The pharmacokinetics of a single oral dose of mycophenolate mofetil in patients with varying degrees of renal function.

BACKGROUND: The purpose of this study was to determine the effect of renal function on the elimination and disposition of mycophenolic acid and its glucuronide metabolite (MPAG) after oral administration of the pro-drug mycophenolate mofetil. In addition, this study sought to examine hemodialysis removal of mycophenolic acid and its MPAG. METHODS: Subjects were stratified into five groups on the basis of iohexol clearance. After an overnight fast, all subjects received a single 1 gm dose of mycophenolate mofetil. Plasma concentrations of mycophenolic acid and MPAG were measured from 0 to 96 hours after administration. Mycophenolic acid and MPAG maximum plasma concentration (Cmax) and the time to reach Cmax (tmax) for each group were determined from the mean plasma concentration-time profiles. Area under the plasma concentration-time curve values for mycophenolic acid and MPAG were calculated by the trapezoidal rule. The half-lives of mycophenolic acid and MPAG were calculated from the terminal portions of the concentration-time profiles. RESULTS: Mycophenolic acid clearance was not associated with changes in glomerular filtration rate (GFR). Cmax tended to increase as GFR declined. MPAG clearance correlated well with GFR (r2 = 0.905). Clearance of mycophenolic acid and MPAG were unaffected by hemodialysis. CONCLUSIONS: Clearance of mycophenolic acid after a single 1 gm oral dose of mycophenolate mofetil is unaffected by renal function. Clearance of mycophenolic acid is unaffected by hemodialysis. Diminished renal function should not require preemptive adjustment of 1 gm doses of mycophenolate mofetil; however dosage adjustment may be warranted on the basis of adverse effects or toxicity in individual patients. Mycophenolate mofetil can be administered irrespective of hemodialysis session without effect on mycophenolic acid exposure.

Chiral kinetics and dynamics of ketorolac.

It has been shown that the analgesic and cyclooxygenase inhibitor activity of ketorolac tromethamine (KT), which is marketed as the racemic mixture of (-)S and (+)R enantiomers, resides primarily with (-)S ketorolac and that the ulcerogenic activity of this agent also resides in (-)S ketorolac. Resolution of individual enantiomers for analysis in plasma samples has been accomplished by two methods: derivatization to form diastereomers that are separated by HPLC, or direct HPLC using a chiral phase column. When mice and rats were given oral solutions of (-)S and (+) KT, it was found that the kinetics and interconversion of the enantiomers were species and dose dependent. Interconversion was higher in mice than in rats; when (-)S KT was administered, 71% of the area under the concentration-time curve (AUC) was due to (+)R ketorolac in mice, compared with 12% in rats. More interconversion was observed at higher doses; the percent of AUC due to (-)S ketorolac when (+)R KT was administered increased from 12% to 25% in mice and from 2% to 8% in rats. In general, more interconversion occurred from (-)S to (+)R ketorolac in the animal studies. Human subjects were given single oral solution doses of racemic KT (30 mg), (-)S KT (15 mg), and (+)R KT (15 mg). The plasma concentrations of (-)S ketorolac were lower than (+)R ketorolac at all sample times after racemic KT (22% of the AUC was due to (-)S ketorolac). When (+)R KT was administered, (-)S ketorolac was not detectable and interconversion was essentially 0%. When (-)S KT was administered, significant levels of (+)R ketorolac were detectable and interconversion was 6.5%. After all doses, plasma half-life was shorter and clearance greater for (-)S ketorolac than for (+)R ketorolac. Thus, in humans very little or no interconversion of (+)R to (-)S was observed, and interconversion of (-)S to (+)R was minimal (6.5%). These data demonstrate that the kinetics and interconversion of the enantiomers of ketorolac is different in animals and humans as well as from most other NSAIDs. This may be due to more rapid excretion or metabolism of (-)S ketorolac and a different mechanism of interconversion.

Vaginal retention of 2% butoconazole nitrate cream: comparison of a standard and a sustained-release preparation.

The purpose of this study was to establish the length of time that butoconazole nitrate 2% standard cream and sustained-release cream could be detected in the vagina after a single administration of 5 g of cream that contained 100 mg of butoconazole. Sixteen healthy subjects received a single vaginal dose of either the standard (8 patients) or the sustained-release preparation (8 patients). Participants returned daily for vaginal examination and collection of specimens to determine the presence of the drug. The specimens were analyzed for butoconazole content using high-performance liquid chromatography. All subjects in both groups had detectable levels of butoconazole present in the vagina for the first 2 days of the study. The sustained-release cream was demonstrated to be present in the vagina in 7 subjects on the third day, 5 on the fourth day, and 1 on the seventh day, while only 1 subject who received standard cream retained it on the third day and none did so thereafter. Analysis of these data demonstrated a median vaginal retention time of 2.57 days with the standard cream and 4.20 days for the sustained-release preparation (P = 0.0024).

