCTION: Patients suffering from von Willebrand disease (VWD) have a variety of bleeding symptoms and require both outpatient care for treatment and, in more severe cases, hospitalization. AIM: To investigate the impact of having VWD on frequency of hospitalization compared to a control group and to evaluate whether regular replacement therapy (prophylaxis) is associated with reduction in the number of hospitalizations. METHODS: Linkage of national population-based registries was used in the Congenital Bleeding Disorders study in Sweden (CBDS). Data were from the von Willebrand Disease Prophylaxis Network (VWD PN). RESULTS: The national registries contained 2790 subjects with a diagnosis of VWD between 1987 and 2009. A total of 13 920 age- and gender-matched controls were identified. There were 2.0 times (range 1.5-2.5) as many inpatient hospitalizations among subjects with VWD compared to controls. The most common causes of hospitalization were gastrointestinal (GI) bleeding (n = 232 as primary diagnosis), menorrhagia (n = 198) and epistaxis (n = 192). Outpatient visits per year were also twice as common among those with VWD. From the VWD PN, 105 subjects were included (VWD type 3, 52.4%; type2A, 22.9%; type 1, 12.4% and other types, 3.9%). A total of 122 hospitalizations due to bleeding episodes, dominated by GI bleeds, were analysed. Significantly fewer hospitalizations occurred after initiation of prophylaxis (75 prior to and 45 after, P = .006). CONCLUSION: Our study indicates that subjects with VWD have a considerably higher consumption of healthcare resources compared to controls and that initiation of prophylaxis may reduce the number of hospitalizations due to bleeding.

Sustained Psoriasis Area and Severity Index, Dermatology Life Quality Index and EuroQol-5D response of biological treatment in psoriasis: 10 years of real-world data in the Swedish National Psoriasis Register.

BACKGROUND: Few studies have analysed the long-term effects of biological treatment in psoriasis. PsoReg, the Swedish national register for systemic psoriasis treatment, started in 2006 and now includes 10 years of real-world data on the effectiveness of biological treatment. OBJECTIVES: To analyse the long-term real-world outcome data of patients who are biologically naïve with moderate-to-severe psoriasis after switching to biological treatment. METHODS: An observational study of patients who are biologically naïve with at least one registration of outcome before switching to biological treatment while included in PsoReg and at least one follow-up visit. Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI) and EuroQol-5D (EQ-5D) values were analysed at 3-5 months, 6-11 months and at least once after ≥ 1 year, up to 9 years after the switch to biological treatment. RESULTS: In total, 583 patients fulfilled the inclusion criteria. Of these, 399, 395 and 373 patients had observed outcome data beyond 1 year on the PASI, DLQI and EQ-5D, respectively, and 164, 168 and 152, respectively, were observed in at least three time periods after the switch. Significant (P < 0·01) improvement in PASI, DLQI and EQ-5D scores was observed 3-5 months after the switch and sustained under the whole observation period. The mean PASI, DLQI and EQ-5D changed from 13·5 ± 9·1, 9·0 ± 8·1 and 0·74 ± 0·22, respectively, before the switch, to 4·0 ± 3·5, 3·7 ± 4·7 and 0·79 ± 0·21, respectively, 1-5 years after the switch. CONCLUSIONS: Biological treatment, as used in clinical practice, shows a stable long-term effectiveness in all the measured dimensions, PASI, DLQI and EQ-5D.

Preference-based valuation of treatment attributes in haemophilia A using web survey.

INTRODUCTION: Clinical trials have shown promising results for extended half-life factor VIII concentrates but little is known about individuals' valuation of haemophilia treatment attributes. AIM: To assess patient/caregiver and population valuation of treatment attributes of prophylactic regimens for people with severe haemophilia A. METHODS: Members ≥16 years of the Swedish Haemophilia Society (FBIS) and of a web-panel representative of the Swedish population were invited to participate in a web-survey investigating preferences for haemophilia treatment attributes using the Time Trade-Off methodology which ranks health states on a scale 0 (dead) to 1 (full health). All respondents assessed the same four treatment scenarios for severe haemophilia A, each described by three stylized attributes: injection interval (every 2nd or 5th day); participation in physical activity (Y/N); annual risk of bleed (1-2 or 5-6 bleeds). RESULTS: The survey had 1657 respondents (68% complete responses; 184/1233 from FBIS/web-panel gave informed consent; mean age 52 years, 51% men). Respondents from FBIS and from the web-panel had the same preference ranking of the four treatment scenarios, but members of FBIS consistently rated significantly higher health utilities; range 0.67-0.73 vs 0.54-0.60. Participation in physical activity implied +0.023 (95% confidence interval 0.015-0.030); a longer injection interval implied +0.038 (0.03; 0.45); and fewer bleeds implied +0.022 (0.015-0.029) utility points. CONCLUSIONS: Patient/caregiver and population preferences indicate that treatment attributes such as frequency of injections and the possibility of participating in physical activity are important attributes impacting quality of life in addition to the control and prevention of bleeding episodes.

Surgery and survival in birth cohorts with severe haemophilia and differences in access to replacement therapy: The Malmö experience.

BACKGROUND: Persons with severe haemophilia require lifelong replacement therapy, prophylaxis, to prevent bleeding. Data describing long-term outcomes of prophylactic treatment are scarce. The aim of this study was to investigate joint surgery and survival among persons with severe haemophilia with special attention to access to prophylaxis in the early years of life. METHODS: Eligible participants had severe haemophilia A or B and were treated at the Malmö centre from the 1960s onward. Time from birth until joint surgery was analysed for participants negative for factor inhibitor and alive in 2000. We compared survival among the entire cohort with severe haemophilia treated at the Malmö centre with the general male population of Sweden and a sample of persons with severe haemophilia from the United Kingdom (UK). RESULTS: Overall, 167 participants were included, 106 (63.5%) of whom had complete data on joint surgery. Among those born before 1970, 1970-1979 and ≥1980 approximately 37%, 21% and 0% had their first joint surgery by age 30, respectively. There were no second joint surgeries reported in cohorts born ≥1970. Persons with severe haemophilia and negative for HIV treated in Malmö have attained approximately similar survival to that of the general male population in Sweden and live slightly longer than persons with severe haemophilia from the UK. DISCUSSION AND CONCLUSION: Prophylaxis in Sweden, although costly, has markedly improved survival and joint outcomes for persons with severe haemophilia. This study highlights the importance of early start of replacement therapy to prevent or postpone serious joint damage.

The association between health utility and joint status among people with severe haemophilia A: findings from the KAPPA register.

INTRODUCTION: People with severe haemophilia A have reportedly impaired health related quality of life (utility) mainly due to recurrent bleeding, arthropathy and treatment burden. AIM: To estimate utilities and evaluate their potential correlates - most importantly the joint status - among people with severe haemophilia A. METHODS: In this cross-sectional study, eligible participants had severe haemophilia A, were aged ≥15, negative for factor VIII inhibitor and included in the KAPPA register of Denmark, Norway and Sweden. Data on demographics, treatment history, haemophilia joint health score, and EQ-5D utility were obtained from the register. We used box plots to present utilities and joint status and ordinary least squares regression to evaluate correlates of utilities. Participants were consecutively enrolled in the KAPPA register between April 2013 and June 2016. RESULTS: Overall, 173 participants with median age of 34 (interquartile range: 25-45) were included. Twelve (6.9%) participants were on episodic treatment while 161 (93.1%) were treated using prophylaxis. Concomitant diseases and positive inhibitor history were reported for 73 (43.2%) and 21 (12.1%) participants, respectively. The highest median utility (1.0) was observed among those aged <29 on prophylaxis and those aged 30-44 who had started prophylaxis by age 3. In the multi-variable regression, joint scores of 16-25 (Coef. -0.18, 95% CI: -0.30, -0.06), 26-35 (Coef. -0.21, 95% CI: -0.36, -0.06) and >35 (Coef. -0.37, 95% CI: -0.52, -0.23) were associated with lower utilities. CONCLUSION: Moderate to severe joint manifestations are associated with reduced utilities among persons with severe haemophilia A.

Comparative burden of arthropathy in mild haemophilia: a register-based study in Sweden.

INTRODUCTION: Mild haemophilia is a congenital bleeding disorder affecting males. The burden of arthropathy in mild haemophilia has not been comprehensively described. AIM: The aim of this study was to compare the incidence, age at diagnosis and surgery for arthropathy and related hospitalizations between people with mild haemophilia and the general population in Sweden. METHODS: This was a register-based cohort study. Eligible participants were those with mild haemophilia born between 1941 and 2008 and a randomly selected, birthdate and sex-matched comparison group from the general population. Follow-up was from birth (or earliest 1984) until death, emigration or end of the study in 2008. Data on arthropathy were obtained from a national patient register. Negative binomial and competing risk regression and Kaplan-Meier estimate curves were used in the analysis. RESULTS: Overall, 315 people with haemophilia and 1529 people in the comparison group were included. Participants with haemophilia born between 1984 and 2008 had a ninefold (95% CI: 3.3-27.2) and 16-fold (95% CI: 6.7-36.5) increased incidence of arthropathy-related hospital admission and arthropathy diagnosis respectively. None in this cohort underwent surgery. Among participants with haemophilia born prior to 1984, the rates of arthropathy diagnosis and surgery of the index joints (knee, elbow, ankle) were increased twofold (95% CI: 1.0-3.2) and fivefold (95% CI: 1.7-17.8) respectively. CONCLUSION: Our data suggested a higher burden of arthropathy among individuals with mild haemophilia compared to the general population. Further research should investigate the need for targeted joint screening programmes among individuals with mild haemophilia.

Impact of childhood-onset type 1 diabetes on schooling: a population-based register study.

AIMS/HYPOTHESIS: We investigated the impact of type 1 diabetes on educational achievements in compulsory and upper secondary school, as well as potential long-lasting effects. METHODS: Altogether 2,485 individuals with type 1 diabetes, diagnosed at the age of <15 years and born in 1972-1978, were selected from the Swedish Childhood Diabetes Register, which was linked to national population registers including the Swedish Education Register. For each individual, four controls from the general population, matched for year of birth and residence at the time of diagnosis, were selected by Statistics Sweden (n = 9,940). We analysed the impact of diabetes on final school grades at 16 years (compulsory school) and 19 years (upper secondary school) and on participation in the labour market at 29 years using linear, logistic, ordered logistic and quantile regression analyses, controlling for demographics and socioeconomic background. RESULTS: Diabetes had a negative effect on mean final grades (scale of 1-5) in compulsory school (-0.07, p < 0.001) and theoretical programmes in upper secondary school (-0.07, p = 0.001). Children with early-onset diabetes (0-4 years) suffered a greater disadvantage as a result of the disease (-0.15, p = 0.001 in compulsory school). The strongest effect was seen in the lowest deciles of the conditional distribution on mean final grades. At age 29, individuals with diabetes were less likely to be gainfully employed (OR 0.82, 95% CI 0.73, 0.91). CONCLUSIONS/INTERPRETATION: The small but significant negative effect of type 1 diabetes on schooling could affect opportunities for further education and career development. Attention must be paid in school to the special needs of children with diabetes.

Daily dosing prophylaxis for haemophilia: a randomized crossover pilot study evaluating feasibility and efficacy.

Regular replacement therapy (prophylaxis) for haemophilia has been shown to prevent development of disabling arthropathy and to provide a better quality of life compared to treatment on demand; however, at a substantially higher cost. Calculations based on pharmacokinetic principles have shown that shortening dose intervals may reduce cost. The aim of this prospective, randomized, crossover pilot study was to address whether daily dosing is feasible, if it reduces concentrate consumption and is as effective in preventing bleeding as the standard prophylactic dosing regimen. In a 12+12 month crossover study, 13 patients were randomized to start either their own previously prescribed standard dose, or daily dosing adjusted to maintain at least the same trough levels as obtained with the standard dose. Ten patients completed the study. A 30% reduction in cost of factor concentrates was achieved with daily prophylaxis. However, the number of bleeding events increased in some patients in the daily dosing arm and patients reported decreased quality of life during daily prophylaxis. Daily treatment had a greater impact on daily life, and the patients found it more stressful.Prophylaxis with daily dosing may be feasible and efficacious in some patients. A substantial reduction of factor consumption and costs can be realized, but larger studies are needed before the introduction of daily prophylaxis into clinical routine can be recommended.

Analysis of three outcome measures in moderate to severe psoriasis: a registry-based study of 2450 patients.

BACKGROUND: As moderate to severe psoriasis is a systemic disease with large effects on health-related quality of life, generic measures that include overall health, not only skin involvement, are necessary. Knowledge about the relationship between the generic preference-based EuroQol 5D (EQ-5D) and dermatology-specific measures in psoriasis is limited. OBJECTIVES: To analyse EQ-5D, the Dermatology Life Quality Index (DLQI) and the Psoriasis Area and Severity Index (PASI) in patients with moderate to severe psoriasis in Swedish clinical practice by demographic characteristics, to compare EQ-5D among patients vs. Swedish population values, and to analyse the relationships between EQ-5D, DLQI and PASI. METHODS: This observational cohort study was based on PsoReg, the Swedish National Registry for Systemic Treatment of Psoriasis. EQ-5D was compared among patients with psoriasis vs. a defined general population in Sweden, retrieved from a previous study. Relationships between measures were examined with correlation tests and regression analysis. RESULTS: In total, 2450 patients (1479 men and 971 women) were included. Median EQ-5D, DLQI and PASI scores were 0·769, 4 and 4·7, respectively. Patients with psoriasis had a significantly lower EQ-5D compared with the defined general population. EQ-5D correlated moderately with DLQI (-0·55) and weakly with PASI (-0·25) (P < 0·001). CONCLUSIONS: When assessing psoriasis treatments and making decisions about treatment guidelines and resource allocation, EQ-5D, DLQI and PASI provide a useful set of complementary tools, answering to different needs. If EQ-5D is not included in the original trial the second-best option in cost-effectiveness studies is to use mapping between DLQI and EQ-5D.

Transversal maxillary dento-alveolar changes in patients treated with active and passive self-ligating brackets: a randomized clinical trial using CBCT-scans and digital models.

OBJECTIVE: To assess transversal tooth movements and buccal bone modeling of maxillary lateral segments achieved with active or passive self-ligating bracket systems in a randomized clinical trial. MATERIALS AND METHODS: Sixty-four patients, with Class I, II, and mild Class III malocclusions, were randomly assigned to treatment with passive (Damon 3 MX) or active (In-Ovation R) SLBs. Impressions and cone-beam CT-scans were taken before (T0) and after treatment (T1). Displacement of maxillary canines, premolars and molars, and buccal alveolar bone modeling were blindly assessed. RESULTS: Twenty-one patients in the Damon and 20 in the In-Ovation group completed treatment according to the prescribed protocol. Eight Damon and 10 In-Ovation patients were excluded as the treatment approach had to be changed because of deviation from the recommended initial plan, while three Damon and two In-Ovation patients did not complete the treatment. Transversal expansion of the upper arch was achieved by buccal tipping in all but one patient in each group. No statistical significant difference in inter-premolar bucco-lingual inclination was found between the two groups from T0 to T1. The bone area buccal to the 2nd premolar decreased on average of 20% in the Damon and 14% in the In-Ovation group. Only few patients exhibited widening of the alveolar process. CONCLUSION: The anticipated translation and buccal bone modeling using active or passive SLBs could not be confirmed. Because of the large interindividual variation, a patient-specific analysis seems to be mandatory as individual factors like pre-treatment teeth inclination and occlusion influenced the treatment outcome of the individual patients.

Bioimpedance spectroscopy: a new tool to assess early esophageal changes linked to gastroesophageal reflux disease?

Bioimpedance spectroscopy can identify pathological changes related to precancerous lesions of the cervix uteri and esophagus. It therefore has the potential to detect early reflux-related changes in the esophageal mucosa, such as dilated intercellular spaces. The reliable detection of dilated intercellular spaces at the time of endoscopy would yield a significant diagnostic advantage for separating patients with functional heartburn from the large proportion of patients with gastroesophageal reflux symptoms but no macroscopic esophagitis or pathological acid exposure. The bioimpedance of the esophageal mucosa, measured with a small caliber probe, was evaluated in a series of preclinical experiments. First, sections of rabbit esophageal epithelium were mounted in Ussing chambers and exposed to solutions at pH 7.4 or pH 1.5 for 45 minutes. Impedance measurements were taken at varying probe pressures. Second, rabbit esophageal epithelia were perfused for 45 minutes in situ with pH 1.1 or control solutions and impedance measurements taken. Samples from both in vitro and in situ experiments were taken for morphological examination by light microscopy. Finally, esophageal bioimpedance was measured in awake dogs with permanent esophagocutaneous stoma. The in situ experiments demonstrated that morphological changes in the esophageal mucosa could be discerned by the use of bioimpedance spectroscopy. The variability in resistivity was species-independent but was affected by the pressure applied to the probe. The results suggest that evaluation of bioimpedance spectroscopy for use in a clinical setting is warranted. Small morphological differences in the esophageal mucosa may be detected by the use of bioimpedance spectroscopy.

Long-term detrimental consequences of the onset of type 1 diabetes on annual earnings--evidence from annual registry data in 1990-2005.

AIMS/HYPOTHESIS: Young adults in the early stages of their participation in the labour market may be particularly vulnerable to the effects of onset of a chronic disease. Our aim was to quantify the consequences of the onset of type 1 diabetes in young adults on annual earnings, using individual-level longitudinal data before and after the onset of diabetes. METHODS: The Econ-DISS database contains annual socioeconomic information for 1990-2005 from Statistics Sweden. Econ-DISS includes data for persons with diabetes onset at the age of 15-34 years between 1983 and 2005, registered in the national Diabetes Incidence Study in Sweden (DISS) database, and for controls. Considering the onset of type 1 diabetes as an unanticipated and significant life event, we compared the progression of annual earnings for 3,650 cases born between 1949 and 1970 before and after onset of diabetes with that of 14,629 controls. Possible confounders--education, participation in the labour market, sick leave and parental education--were analysed. RESULTS: We found no differences between the groups in annual earnings or participation in the labour market before onset of diabetes. After onset, persons with type 1 diabetes gradually lagged behind the controls. Their median annual earnings were lower in each year from 1995 to 2005 (p < 0.01). The difference in 2005 was euro (EUR) 1,411 (5.3%). Controlling for confounders, duration of type 1 diabetes > or = 10 years was associated with 4.2% (men) and 8.1% (women) lower average annual earnings for persons with upper secondary education only who were active in the labour market. CONCLUSION/INTERPRETATION: The onset of type 1 diabetes in young adults has long-term detrimental consequences on earnings that cannot be attributed to confounders.

The role of GABA(A) receptors in the control of transient lower oesophageal sphincter relaxations in the dog.

BACKGROUND AND PURPOSE: Transient lower oesophageal sphincter relaxations (TLESRs) are triggered by activation of mechanosensitive gastric vagal afferents and are the major cause of gastroesophageal reflux and therefore an important target for therapeutic intervention in gastroesophageal reflux disease (GERD). Activation of the metabotropic GABA(B) receptor has shown to inhibit TLESRs. The aim of the present study was to assess the role of the ionotropic GABA(A) receptor in the regulation of TLESRs. EXPERIMENTAL APPROACH: TLESRs were quantified using Dentsleeve manometry in dogs, and GABA(A) agonists were given i.v. prior to gastric distension. Immunohistochemistry and RT-PCR were used to localize GABA(A) receptors in the dog nodose ganglion, the source of vagal afferents which initiate TLESRs. KEY RESULTS: The prototypical GABA(A) agonist muscimol produced a dose-dependent inhibition of TLESRs ranging from 19 to 56%. The two other GABA(A) agonists evaluated, isoguvacine and 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol (THIP), as well as the GABA(A) positive allosteric modulator diazepam, had no major effects on TLESRs. Evaluation of higher doses was limited by emesis (THIP and isoguvacine) or restlessness/sedation (diazepam). Of the predominant GABA(A) receptor subunits (alpha, beta and gamma components), alpha and beta but not gamma were detected in the dog nodose ganglion by RT-PCR, while immunohistochemistry in addition demonstrated nerve fibres expressing the gamma subunit. CONCLUSIONS AND IMPLICATIONS: The present observations demonstrate that GABA(A) receptors exert an inhibitory control of TLESRs. These results warrant further studies using GABA(A) isoform-selective agonists to define the identity of receptors involved.

