John Rowell

The D2 dopamine receptor A1 allele and opioid dependence: Association with heroin use and response to methadone treatment

A total of 95 Caucasian opioid-dependent patients were followed over a one-year period in an outpatient methadone treatment program. The frequency of the TaqI A(1) allele of the D(2) dopamine receptor (DRD2) gene was 19.0% in these patients compared with 4.6% in controls free of past and current alcohol and other drug abuse and free of family history of alcohol and other drug abuse (p = 0.009). Twenty-two of these patients dropped out of the methadone program (Group A), 54 had a successful treatment (Group B), and 19 had a poor treatment (Group C) outcome. The frequency of the A(1) allele was highest in Group C (42.1%), followed by Group A (22.7%) and was lowest in Group B (9.3%). The more than fourfold higher frequency of the A(1) allele in the poor treatment outcome group compared with the successful treatment outcome group was significant (p = 0.00002). Moreover, the average use of heroin (grams/day) during the year prior to study entry was more than twice as great in patients with the A(1)(+) allele (A(1)/A(1) or A(1)/A(2) genotype) than those with the A(1)(-) allele (A(2)/A(2) genotype) (A(1)(+) allele = 0.55 +/- 0. 10, A(1)(-) allele = 0.25 +/- 0.05; p = 0.003). The results indicate that DRD2 variants are predictors of heroin use and subsequent methadone treatment outcome and suggest a pharmacogenetic approach to the treatment of opioid dependence.

Association of the D2 dopamine receptor A1 allele with alcoholism : Medical severity of alcoholism and type of controls

D2 dopamine receptor (DRD2) A1 allele frequency was determined in alcoholics of varying medical severity from three different inpatient settings and in various controls. A1 frequency was .15 in 68 alcoholics in a detoxification unit (group A), .19 in 90 alcoholics in a rehabilitation unit (group B), and .31 in 43 alcoholics in a gastroenterology unit (group C). Group C had a higher A1 frequency than group B (p = .045) or group A (p = .005) alcoholics. In 46 controls (group D), A1 frequency was .18. In subsets of these controls, A1 frequency was .14 in 39 subjects with a negative family history (FH-) of alcoholism (group E), .06 in 34 subjects without previous hazardous alcohol consumption (group F), and .05 in 30 subjects with FH- and without previous hazardous alcohol consumption (group G). A1 frequency was significantly higher in group C alcoholics than group F (p = .0002) or group G (p = .0002) controls; however, no A1 frequency difference was found among group A alcoholics and any of the control groups. The severity of alcoholism and the type of controls used are important determinants of DRD2 A1 allele association with alcoholism.

Potential supplementary utility of combined PFA-100 and functional von Willebrand factor testing for the laboratory assessment of desmopressin and factor concentrate therapy in von Willebrand disease

We performed a retrospective audit of cross-laboratory testing of desmopressin and factor concentrate therapy to assess the potential utility of supplementary testing using the PFA-100 with functional von Willebrand factor (VWF) activity testing. Data were evaluated for a large number of patients with von Willebrand disease of type 1, type 2A or type 2M, as well as a comparative subset of individuals with haemophilia or carriers of haemophilia. Laboratory testing comprised pre and postdesmopressin, or pre and postconcentrate, evaluation of factor VIII, VWF antigen (VWF:Ag) and VWF ristocetin cofactor activity as traditionally performed, supplemented with collagen-binding (VWF:CB) testing and PFA-100 closure times. In brief, both therapies tended to normalize VWF test parameters and closure times in individuals with type 1 von Willebrand disease, with the level of correction in closure times related to the level of normalization of VWF, particularly the VWF:CB. However, although occasional correction of closure times was observed in patients with type 2A or type 2M von Willebrand disease, these did not in general normalize PFA-100 closure times either with desmopressin or factor concentrate therapy. In these patients, improvement in closure times was more likely in those in whom VWF:CB values normalized or when VWF:CB/VWF:Ag ratios normalized. This study confirms that there is a strong relationship between the presenting levels of plasma VWF and PFA-100 closure times, and that the supplementary combination of PFA-100 and VWF:CB testing might provide added clinical utility to current broadly applied testing strategies limited primarily to VWF:Ag, VWF ristocetin cofactor and factor VIII:coagulant. Future prospective investigations are warranted to validate these relationships and to investigate their therapeutic implications.

