Pharmacokinetics and effects of intravesical oxybutynin on the paediatric neurogenic bladder.

OBJECTIVE: To evaluate the pharmacokinetics of both oxybutynin and its active metabolite, N-desethyl oxybutynin (NDO), when the drug is instilled directly into the bladder in children with myelodysplasia and neurogenic bladder disturbance, in whom it may improve continence and decrease the risk of upper urinary tract deterioration. PATIENTS AND METHODS: The study comprised 13 children (five girls and eight boys, mean age 9.3 years, range 1-15) with neurogenic bladders who were treated using clean intermittent catheterization and intravesical instillation of a sterile, pharmacy-produced solution of oxybutynin. Steady-state minimum plasma levels of oxybutynin and NDO, together with their effect on urodynamic variables and incontinence, were evaluated. The dose (0.04-0.17 mg/kg, mean 0.1 mg/kg) was instilled twice daily. RESULTS: The effects of the drug on incontinence and urodynamic variables were pronounced, improving both in most cases. Minimum plasma levels were < 0.3-7.2 ng/mL for oxybutynin and 0.8-14 ng/mL for NDO. The ratio of oxybutynin to NDO was 0.29-0.83 (mean 0.47). CONCLUSION: There was no clear relationship between minimum plasma levels of the drug or NDO and their clinical effects; however, the combination of oxybutynin and NDO seemed to be more strongly correlated with the clinical effects.

GLP-1 tablet in type 2 diabetes in fasting and postprandial conditions.

OBJECTIVE: To examine the absorption of glucagon-like peptide (GLP)-1(7-36) amide from the buccal mucosa of type 2 diabetic patients. Previously, the effects of the peptide have been studied following intravenous and subcutaneous injection. Now, a mucoadhesive, biodegradable buccal GLP-1 tablet (9 mm) containing 119 nmol has been developed as a possible alternative to injection. RESEARCH DESIGN AND METHODS: A total of 10 type 2 diabetic patients received a single tablet under fasting conditions and before a standard meal in this randomized placebo-controlled study. RESULTS: The mean peak GLP-1 concentration was 125.1 pmol/l and occurred 30 min after application. The mean placebo-adjusted area under the curve was 5,334 min pmol/l, consistent with a relative bioavailability of 6% vs. intravenous injection and 42% vs. subcutaneous injection. The half-life of total peptide activity after buccal administration was 17 min. The placebo-adjusted glucose concentrations decreased by 1.4 mmol/l in fasting experiments and by 4.2 mmol/l after a standard mixed meal. In the fasting state at 30 min, plasma insulin increased by 185% and glucagon decreased by 20%, consistent with the increase in plasma GLP-1 concentrations. The peptide exerted a significant insulinotropic effect during meals (calculated as an insulinogenic index, 0-120 min; 84.1 vs. 45.7 in placebo experiments). CONCLUSIONS: Potentially therapeutic plasma levels of GLP-1 were achieved after administration of a single buccal tablet in type 2 diabetic patients. The peptide had a marked glucose-lowering effect during the first 2 h. This new GLP-1 tablet may become a feasible alternative treatment for type 2 diabetic patients, although a more prolonged pharmacokinetic profile is required.

Potential therapeutic levels of glucagon-like peptide I achieved in humans by a buccal tablet.

OBJECTIVE: Glucagon-like peptide I(7-36) (GLP-I) amide, an endogenous incretin, has been identified as a potential adjunct to the treatment of NIDDM and has been studied following intravenous and subcutaneous injection. A mucoadhesive buccal GLP-I tablet containing 119 nmol has been developed to provide transmucosal absorption as a possible alternative to injection treatment. RESEARCH DESIGN AND METHODS: Eight healthy volunteers received a single tablet under fasting conditions in this randomized double-blind placebo-controlled study. A total GLP-I immunoreactivity was measured using COOH-terminal radioimmunoassay (RIA) (total peptide activity) and NH2-terminal RIA (active, nondegraded peptide). RESULTS: The mean (+/- SE) peak GLP-I concentration was 117 +/- 19 pmol/l and occurred 30 +/- 4 min after application. The mean placebo-adjusted area under curve was 8,145 +/- 873 pmol.min-1.l-1, consistent with a relative bioavailability of 7% versus intravenous injection and 47% versus subcutaneous injection. The levels of active peptide increased in parallel with total GLP-I. Half-life of peptide activity after buccal administration was 27 and 24 min measured with COOH-terminal and NH2-terminal RIA, respectively. Placebo adjusted insulin concentrations increased to a peak of 252 +/- 57 pmol/l, glucose decreased 1.4 +/- 0.2 mmo/l, and glucagon decreased 17 +/- 3 ng/l, consistent with the increase in plasma GLP-I concentrations. CONCLUSIONS: Therapeutic plasma levels of GLP-I in humans were achieved after a single buccal tablet. No increased degradation of GLP-I was found in the buccal mucosa compared to subcutaneous tissue. This alternative treatment form may be feasible in in the future for NIDDM.

Successful treatment of hepatosplenic candidiasis with a liposomal amphotericin B preparation.

The case of a granulocytopenic patient with acute undifferentiated leukaemia and hepatosplenic candidiasis who was refractory to conventional deoxycholate amphotericin B (AmpB) and 5-flucytosine therapy is reported. He experienced severe AmpB-related side-effects, and was subsequently successfully treated with a pharmaceutical preparation of AmpB (5.7 g) entrapped in sonicated liposomes, composed of lecithin, cholesterol and stearylamine in a molar ratio of 4:3:1. Three months later, during maintenance chemotherapy, liposomal AmpB (5.1 g) was reinstituted due to the finding of biopsies positive for Candida albicans at bronchoscopy. After healing of the patient's fungal infection a left upper lobe resection was performed, which showed advanced fibrosis with signs of inflammation, but no evidence of fungal disease. Since no acute side-effects and only moderate hypokalaemia were observed, it appears that liposomal AmpB is superior to conventional AmpB treatment in granulocytopenic patients with hepatosplenic candidiasis and unbearable therapy-related side-effects.

Studies on the evaluation of preservative efficacy--II. The determination of antimicrobial characteristics of benzylalcohol.

A successful kinetic approach to the screening of preservation efficacy of benzylalcohol--a neutral-type preservative--is described. The D-value, activation energy (Ea), temperature coefficient (Q10) and concentration exponent (n) were used as parameters in determining the influence of different factors on the efficacy of benzylalcohol. Factors, such as the pH of the solution, temperature and concentration of the preservative were investigated. The study was carried out using five micro-organisms: Aspergillus niger, Candida albicans, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus.