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.     

Specific antigenic preparations as inducers of blood leukocyte respiratory burst in chemiluminescent analysis

Functional activity of blood leukocytes of normal subjects and patients with herpesvirus infection was studied by the chemiluminescent method in vitro with specific antigenic preparations (tick-borne encephalitis vaccine, ADPT vaccine, and herpetic vaccine). Functional response of blood leukocytes to vaccine preparations is specific and depends on the antigen and metabolic status of cells of recipients. The range of chemiluminescent response of blood leukocytes is wide: no changes in tick-borne encephalitis vaccine, weak response to herpetic vaccine, and pronounced changes in functional activity in response to ADPT vaccine. Testing with different doses of specific inducers helps additionally evaluate the metabolic reserve of blood leukocytes. A pronounced response of leukocytes to specific antigenic preparations in vitro (e.g. to ADPT vaccine) prompts development of methods for predicting the reaction of nonspecific reactivity system to vaccination.     

Method of intrapulmonary therapy of lung diseases using needle jet injector

A procedure for intrapulmonary endolymphatic therapy is described. Transthoracic intrapulmonary administration of antibiotics was performed with a needle jet injector (NJI-1). Pharmacokinetics of penicillin after its transthoracic intrapulmonary administration to patients was studied. Investigation of elimination of the antibiotics after their administration with NJI-1 showed that the main part of the antibiotics (up to 70 per cent) accumulated in the endolymphatic system of the lungs. Favourable clinical effects of the antibiotic needle jet injection were observed in the patients with acute nonspecific pulmonary diseases: decreased hospitalization terms and lower total course doses of the antibiotics.     

Cyclooxygenase-2--specific inhibitors and cardiorenal function: a randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients

BACKGROUND: Arthritis and hypertension are common comorbid conditions affecting elderly adults. Use of nonsteroidal anti-inflammatory drugs in patients treated with antihypertensive medication can lead to destabilization of blood pressure control and other cardiorenal events. The potential for similar interactions with cyclooxygenase-2-specific inhibitors has not been fully explored. The authors evaluated the cardiorenal safety of two new cyclooxygenase-2-specific inhibitors, celecoxib and rofecoxib.METHODS: This study was a 6-week, randomized, parallel-group, double-blind trial in patients with osteoarthritis who were > or =65 years of age and were taking antihypertensive agents. Patients received once-daily celecoxib 200 mg or rofecoxib 25 mg. The primary endpoints were the development of edema, changes in systolic blood pressure, and changes in diastolic blood pressure as measured at any time point in the study. Measurements occurred at baseline and after 1, 2, and 6 weeks of treatment. FINDINGS: Eight hundred ten patients received study medication (celecoxib, n = 411; rofecoxib, n = 399). Nearly twice as many rofecoxib- compared with celecoxib-treated patients experienced edema (9.5% vs. 4.9%, P = 0.014). Systolic blood pressure increased significantly in 17% of rofecoxib- compared with 11% of celecoxib-treated patients (P = 0.032) at any study time point. Diastolic blood pressure increased in 2.3% of rofecoxib- compared with 1.5% of celecoxib-treated patients (P = 0.44). At week 6, the change from baseline in mean systolic blood pressure was +2.6 mmHg for rofecoxib compared with -0.5 mmHg for celecoxib (P = 0.007). CONCLUSIONS: Patients taking antihypertensive therapy and receiving cyclooxygenase-2-specific inhibitors should be monitored for the development of cardiorenal events. Patients receiving celecoxib experienced less edema and less destabilization of blood pressure control compared with those receiving rofecoxib.     

The repopulation potential of fetal liver hematopoietic stem cells in mice exceeds that of their liver adult bone marrow counterparts

Varying, limiting numbers of unseparated or purified cells (Ly-5.1), either from 14.5-day-old fetal liver (FL) or from adult bone marrow (BM) were coinjected with 10(5) unseparated BM cells (Ly-5.2) into lethally irradiated adult C57B1/6 recipients (Ly-5.2). The kinetics of donor cell repopulation of the lymphoid and myeloid compartments by Ly- 5.1+ donor hematopoietic stem cells (ie, competitive repopulation units [CRU]) were monitored at various time points after the transplantation by Ly-5 analysis of the peripheral white blood cells (WBC). Recipients that had received on average less than 2 adult BM or FL CRU did not show a significant difference in the level of donor-reconstitution when analyzed 4 weeks after the transplantation, However, at 8 and 16 weeks, the FL recipients showed a significantly higher percentage of donor- derived nucleated peripheral blood cells than did the recipients of adult BM cells. Analysis of individual mice showed that approximately 80% of the recipients of FL CRU showed an increase in mature WBC output between 4 and 8 weeks after transplantation, whereas this occurred in less than 40% in the recipients of adult BM cells. In addition to this effect on mature cell output, the cellularity of the reconstituted BM was significantly higher in recipients of FL CRU than in recipients of adult BM CRU, even at 7 to 9 months after transplantation, which is consistent with an increased clonal expansion of FL CRU. When marrow cells from primary recipients of FL CRU were injected into secondary recipients, a significantly higher percentage of these mice showed donor-reconstitution of their lymphoid and myeloid compartments (P < .01) and to a greater extent (P < .008) as compared with mice that had received marrow cells from primary recipients of similar numbers of adult BM CRU. Taken together, these results show that individual FL CRU exhibit a greater proliferative activity in vivo than similar cells from adult BM that is accompanied by a greater production of daughter CRU.     

Treatment of patients with acute lung abscesses by intrapulmonary injections of antibiotics and endobronchial administration of autologous macrophages

The stay in hospital was compared for patients with acute abscesses of the lungs treated according to the standard scheme and a new method of intrapulmonary antibiotic injections and endobronchial administration of actologous macrophages. The proposed treatment proved more efficient, as it resulted in a 12.1 +/- 0.3 day decrease in the duration of hospital stay versus control group on conventional regime.