How we use recombinant activated Factor VII in patients with haemophilia A or B complicated by inhibitors

The management of bleeds in patients with haemophilia A or B complicated by inhibitors is complex. Recombinant activated Factor VII (rFVIIa; NovoSeven RT) is an established therapy in these patients. To develop a consensus‐based guide on the practical usage of rFVIIa in haemophilia complicated by inhibitors, nine expert haemophilia specialists from Australia and New Zealand developed practice points on the usage of rFVIIa, based on their experience and supported by published data. Practice points were developed for 13 key topics: control of acute bleeding; prophylaxis; surgical prophylaxis; control of breakthrough bleeding during surgery or treatment of acute bleeds; paediatric use; use in elderly; intracranial haemorrhage; immune tolerance induction; difficult bleeds; clinical monitoring of therapy; laboratory monitoring of therapy; concomitant antifibrinolytic medication; practical dosing. Access to home therapy with rFVIIa is important in allowing patients to administer treatment early in bleed management. In adults, 90–120 μg/kg is the favoured starting dose in most settings. Initial dosing using 90–180 μg/kg is recommended for children due to the effect of age on the pharmacokinetics of rFVIIa. In the management of acute bleeds, 2‐hourly dosing is appropriate until bleeding is controlled, with concomitant antifibrinolytic medication unless contraindicated. The practice points provide guidance on the usage of rFVIIa for all clinicians involved in the management of haemophilia complicated by inhibitors.

The DRD2 A1 allele : a behavioural genetic risk factor in hepatitis C infection of persistent drug abusers

Hepatitis C is highly prevalent among intravenous drug abusers, but to date research has not widely explicated behavioural risk factors regarding acquisition of infection. The A allele of the D dopamine receptor (DRD2) gene is a hypothesized risk factor in the development of severe drug dependence and alcoholism. The present study compares the frequency of the A1 allele of the DRD2 gene among 37 patients presenting to a hepatitis clinic for treatment of hepatitis C, 23 hepatitis C‐negative drug‐abusing patients maintained on methadone and 33 non‐drug‐abusing controls. The results indicated that hepatitis C‐positive patients were significantly more likely to display the A1 allele than hepatitis C‐negative patients, who were in turn more likely to have the A1 allele than controls. Furthermore, the hepatitis C subjects manifested more persistent drug‐seeking behaviour than the other drug‐abusing group. The implications of this finding in terms of drug‐related reward are discussed. Future research should attempt to evaluate host risk factors, in order to enable more precisely targeted attempts at harm minimization.

Experience with Recombinant Factor VIla in Australia and New Zealand

Recombinant factor VIIa (rFVIIa; NovoSeventrademark) was availablefor compassionate use in Australia and New Zealand from 1991 to 1994. Over this period there were 18 treatment episodes in 9 patients, age 8-66 years, with haemophilia A and high titre inhibitors cross-reacting with porcine factor VIII. There were no significant adverse effects. Treatment with rFVIIa resulted in a successful outcome in 8 potentially life-threatening (retroperitoneal, subdural, gastro-intestinal) bleeds. Elective cystoscopy, repair of a cranial flap, yttrium synovectomy and inguinal herniotomy were performed successfully, as was surgical decompression of a flexor pollicis longus bleed. Treatment of a patient with an infected haematoma had limited success, attributed to intermittent suboptimal doses. In 2 patients, satisfactory haemostasis was achieved for multiple dental extractions; subsequent oozing was attributed to suboptimal rFVIIa and/or antifibrinolytic therapy.

Challenges in hemophilia care in Australia and New Zealand.

