Pharmacokinetic profile of recombinant human N-acetylgalactosamine 4-sulphatase enzyme replacement therapy in patients with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome): a phase I/II study

AIM: Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome) is a lysosomal storage disease caused by a deficiency of the enzyme-N-acetylgalactosamine 4-sulphatase (ASB). Enzyme replacement therapy with recombinant human ASB (rhASB) has been studied in a randomized, double-blind, two-dose (0.2 and 1.0 mg/kg/week) phase I/II study (n = 7) followed by an open-label single dose (1.0 mg/kg/week) extension study. We report the pharmacokinetic profile of rhASB and the impact of antibody development. METHODS: Pharmacokinetic analysis was performed at weeks 1, 2, 12, 24, 83, 84 and 96. Infusions were administered over 4 hours using a ramp-up protocol. Plasma ASB and rhASB antibody concentrations and urine glycosaminoglycan (GAG) concentrations were determined. RESULTS: The area under the plasma concentration-time curve (AUC(0-t)) for the high-dose group increased from week 1 to week 2, but remained unchanged at weeks 12 and 24. A large difference in mean AUC(0-t) was observed between the low- and high-dose groups. Pharmacokinetic results at weeks 83, 84 and 96 were similar to those at week 24. Six patients developed antibodies to rhASB. One patient developed high antibody levels in combination with a high ASB concentration, while a second patient also developed high antibody levels with undetectable ASB concentrations. Antibodies from the second patient blocked detection of ASB. By week 72, antibody levels had decreased in all patients. The high-dose rhASB produced a more rapid and greater percentage reduction in urinary GAG concentrations than the lower dose (70% versus 55% at 24 weeks). Antibody levels did not appear to influence urinary GAG concentrations. CONCLUSION: Pharmacokinetic parameters appear to be independent of the duration of treatment and are not linear between the 0.2 and 1.0 mg/kg/week doses. Antibodies to rhASB develop in most patients, but their concentration decreases over time. Antibody formation may influence pharmacokinetic parameters during the early phases of treatment, although it appears to have limited impact on biochemical efficacy.     

Dynamics of heart rate variability in ischemic heart disease patients after coronary artery bypass grafting

AIM: To study dynamics of 24-hour heart rate variability (HRV) after coronary artery bypass grafting (CABG) and to elucidate relationship between HRV dynamics and clinical course of the disease. METHODS AND MATERIAL: A novel methodological approach to evaluation of HRV based on measurement of mean weighted rhythmogram variation (MWRV) was implemented.Ninety patients were studied before CABG. Then HRV was assessed in 2 weeks (61 patients), 2 (45 patients), 6 (24 patients)and 12 (33 patients) months after surgery. RESULTS: At all study points HRV was lower in CHD patients than in healthy persons. Substantial lowering of average MWRV 2 weeks after surgery was followed by return to preoperative level by the end of 2 months, leveling off until 6 months and some decline by the end of a year. Individual changes of MWRV were assessed in 29 patients in whom HRV was evaluated at 5 or 4 study points. Three types of MWRV changes were distinguished: type 1 - "normal" dynamics (9 patients) - elevation of MWRV 2, 6 and 12 months; type 2 (10 patients) - elevation of MWRV after 2 and 6 months with subsequent lowering by the end of 1 year; type 3 (10 patients) - lowering of MWRV In 2 and/or 6 months. The following relationships between MWRV changes and clinical course after surgery were observed: there were no complications among patients with type 1 MWRV dynamics; 8 of 10 type 2 patients had signs of heart failure, or blood pressure elevation, or recurrence of angina by the end of 1 year: among 10 type 3 patients 6 experienced various complications. Recurrence of angina at various intervals after CABG occurred in 5 patients and in all it was associated with MWRV decrease. CONCLUSION: Pronounced decrease of MWRV between 2 and 12 months after CABG is associated with worse clinical course and its detection should trigger additional investigation and care of a patient.     

