[Association of gene polymorphisms DRD3 rs6280, COMT rs4680 and HTR2A rs7322347 with schizophrenia]. / Assotsiatsiya geneticheskikh polimorfizmov rs6280 gena DRD3, rs4680 gena COMT, rs7322347 gena HTR2A s shizofreniei.

OBJECTIVE: To check the association of genetic polymorphisms rs6280 of the DRD3 gene, rs4680 of the COMT gene, rs7322347 of the HTR2A gene with schizophrenia. MATERIAL AND METHODS: The sample included 300 inpatients with paranoid schizophrenia. Inclusion criteria: age 18-50 years, established diagnosis «Schizophrenia, paranoid form¼, duration of psychiatric disorders not less than 5 years. The healthy control group consisted of 290 subjects. The association between polymorphisms and the study groups was assessed by logistic regression. RESULTS: The CC genotype of the rs6280 polymorphism is associated with schizophrenia (OR 3.37 (1.50; 8.03)). The TT genotype of the rs7322347 polymorphism is associated with controls (OR 1.83 (1.25; 2.68)). CONCLUSION: These analyses confirmed the hypothesis that the genetic polymorphisms rs7322347 of the HTR2A gene (p=0.006) and rs6280 of the DRD3 gene (p=0.004) were associated with the disease. The hypothesis of an association of the rs4680 polymorphism of the COMT gene could not be confirmed.

Quantitative CT analysis using functional imaging is superior in describing disease progression in idiopathic pulmonary fibrosis compared to forced vital capacity.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is chronic fibrosing pneumonia with an unpredictable natural disease history. Functional respiratory imaging (FRI) has potential to better characterize this disease. The aim of this study was to identify FRI parameters, which predict FVC decline in patients with IPF. METHODS: An IPF-cohort (treated with pamrevlumab for 48 weeks) was retrospectively studied using FRI. Serial CT's were compared from 66 subjects. Post-hoc analysis was performed using FRI, FVC and mixed effects models. RESULTS: Lung volumes, determined by FRI, correlated with FVC (lower lung volumes with lower FVC) (R2 = 0.61, p < 0.001). A negative correlation was observed between specific image based airway radius (siRADaw) at total lung capacity (TLC) and FVC (R2 = 0.18, p < 0.001). Changes in FVC correlated significantly with changes in lung volumes (R2 = 0.18, p < 0.001) and siRADaw (R2 = 0.15, p = 0.002) at week 24 and 48, with siRADaw being more sensitive to change than FVC. Loss in lobe volumes (R2 = 0.33, p < 0.001), increasing fibrotic tissue (R2 = 0.33, p < 0.001) and airway radius (R2 = 0.28, p < 0.001) at TLC correlated with changes in FVC but these changes already occur in the lower lobes when FVC is still considered normal. CONCLUSION: This study indicates that FRI is a superior tool than FVC in capturing of early and clinically relevant, disease progression in a regional manner.

[The effect of biguanide derivatives on oxidative stress in rats with hyperglycemia]. / Vozdeistvie biguanidinovykh proizvodnykh na razvitie oksidativnogo stressa pri giperglikemii u krys.

The effect of the synthetic biguanide derivatives N-[imino(1-piperidinyl)methyl]guanidine (NIPMG) and 1,3-dimethyl-5-[(carbamimidamidomethanimidoil) amino]benzoyl-1,3dicarboxylate (DCB) on the degree of proteins oxidative modification (POM) and the DNA fragmentation, the content of the lipid peroxidation primary products - conjugated dienes (CD), and the activity of glutathione antioxidant system in the liver and heart of rats with experimental hyperglycemia was investigated. Administration of the biguanides (15.0 mg/kg) to hypoglycemic rats promoted reduction of the free radical processes intensity in the studied tissues. Data about CD and POM level changes in hyperglycemic rats treated by NIPMG and DKB correlate with the results of DNA fragmentation degree evaluation. At the same time, the activity of antioxidant enzymes (glutathione peroxidase and glutathione reductase), and the reduced glutathione content in the liver and heart of rats changed toward control values. For metformin, which was used as a comparison drug, changes in the studied parameters in the same direction were also found. These results indicate the ability of the tested biguanide derivatives to exhibit a positive regulatory effect on free radical homeostasis, reducing the degree of oxidative stress at this pathology.