Abstract Background: Health and life expectancy for people with hemophilia have improved significantly in recent years, but we face new challenges, especially in the context of resource-constrained health services. Aim: This paper aims to highlight such challenges and propose practical solutions. Methods: Nine hemophilia specialists from Australia and New Zealand reached consensus on areas of greatest need for improvement in hemophilia care in these countries, based on clinical experience and published data, and agreed on how to address these. Results: Demography, optimizing treatment and assessing treatment success were identified as broad areas of challenge which included: comorbidities in ageing patients; transitioning from pediatric to adult care; equity of care for remote populations; weight-based dosing in obese patients; tailoring prophylaxis; accurate diagnosis of acute joint pain; managing chronic arthropathy; providing psychosocial support; consistency in definitions and assessment; and quantifiable outcome measures. Practice points included increased cross-specialty coordination and including psychologists and rheumatologists as part of comprehensive care teams; close collaboration between pediatric and adult centers to facilitate transition of care; systems such as telehealth that ensure continuity of care for remote populations; using pharmacokinetic data to tailor therapy; rapid and accurate diagnosis of acute joint pain; using data from bleeding registries to assess treatment effects and help with service planning; and ensuring consistency through benchmarking and standardization of HTCs. Summary: Achieving treatment equity, optimal outcomes and cost savings may be possible through investing in national governance structures, expanding the comprehensive model of care and implementing innovative solutions tailored to local needs.

How we use recombinant activated Factor VII in patients with haemophilia A or B complicated by inhibitors. Working group of hematology experts from Australia and New Zealand, Melbourne, April 2011.

The management of bleeds in patients with haemophilia A or B complicated by inhibitors is complex. Recombinant activated Factor VII (rFVIIa; NovoSeven RT) is an established therapy in these patients. To develop a consensus‐based guide on the practical usage of rFVIIa in haemophilia complicated by inhibitors, nine expert haemophilia specialists from Australia and New Zealand developed practice points on the usage of rFVIIa, based on their experience and supported by published data. Practice points were developed for 13 key topics: control of acute bleeding; prophylaxis; surgical prophylaxis; control of breakthrough bleeding during surgery or treatment of acute bleeds; paediatric use; use in elderly; intracranial haemorrhage; immune tolerance induction; difficult bleeds; clinical monitoring of therapy; laboratory monitoring of therapy; concomitant antifibrinolytic medication; practical dosing. Access to home therapy with rFVIIa is important in allowing patients to administer treatment early in bleed management. In adults, 90–120 μg/kg is the favoured starting dose in most settings. Initial dosing using 90–180 μg/kg is recommended for children due to the effect of age on the pharmacokinetics of rFVIIa. In the management of acute bleeds, 2‐hourly dosing is appropriate until bleeding is controlled, with concomitant antifibrinolytic medication unless contraindicated. The practice points provide guidance on the usage of rFVIIa for all clinicians involved in the management of haemophilia complicated by inhibitors.

A preliminary case series evaluating the safety and immediate to short-term clinical benefits of joint mobilization in hemophilic arthritis of the lower limb

Abstract Objectives: Arthritis resulting from recurrent intra-articular bleeding in individuals with hemophilia can be severely debilitating due to joint pain and stiffness with subsequent loss of mobility and function. Very limited studies have investigated the potential benefits of joint mobilization for this condition. This case series is a preliminary investigation of safety, as well as immediate and short-term clinical benefits, associated with gentle knee and ankle joint mobilization in people with hemophilic arthropathy. Methods: A single intervention of joint mobilization was applied to the affected knees and/or ankles of 16 individuals with severe or moderate hemophilia within a public hospital setting. Adverse events, as well as immediate (pain-free passive joint range, Timed Up and Go Test with maximum pain numerical rating scale) and short-term (Lower Extremity Functional Scale) effects of the intervention were evaluated with a repeated measures ANOVA. Results: There were no adverse events. An immediate significant increase was observed in pain-free passive ankle joint range of motion (p < 0.05) following the joint mobilization intervention. Discussion: The findings of this case series suggest that gentle joint mobilization techniques may be safely considered as part of a multimodal management approach for hemophilic arthropathy.

Demonstration of a novel Xp22.2 microdeletion as the cause of familial extreme skewing of X-inactivation utilizing case-parent trio SNP microarray analysis

We report a kindred referred for molecular investigation of severe hemophilia A in a young female in which extremely skewed X‐inactivation was observed in both the proband and her clinically normal mother.