Treatment of overactive bladder with modified intravesical oxybutynin chloride.

Intravesical oxybutynin chloride has been reported to be effective for overactive bladder, although sometimes the efficacy does not last long enough. To improve this deficiency, we report the effects of intravesical oxybutynin chloride with hydroxypropylcellulose (modified intravesical oxybutynin). Modified intravesical oxybutynin (5 mg/10 mL, twice a day) was administered to six overactive bladder patients for more than 1 year (two men and four women; average age, 56.5 years) who did not respond to oral anticholinergic agents and electric stimulation. Cystometography (CMG) was performed before, 2 hours, and 1 week after the start of modified intravesical oxybutynin. In addition, plasma levels of oxybutynin and its active metabolite, N-desethyl-oxybutynin (DEOB), were measured by high-performance liquid chromatography before, 1, 2, and 4 hours after the initial treatment of modified intravesical oxybutynin. CMG studies revealed that two of the six patients did not demonstrate uninhibited contractions 1 week after the treatment and that cystocapacity of before, 2 hours, and 1 week after the initial modified intravesical oxybutynin was 141.8+/-15.3, 210.0+/-35.5, and 305.0+/-21.3 mL, respectively. Plasma levels of oxybutynin and DEOB before, 1, 2, and 4 hours after the first instillation of modified intravesical oxybutynin were oxybutynin; not detected, 8.8+/-2.5, 6.8+/-1.1, 3.0+/- 1.0 ng/ml, and DEOB; not detected, 4.2+/-1.3, 6.4+/-1.7, 5.1+/- 1.4 ng/ml, respectively. No side effects were observed in any of the patients. Modified intravesical oxybutynin is an effective and safe therapy option for overactive bladder patients who do not respond to other treatments such as oral anticholinergic agents and electric stimulation.

Distribution of intrathecally administered ACNU in mongrel dogs: pharmacokinetics and quantitative autoradiographic study.

The pharmacokinetics of 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) in the cerebrospinal fluid (CSF), were determined in dogs after ventriculolumbar perfusion (VLP, n = 6), and bolus injection into the ventricle (VB, n = 2), cisterna magna (MB, n = 5), and lumbar cistern (LB, n = 3), by high-performance liquid chromatography. The VLP method introduced effective amounts of ACNU into the lumbar cistern for cell kill in vitro. That is, the areas under the time concentration curve (AUC) of ACNU in the lumbar CSF for those receiving a 1.5 mg perfusion of ACNU were 481, 791, and 520 micrograms.min/ml and those receiving a 5 mg perfusion were 1,081, 2,048, and 1,215 micrograms.min/ml, respectively. These values were superior to 3-log cell kill condition of 9L gliosarcoma and 1.5-log cell kill of HU-126 human glioma cell line. Among the groups to which 5 mg of ACNU was administered, the VLP method attained significantly higher AUC values in the lumbar CSF than MB method. Quantitative autoradiography using an imaging plate system was performed in the VLP group (n = 2), VB group (n = 1), MB group (n = 2), and LB group (n = 2) using a 10 microCi/kg [ethylene-14C] ACNU dose which is thought to be related to the alkylating activity of ACNU. The VLP method attained a stable and abundant distribution of ACNU in the neural axis from the ventricular cavity to the lumbar cistern, but the cerebral convexity surface was devoid of a significant level of ACNU. When the MB method was used, the pharmacokinetic data varied in the cisterna magna and lumbar region, and again no significant level of ACNU was detected in the ventricular cavity. With the LB method, although a rich distribution was detected in the spinal cord, the concentration decreased abruptly at the upper cervical level. The VB method was unsatisfactory for obtaining an effective amount of ACNU in the lumbar region. The research and testing to date indicate that the VLP method is the procedure of choice in the treatment of meningeal dissemination.

Clinical significance of benzoate-metabolizing capacity in patients with chronic liver disease: pharmacokinetic analysis.

Benzoate-metabolizing capacity was studied in control subjects and in liver disease patients after intra-venous loading of 15 mg benzoate per kg of body weight. In the 7 control subjects, the mean level (+/- SEM) of Cmax for serum benzoate was 104.1 +/- 6.8 micrograms/ml, AUC was 2.57 +/- 0.32 mg.min/ml, MRT was 21.5 +/- 1.5 min and T1/2 was 15.5 +/- 1.3 min. For serum hippurate, on the other hand, Tmax was 27.9 +/- 6.0 min, Cmax was 33.4 +/- 2.1 micrograms/ml, AUC was 1.96 +/- 0.13 mg.min/ml, MRT was 39.6 +/- 2.9 min and T1/2 was 30.7 +/- 2.4 min. In 12 patients with chronic hepatitis, Cmax, AUC, MRT and T1/2 for benzoate and Tmax, MRT and T1/2 for hippurate remained at control levels, but Cmax and AUC for hippurate were slightly decreased compared to controls. However, in 18 patients with liver cirrhosis, Cmax and AUC for benzoate were in the control range but MRT and T1/2 were significantly delayed (p less than 0.01 for both). Moreover, the MRT value was increased in proportion to the severity of liver disease (p less than 0.01). AUC for hippurate was not changed to any extent, and Tmax, MRT and T1/2 were slightly delayed, while Cmax was significantly reduced. AUC, MRT and T1/2 for benzoate and Tmax, MRT and T1/2 for hippurate showed significant correlation with serum albumin levels, prothrombin time and indocyanine green clearance rate. These results suggest that benzoate-metabolizing capacity, especially as indicated by the MRT value for serum benzoate, appears to be a better index than the indocyanine green clearance rate for determining hepatic functional reserve in chronic liver disease.

[Intrathecal distribution of ACNU by various modes of its administration analyzed by HPLC and autoradiography].

Various modes of administration of ACNU (nimustine hydrochloride) were tried to make clear which mode is the best method to obtain intrathecal diffuse distribution of ACNU to match the condition of killing of glioma cells (10 micrograms/ml; greater than 30 min.). Tried modes of administration included 1)bolus injection into ventricular cavity, 2)bolus injection into cisterna magna, 3)bolus injection into lumbar subarachnoid space, 4)ventriculo-lumbar perfusion, 5)chiasmatic cistern-lumbar perfusion. Used dose of ACNU was 5 mg/body for all modes of administration. ACNU level in CSF was measured by HPLC method specially developed by authors. To make clear intrathecal distribution of ACNU, autoradiography using 14C-ethylene-ACNU was studied after administration of 10 muCi/Kg of radioactive ACNU. The images were studied by image analyzer system (BAS-2,000 system developed by Fuji Film Co. Ltd). Among the modes of administration tried, ventriculo-lumbar perfusion method gave the best results in terms of lumbar, ventricular, cisterna magna, and basal cistern distribution of ACNU to match the cell kill condition experimentally ascertained. Although, bolus injection of ACNU into cisterna magna gave sufficient amount of ACNU in lumbar region, the initial level of ACNU was too high in cisterna magna, and administration of ACNU once a week for three times in a canine cisterna magna resulted in considerable deterioration of brain stem and basal structure. In addition to it, the level of ACNU in ventricular cavity was not detectable. Lumbar bolus injection resulted in also too much ACNU accumulation at the injected lumbar area, and at the cisterna magna region, ACNU was not detectable.(ABSTRACT TRUNCATED AT 250 WORDS)

The measurement of internal pressure of ampoules and its application to commercial products.

This paper reports a method for determining the internal pressures of ampoules, from the head space and the change in volume on opening, as measured by displacement of water. Using this method, internal pressures of commercial ampoules were shown to be lower than atmospheric pressure. For example, the ratio of internal pressure to atmospheric pressure in a commercial ampoule of 5 mL distilled water was 0.884 at room temperature (23 degrees C).

Rapid and simple method for the determination of nimustine hydrochloride in human blood and brain by high-performance liquid chromatography.

A simple method for the determination of nimustine hydrochloride in blood and brain by high-performance liquid chromatography was developed. A pH 4.52 buffer was used in the extraction from blood and a pH 5.0 buffer was used for brain. A pre-packed Extrelut column was used to make the extraction procedure uncomplicated. At room temperature light-resistant test-tubes were unnecessary. The lower limit of detection was 50 ng/ml for blood and 100 ng/g for brain. This method may be useful for the determination of nimustine hydrochloride in blood and brain samples from patients.

Determination of thiamazole in serum by high-performance liquid chromatography with electrochemical detection.

A simple and sensitive method for the determination of thiamazole in serum by high-performance liquid chromatography with electrochemical detection is described. Thiamazole in serum was quantified without an extraction procedure at concentrations down to 10 ng/ml. This method was applied to determine the serum concentration of the drug in two healthy volunteers given a single oral dose of 10 mg of thiamazole. The concentration of the drug reached a maximum at 3-4 h after the oral dose and two elimination phases were observed.