Injury to the human median and ulnar nerves in the forearm--analysis of costs for treatment and rehabilitation of 69 patients in southern Sweden.

This study analysed the costs of median and ulnar nerve injuries in the forearm in humans and factors affecting such costs. The costs within the health-care sector and costs of lost production were calculated in 69 patients with an injury to the median and/or ulnar nerve in the forearm, usually caused by glass, a knife, or a razorblade. Factors associated with the variation in costs and outcome were analysed. The total median costs for an employed person with a median and an ulnar nerve injury were EUR 51,238 and EUR 31,186, respectively, and 87% of the total costs were due to loss of production. All costs were higher for patients with concomitant tendon injuries (4 tendons). The costs within the health-care sector were also higher for patients who changed work after the injury and if both nerves were injured. Outcome was dependent on age and repair method.

Costs of on-demand and prophylactic treatment for severe haemophilia in Norway and Sweden.

The expected annual cost (in the year 2000 prices) for a 30-year-old patient with average individual and treatment characteristics for on-demand EUR 51,832 (95% CI: 44,324-59,341) and for prophylaxis EUR 146,118 (95% CI: 129,965-162,271), was obtained from panel-data analysis of an 11-year retrospective panel of 156 patients with severe haemophilia in Norway and Sweden. Costs included haemophilia-related treatment costs within the health-care sector (factor concentrate, doctors' visits, diagnostic procedures, hospitalisation, invasive procedures, etc.) and cost for haemophilia-related resource use in other sectors (lost production, use of special equipment, adaptation of workplace and domicile, etc). Although costs of lost production, reconstructive surgery and hospitalisation were higher for on-demand, they did not balance out the higher costs of factor-concentrate consumption in prophylaxis. The cut-off risk of premature death, where on-demand and prophylaxis would have been equally costly, was 3.7 percentage units higher for on-demand than for prophylaxis. Such a great risk difference has not been reported elsewhere to our knowledge. Estimated cost-elasticities indicated that annual costs of prophylaxis would increase by approximately the same proportion as a potential increase in the price of factor concentrate and decrease less than proportionately with a reduction in prescribed dose kg(-1). For on-demand, the annual costs would increase by approximately the same proportion as an increase in the prescribed dose kg(-1).

Willingness to pay for on-demand and prophylactic treatment for severe haemophilia in Sweden.

The objective of the present paper was to provide an estimate of the benefits of on-demand and prophylaxis treatment strategies for severe haemophilia in monetary terms. Using the contingent-valuation method, which simulates a missing market by asking people about their willingness to pay (WTP), we asked a representative sample (n = 609) of the Swedish population if they would be willing to pay a specific amount (bid) so that patients with severe haemophilia could receive on-demand treatment and another bid for prophylactic treatment. Different respondents were offered different bids and the bid vector ranged from 71 Euro cents to EUR 130. The order of the bid questions was randomized so that half of the respondents were asked first about their WTP for on-demand treatment, and then about their WTP for prophylaxis, while the order was reversed for the other half of the respondents. The mean estimated WTP (year 2002) was EUR 39 (95% CI 31-47) for on-demand and EUR 65 (95% CI 55-73) for prophylaxis. Our sensitivity analysis showed that the ranking of the two treatment alternatives was robust in that the WTP was greater for prophylaxis in all possible subsets. The point estimates of WTP varied somewhat in subsets defined by individual characteristics, but confidence intervals always overlapped that of the main results. The WTP for on-demand and prophylaxis exceeded the calculated cost of treatment per taxpayer of providing on-demand and prophylactic treatment, respectively, based on our previous results.

Sample preparation and determination of gabapentin in venous and capillary blood using liquid chromatography-tandem mass spectrometry.