Role of phagocytosis activation in the mechanism of therapeutic effect of medical ozone in patients with sluggish purulent inflammations of maxillofacial soft tissues

Sixty-three patients with local sluggish suppurative inflammations of maxillofacial soft tissues were examined. Medical ozone was added to the treatment protocols of 30 of these patients. Before treatment peripheral blood leukocyte phagocytic activity was decreased in 54 patients, which corresponded to clinical form of a sluggish inflammation. Traditional therapy did not appreciably change the level of phagocytosis. Addition of medical ozone exposure to therapy promoted normalization of leukocyte phagocytic activity and accelerated liquidation of inflammation.     

Dynamics of immune status in patients with phlegmons of the maxillofacial area during endolymphatic antibiotic therapy]

Studies of immunotropic effects of ampicillin, gentamicin sulfate, lincomycin, and rifampicin SV used in endolymphatic therapy of patients with maxillofacial phlegmons demonstrated a pronounced immunomodulating effect of rifampicin SV in polygluquine. The immunomodulating effect of lincomycin was lower, and that of ampicillin virtually null. Gentamicin sulfate suppressed some parameters of the immune status.     

Detection of natural anti-angiotensin converting enzyme antibodies in human serum using immunoenzyme technique

Solid-phase enzyme immunoassay (EIA) was developed for detecting natural antibodies to angiotensine-converting enzyme (ACE). Optimal conditions for detecting natural anti-ACE by EIA in the sera of donors and patients with disorders of arterial pressure are selected. The findings indicate that the level of natural anti-ACE is normally constant, while in the patients it is increased in 50% cases.     

Thirteen-year prospective study between fish consumption,long-chain N-3 fatty acids intakes and cognitive function

Objectives  

Because of their structural, anti-inflammatory and antithrombic properties, longchain n-3 fatty acids may be key factors in the aging process. We sought to elucidate the association between intake of long-chain n-3 fatty acids and/or fish and cognitive function evaluated 13 years after dietary assessment.     

Consumption of dairy products and cognitive functioning: Findings from the SU.VI.MAX 2 study

Objectives

Research concerning the link between dairy product intake and cognition is scant while experimental studies suggest links through various biological mechanisms. This study’s objective was to examine the cross-time associations of total and specific dairy product consumption with cognitive performance in aging adults. We also explored compliance with dairy intake recommendations in France.

Design

The study was based on the «Supplémentation en Vitamines et Minéraux Antioxydants» randomized trial (SU.VI.MAX, 1994-2002) and the SU.VI.MAX 2 observational follow-up study (2007-2009).

Setting

A general-population cohort in France.

Participants

N=3,076 participants included in both the SU.VI.MAX and SU.VI.MAX 2 studies.

Measurements

Dairy product consumption was estimated using repeated 24h records (1994-1996; mean=10 records, SD=3). Cognitive performance was assessed by neuropsychologists after an average of 13 years post-baseline via a battery of six validated tests. Mean age at the time of the cognitive function evaluation was 65.5 (SD=4.6) years. Principal component analysis revealed factors for verbal memory and working memory. Associations of energy-adjusted dairy product consumption and compliance with the respective dietary guidelines with subsequent cognitive impairment were examined using ANCOVA, providing mean differences (95% confidence intervals, CI) according to tertiles (T), adjusted for confounders including overall dietary patterns.

Results

Total dairy product consumption was not associated with cognitive function. However, milk intake was negatively associated with verbal memory performance: mean difference T3 versus T1= -0.99 (-1.83, -0.15). Among women, consuming more than the recommended amount of dairy was negatively associated with working memory performance: excess versus adequate = -1.52 (-2.93, -0.11).

Conclusion

Our results indicate that dairy products consumption and especially compliance with dietary guidelines regarding dairy product intake are differentially associated with performance in specific cognitive domains after a comprehensive adjustment for lifestyle factors, health status markers and dietary patterns. Further longitudinal research is needed given the limited data available.