Psychometric evaluation of a patient-reported symptom assessment tool for adults with haemophilia (the HAEMO-SYM).

In patients with haemophilia, repeated bleeding events result in significant comorbid conditions that can degrade health-related quality of life. Clinician-reported symptom measures are available for use in patients with haemophilia A or B; however, there has not been a validated patient-reported symptom evaluation instrument available for haemophilia to date. The objective of this study was to develop and evaluate a self-report instrument, the HAEMO-SYM, for measuring symptom severity in patients with haemophilia. Eighty-four haemophilic subjects from Canada and the USA were enrolled and completed the HAEMO-SYM, SF-36, and Health Assessment Questionnaire-Functional Disability Index (HAQ-FDI). Four-week reproducibility was evaluated in 72 stable subjects. Construct validity was assessed by correlating subscale scores with the SF-36, HAQ-FDI, a coping questionnaire and clinical scores. The final 17-item HAEMO-SYM has two subscales: pain and bleeds. Internal consistency reliability was good (Cronbach's alphas, 0.86-0.94) and test-retest reliability was good (Intraclass Correlation Coefficients, 0.75-0.94). HAEMO-SYM subscale scores were significantly correlated with SF-36 scores (P < 0.05 for all except HAEMO-SYM Pain and SF-36 Mental Health), HAQ-FDI scores (P < 0.05 for all but HAEMO-SYM Bleeds with HAQ-FDI Hygiene and Reach), Gilbert scale (P < 0.01), coping (P < 0.05) and global pain (P < 0.001). Mean HAEMO-SYM scores varied significantly in groups defined by severity, HIV status and treatment regimen. Greater symptom severity was associated with more severe disease, HIV-positive status and prophylaxis treatment. The results of this study suggest that the HAEMO-SYM, a haemophilia-specific symptom severity instrument, has good reliability and provides evidence that supports construct validity in patients with haemophilia.

Stability, efficacy, and safety of continuously infused sucrose-formulated recombinant factor VIII (rFVIII-FS) during surgery in patients with severe haemophilia.

Bolus injection (BI) of sucrose-formulated recombinant factor VIII (rFVIII-FS) is an approved treatment for haemophilia patients undergoing major surgery. Continuous infusion (CI) during surgery has potential benefits by providing steady administration of replacement factor to the patient, avoiding high peaks and low troughs. We tested the stability of rFVIII-FS under CI conditions and conducted a single-centre, open-label, phase III study to evaluate the efficacy and safety of CI using rFVIII-FS in haemophilia A patients undergoing surgery. Patients received bolus rFVIII-FS to achieve >or=80% FVIII levels 30-60 min presurgery, followed by CI of rFVIII-FS at a rate calculated to maintain haemostatic factor levels until days 8-10 post surgery. The rate of infusion was adjusted according to daily calculations derived from the actual clearance. The stability of rFVIII-FS was found to be appropriate for CI for 7 days under the same conditions as clinical settings. Fourteen patients (mean age 37.8 years) receiving on-demand FVIII treatment without a history of inhibitors underwent 15 surgical procedures including joint replacements, synovectomies, multiple tooth extractions, and cholecystectomy. Bleeding was similar to that observed in non-haemophilia patients undergoing similar operations in the same department. Haemostasis during surgery was considered by the attending surgeons as 'excellent' or 'good' in all cases; study investigators rated all 15 cases as 'excellent' overall. There were no adverse events, including inhibitor formation, related to rFVIII-FS. rFVIII-FS was found to be suitable for use in CI in haemophilia A patients undergoing major surgery.

Cross-cultural development and psychometric evaluation of a patient-reported health-related quality of life questionnaire for adults with haemophilia.