An analytical method for the determination of gabapentin in serum obtained from venous blood samples has been developed using high-performance liquid chromatography (HPLC)-tandem mass spectrometry. In addition, a comparative study between capillary plasma samples and venous serum samples was carried out. This demonstrates the potential for the use of the described analytical system using very small amounts of blood. As internal standard (S)-(+)-alpha-amino-cyclohexane-propionic acid hydrate was used. Gabapentin and the internal standard are structural isomers, but have different m/z values for the fragments after collision induced dissolution. Gabapentin has 172-->154 and 172-->136 transitions and amino-cyclohexane-propionic acid hydrate has a 172-->126 transition which can be detected in tandem MS. Analysis of gabapentin was carried out on a C8 HPLC column using an isocratic mobile phase consisting of ammonium acetate (pH 3.0; 5mM)-methanol (96:4, v/v). The analytical method was validated for venous serum samples. Limit of detection was 1.6ng/ml and lower limit of quantification was 7.5ng/ml. R.S.D. values and bias values were within the range of acceptance for all concentration levels. The method developed for venous serum samples is being used in a gabapentin monitoring study using population pharmacokinetic modeling.

Analgesic effect of dextromethorphan in neuropathic pain.

BACKGROUND: Dextromethorphan, a clinically available N-methyl-D-aspartic acid (NMDA) receptor antagonist, has an analgesic effect in patients with diabetic neuropathy. The aim of this study was to evaluate the analgesic and adverse effects of a single high dose of dextromethorphan on spontaneous pain in patients suffering long-term neuropathic pain of traumatic origin. METHODS: Fifteen patients with post-traumatic neuropathic pain participated in this placebo-controlled, double-blind, randomized crossover study. On two separate occasions, the participants received 270 mg of dextromethorphan hydrobromide or placebo. Pain intensity, adverse effects and serum concentrations of dextromethorphan and metabolites were registered. RESULTS: Dextromethorphan had a statistically significant analgesic effect compared with placebo, but the effect varied markedly among the patients. Light-headedness was the most important adverse effect reported. Extensive metabolizers of dextromethorphan had an apparently better analgesic effect than poor metabolizers. CONCLUSION: This report indicates that a single high dose of dextromethorphan has an analgesic effect in patients with neuropathic pain of traumatic origin. The main metabolite dextrorphan seems to be important for the analgesic effect. At the relatively high dose studied, the clinical usefulness of dextromethorphan is limited to that portion of the patient population experiencing analgesia without an unacceptable level of adverse effects.

Economic evaluation: what are we looking for and how do we get there?

The interest in economic evaluation of alternative strategies for haemophilia treatment has increased through the years. Few studies have actually been undertaken, however, and most of them have been simple cost-minimization or cost-effectiveness analyses. From the perspective of the binational project 'Treatment strategies for severe haemophilia-prophylaxis vs. on-demand', the present paper discusses the pros and cons of different methods for economic evaluation and their data requirements. Severe haemophilia is a rare disease that requires lifelong treatment. In addition, treatment has both short- and long-term effects which are likely to differ between strategies. Accordingly, regardless of the chosen evaluation method, data requirements are non-trivial. Hence, the various problems connected to the generation of data, as well as how they may be addressed, are also discussed.

On-demand vs. prophylactic treatment for severe haemophilia in Norway and Sweden: differences in treatment characteristics and outcome.

Using an 11-year panel of 156 Norwegian and Swedish patients with severe haemophilia, and including retrospective case-book data from birth, we compared the differences in the haemophilia-related resource use between on-demand and prophylactic treatment. Patients treated on-demand had more surgery (arthrodeses, prostheses implantations and synovectomies) and more days lost from work. Median annual factor-concentrate consumption among adults (18+) was 211,000 IU [interquartile range (IQR) 154,000-268,000] or 3,024 IU kg-1 year(-1) for patients on prophylactic treatment and 55,000 IU (IQR 28,000-91,000) for on-demand patients (780 IU kg(-1) year(-1)). This was partly explained by the fact that the median dose per kg body weight was twice as great 28, (IQR 24-32) for prophylaxis compared with 14 (IQR 12-16) for on-demand. Prescribed dose per kg body weight was found to be an important factor explaining the variation in total annual factor-concentrate consumption per patient for both types of treatment. Other variables included in the panel-data regression analysis were the number of weeks on secondary prophylaxis for on-demand patients and age, body weight and type of haemophilia for children (0-17 years) on prophylaxis. Differences were consistently substantial and will affect both costs and benefits of the two treatment strategies.