Co-morbidities of haemophilia, such as arthropathy and blood-borne infections, can adversely affect the quality of life of adult patients with haemophilia. The purpose of this study was to develop and validate a haemophilia-specific health-related quality of life questionnaire for adults (HAEMO-QoL-A). Subjects with varying severities of haemophilia completed the HAEMO-QoL-A at baseline and 4 weeks. Other assessments included the SF-36 and Health Assessment Questionnaire - Functional Disability Index (HAQ-FDI). Two-hundred and twenty-one participants completed the 41-item HAEMO-QoL-A covering six domains (Physical Functioning, Role Functioning, Worry, Consequences of Bleeding, Emotional Impact and Treatment Concerns) and four independent items. Internal consistency was good-to-excellent (Cronbach's alpha-range: 0.75-0.95). Test-retest reproducibility was good, with intraclass correlation coefficients >0.80 except for the Emotional Impact domain (0.79). Concurrent validity between the HAEMO-QoL-A total and subscale scores and all SF-36 subscale scores were generally good (correlations range: 0.13-0.87). Significant correlations between the HAEMO-QoL-A and the HAQ-FDI ranged from -0.14 to -0.69. There were non-significant correlations with the Treatment Concerns subscale and with the Worry subscale. The HAEMO-QoL-A discriminated significantly between adults with haemophilia by severity and HIV status. The Physical Functioning subscale discriminated between patients receiving prophylactic or on-demand therapy. The HAEMO-QoL-A is a valid and reliable instrument for assessing quality of life in haemophilia patients.

Safety and pharmacokinetics of a recombinant factor VIII with pegylated liposomes in severe hemophilia A.

BACKGROUND: BAY 79-4980 is a sucrose-formulated recombinant factor VIII (rFVIII-FS) combined with pegylated liposomes to prolong activity. OBJECTIVES: To investigate the safety, tolerability, bioavailability, pharmacokinetics and pharmacodynamics of a single administration of BAY 79-4980 compared with standard rFVIII-FS in patients with severe hemophilia A. METHODS: This randomized, double-blind study consisted of two crossover substudies comparing two doses of liposomal rFVIII-FS with standard rFVIII-FS. Males (12-60 years) with severe hemophilia A received a single infusion of standard rFVIII-FS (35 IU kg(-1)) followed by a single infusion of BAY 79-4980 (13 or 22 mg kg(-1) pegylated liposomes) or vice versa, with 12 observation days and a 2-day washout period between treatments. RESULTS: Twenty-six subjects were enrolled at two centers. No serious adverse events were reported. Transient increases in complement C3a, but not CH50, were seen in subjects receiving both the low- and high-liposome-dose BAY 79-4980. Mild transient elevations of total and low-density lipoprotein cholesterol were observed. There were no clinically significant differences in clotting or laboratory parameters or in pharmacokinetic behavior between BAY 79-4980 and standard rFVIII-FS. The number of subjects with spontaneous bleeds on days 1-14 postinfusion was low, and group comparisons were inconclusive. CONCLUSIONS: Single-dose administration of BAY 79-4980 is well tolerated in patients with severe hemophilia A. Plasma pharmacokinetics of FVIII cannot explain the extended protection from bleeding observed previously with BAY 79-4980. Further studies of efficacy and long-term safety of chronic administration are planned.

Health-related quality of life assessment in adult haemophilia patients: a systematic review and evaluation of instruments.

The objective of this study was to review and evaluate the performance of health-related quality of life (HRQL) and other health status measures used in studies of adult haemophilia and provide recommendations for future research. A systematic literature review was performed to identify HRQL and health status measures used in haemophilia. Literature was identified using medical databases, Internet and manual searches. The search was restricted to articles published in English since 1986. Ninety-six abstracts were located; 19 relevant articles were selected for detailed review. Three main types of HRQL measures were identified: generic psychometric-based HRQL (SF-36 and SF-12), utility-based HRQL [EQ-5D and Health Utilities Index (HUI)], and musculoskeletal-specific HRQL (Arthritis Impact Measurement Scale 2, AIMS 2) instruments. No patient-rated haemophilia-specific HRQL instrument was found. The SF-36, the EQ-5D, and the HUI were able to discriminate haemophilia patient subgroups with respect to disease severity and HIV comorbidity status. Sixteen additional scales were identified that were used to measure the different aspects of physical, psychological, and social functioning of patients. There were no clinical studies of haemophilia carried out that employed HRQL instruments, thus responsiveness of these instruments could not be evaluated. The variety of instruments used in haemophilia studies highlights the need for a tool that can capture the full impact of haemophilia and its treatment on patients' HRQL. Developing such a tool poses the unique challenge of accounting for common comorbidities, such as HIV and chronic hepatitis that may have a greater HRQL impact than the underlying disease.

Results of an orthopaedic survey in young patients with severe haemophilia in Spain.

This paper outlines the results obtained in a cross-sectional study of a group of young patients with severe haemophilia A and B. The primary aim of the study was to ascertain the level of orthopaedic complications in the group, the effects that these complications have on quality of life, and the medical resources used on these patients. The secondary aim was to relate their current orthopaedic state to the type of treatment received before the study. The study was carried out in 11 hospitals in Spain, where 70 severe haemophilia patients (factor VIII [FVIII] < 2%), with an average age of 21.6 and a median age of 22, and no inhibitors, were monitored. The percentage of patients suffering from articular complaints was 84.3% and 85.7% according to the Gilbert and Petterson scales, respectively. Furthermore, pain was reported in 16.1% of joints, most frequently in ankles. Using the SF-36 Health Survey, patients were observed to have a poorer quality of life relative to healthy controls. Despite high levels of both the coagulant factor given to patients and the financial resources dedicated to their treatment, the type of treatment (on demand and/or as secondary prophylaxis) provided to the young adults was found to be incapable of preventing haemophilic arthropathy and subsequent negative quality of life consequences.

Single-dose ciprofloxacin versus 3 days of norfloxacin in uncomplicated urinary tract infections in women.

A double-blind, randomized controlled study to evaluate the efficacy and safety of a single dose of 500 mg of ciprofloxacin versus 3 days 400 mg twice-daily of norfloxacin in uncomplicated urinary tract infection in women was designed. Patients underwent four visits: baseline, and at 3, 7 and 28 days. The main efficacy variables were clinical and microbiological outcome at day 7. Analyses on both valid patients and intention-to-treat populations were performed. Two hundred and twenty-six patients (114 receiving ciprofloxacin and 112 receiving norfloxacin) were considered valid for efficacy evaluation. Bacteriologic cure was 91.2% in the ciprofloxacin group and 91.9% in the norfloxacin group. Clinical resolution was 91.2 and 93.8%, respectively. Both treatments were equally efficacious (P = 0.016).

Efficacy of a sucrose-formulated recombinant factor VIII used for 22 surgical procedures in patients with severe haemophilia A.

A sucrose-formulated recombinant FVIII (rFVIII-SF) was investigated under clinical trial conditions during surgical procedures in previously treated patients (PTPs). Fifteen PTPs with severe haemophilia A (FVIII < or = 1%) underwent 22 surgical procedures. The procedures performed cover a spectrum from minor to major surgery. Haemostatic outcome was assessed by the investigators to be excellent in 16 procedures and good in the remaining six procedures. It is concluded that rFVIII-SF is efficacious and safe in severe haemophilia A patients undergoing minor or major surgery.

Sucrose formulated recombinant human antihemophilic factor VIII is safe and efficacious for treatment of hemophilia A in home therapy--International Kogenate-FS Study Group.

To add an increased level of safety to antihemophilic factor replacement therapy, a full-length, recombinant Factor VIII (rFVIII) product has been developed without human-derived plasma proteins during purification and formulation and using an additional solvent/detergent viral inactivation step. This first clinical trial of a sucrose-formulated full-length rFVIII (rFVIII-FS) was conducted in previously treated patients (> or = 100 prior exposure days) with severe (<2% FVIII) hemophilia A in North America (NA) and Europe (EU). Pharmacokinetic profiles for rFVIII-FS were compared with those of currently licensed rFVIII product (Kogenate) in 35 patients. Safety and efficacy during home therapy were evaluated in 71 patients. The new formulation displayed a pharmacokinetic profile similar to that of rFVIII. Patients on home therapy received a cumulative total of 11,867 exposure days, 12,546 infusions, and 22,443,694 IU of rFVIII-FS. Of 2585 bleeds, 93.5% were treated with 1-2 infusions and 80.5% of responses were rated as excellent or good. No evidence of de novo inhibitor formation was observed. Only 0.27% of infusions were associated with any drug-related adverse event. Except for an episode of intermittent chest pain with palpitations which ceased after treatment with analgesics, associated adverse events were mild or moderate. Overall, rFVIII-FS provided excellent hemostatic control, was well-tolerated, and caused no significant adverse effects, thus demonstrating safety and efficacy for treatment of bleeds in patients with hemophilia A.

The orthopaedic status of severe haemophiliacs in Spain.

This paper provides an outline of the results obtained in a cross-sectional study conducted primarily with the aim of ascertaining orthopaedic complications in a group of young severe A and B haemophiliacs, the effects which these complications have on the medical resources used with these patients, and the impact of severe haemophilia on their quality of life. Its secondary aim was to link their current orthopaedic status to the type of treatment they had received prior to the study. Eleven Spanish hospitals took part in this study, monitoring 70 severe haemophiliacs (FVIII:C <2%) without inhibitors who had a mean age of 21.6 years and a median age of 22. Retrospective data collected from birth to the conclusion of the study were used and, for certain variables, data from the last 12 months. The type of treatment given had been on-demand treatment, together with prophylaxis of variable time periods, which in 32 cases (45.7%) were prolonged (>6 months). In 40 cases (57.1%) the patients underwent one or more periods of prophylaxis. Thirty-three patients (47.8%) had over 1000 days of administration of factors VIII and IX. The analysis of the total study group reveal an average of 348 bleeding episodes per patient. The findings of this study revealed that 84.3% of these patients suffer from articular complaints on the Gilbert scale, and 85.7% on the Pettersson scale. In addition, pain was reported in 16.1% of the joints, the most frequently affected being the ankle joints. Twenty-six patients (37%) had undergone orthopaedic surgery from the time of birth to the conclusion of the study. The quality of life of the severe haemophiliacs reviewed seems to have been affected. During the last 12 months, there were 216 outpatient haematological visits and 176 orthopaedic-rehabilitation visits, as well as 12 radiological explorations and two hospitalizations. During these 12 months, medical expenditure totalled $55 473 per patient per year, the most important item being factor concentrates VIII/IX ($54 119 per patient per year). The type of treatment given to these patients (on-demand and/or as secondary prophylaxis) was found to be incapable of preventing haemophilic arthropathy or guaranteeing an acceptable quality of life, although both the administration of coagulant factor concentrate to such patients and the financial resources dedicated to their treatment was very high. Consequently, a strategic change is to be considered for the prevention of haemophilic arthropathy, based on the introduction of replacement treatment involving continuous administration of factors VIII and IX in primary prophylaxis regimens from the first years of life.

Pharmacokinetics of triflusal and its main metabolite HTB in healthy subjects following a single oral dose.

The pharmacokinetic profile of triflusal (2-acetoxy-4-trifluoromethyl benzoic acid) and its main metabolite HTB (2-hydroxy-4-trifluoromethyl benzoic acid) has been studied in 8 healthy subjects (4 males and 4 females), after a single oral dose of 900 mg of triflusal. Plasma concentrations were determined by a sensitive HPLC method. Sampling was performed up to 120 h post medication. Triflusal displays a Cmax of 11.6 +/- 1.7 micrograms/ml and a tmax of 0.88 +/- 0.26 h. The elimination half-life (t1/2) was 0.55 h with a clearance (Cl/F) of 45.5 +/- 11.0 l/h. HTB kinetic parameters were: tmax 4.96 +/- 1.37 h and Cmax 92.7 +/- 17.1 micrograms/ml, with an elimination t1/2 of 34.3 +/- 5.3 and a clearance of 0.18 +/- 0.04 l/h. The results obtained in this study show a rapid absorption of triflusal and an immediate biotransformation into HTB. The long lasting platelet anti-aggregatory effect of triflusal in spite of its short t1/2, could be explained by the irreversible inhibition of platelet cyclo-oxygenase and the sustained levels of HTB, which also possess anti-aggregant properties.

[Frequency and duration of minor epileptic seizures during treatment while undergoing multiple-day telemetric EEG monitoring]. / Chastota i dlitel'nost' malykh épilepticheskikh pripadkov vo vremia lecheniia pod kontrolem mnogosutochnoi telemetricheskoi registratsii EEG.

The article presents statistical data on the time characteristics of petit mal epilepsy registered in the course of prolonged telemetric EEG recording in 3 epileptic patients in the process of treatment. The time-course of the frequency and also the average and total daily length of attacks during sleep or wakefulness are analyzed. The pattern of the genesis of paroxysms was found to be different: paroxysms were more likely both to arise and stop in sleep than in wakefulness. Nocturnal attacks were noted to be more resistant to therapeutic measures as compared with diurnal ones.