Determination of oxfendazole in cow milk by reversed-phase high-performance liquid chromatography.

A specific and sensitive high-performance liquid chromatographic method for the analysis of oxfendazole in cow milk is described. Oxfendazole was extracted from milk using a mixture of acetone and chloroform under alkaline conditions. The solvents were evaporated, and the oily residue was purified by hexane-acetonitrile partition and acid-base extraction. The residue obtained after cleanup was redissolved in methanol for chromatographic analysis. Chromatography was performed on a reversed-phase column with acetonitrile-water as the mobile phase. As low as 0.005 microgram of oxfendazole/g can be measured by this method using 50 g of milk. The method was applied to measure oxfendazole in the milk of a cow given an oral 5-mg/kg dose.

An indirect (derivatization) and a direct HPLC method for the determination of the enantiomers of ketorolac in plasma.

An indirect and a direct HPLC method for the quantification of the (R) and (S) enantiomers of ketorolac are described here. The indirect method employs the chiral amine (+)-R-1-(1-naphthyl)ethylamine to form disastereomeric amides; separation of the disastereomeric derivates is achieved by normal-phase HPLC with a mobile phase of ethyl acetate-hexane. The direct method uses a C18 solid-phase extraction column to extract ketorolac enantiomers from plasma; the reconstituted extract is then injected onto an alpha 1-acid glycoprotein chiral column using a mobile phase of isopropanol-phosphate buffer (0.05 M; pH 5.5). Both methods are reproducible, accurate, and stereospecific, and both have equivalent quantification limits (0.02 microgram ml-1 of plasma for each enantiomer), ranges (0.02-2.0 micrograms per aliquot of plasma), precision (% relative standard deviations of < or = 10.5% and < or = 10.8% for (R)- and (S)-ketorolac respectively), and accuracy (mean recoveries of 88.4-110% and 90.1-110% for (R)- and (S)-ketorolac respectively). Results of analyses of clinical samples by the two methods showed excellent agreement (slope near 1.0 and coefficients of correlation between 0.9740 and 0.9864 for both enantiomers).

[An attempt to use ofloxacin in patients with mucoviscidosis]. / Opyt primeneniia ofloksatsina u bol'nykh mukovistsidozom.

The literature data and the data of the authors on the pathogenesis and pathogenetic and etiotropic therapy of mucoviscidosis are presented. The use of ofloxacin as an antibacterial agent in the complex treatment of mucoviscidosis is considered expedient. The drug was administered intravenously in a dose of 400 mg twice a day for 5 days followed by the oral use of the drug in the form of tablets according to the same scheme. The microbiological investigation of the sputum specimens revealed diagnostically significant titers of Pseudomonas aeruginosa, Staphylococcus aureus and Klebsiella spp. The isolates except for one case (Ps.aeruginosa) were susceptible to ofloxacin. The treatment with ofloxacin in accordance with the above scheme resulted in a rapid improvement of the patient state: the intoxication lowered, the expectoration and the sputum viscosity decreased, the body temperature normalized by the 5th day. The drug tolerance after the intravenous and enteral administration was good. The intravenous injections of ofloxacin induced a 1.5-fold increase in the intensity of the neutrophil oxygen burst. After the drug enteral administration there was observed a 2-fold increase the intensity of the neutrophil oxygen burst.

[Treatment of patients with pneumonia, chronic obstructive bronchitis and mucoviscidosis with cefpirome]. / Lechenie bol'nykh s pnevmoniiami, khronicheskim obstruktivnym bronkhitom i mukovistsidozom tsefpiromom.

Twenty two patients with inflammatory respiratory tract infection were treated with cefpirome. Among the patients 14 were with severe pneumonia, 4 with exacerbated obstructive chronic purulent bronchitis and 4 with mucoviscidosis. All the patients were subjected to clinical, laboratory and x-ray examinations, electrocardiography, estimation of the external respiration and sputum bacteriological tests. The cefpirome susceptibility was determined by the agar diffusion assay with standard disks from Roussel Uclaf. Cefpirome was administered by slow intravenous infusion in a daily dose of 2 to 4 g every 12 hours depending on the disease severity. After 2 or 3 days of the patient afebrile temperature and normal differential blood count the therapy was discontinued. The favourable time course of the disease was recorded in 12 out of the 14 patients with pneumonia. Recovery and clinical improvement were stated in 64.3 and 21.4 per cent of the cases respectively. In 2 patients the treatment failed. In all the patients with exacerbated severe chronic purulent bronchitis the cefpirome therapy resulted in the disease remission. The clinical effect of the mucoviscidosis treatment was observed in 3 out of the 4 patients. The drug tolerance in the doses used was good.

[The treatment of infectious-allergic bronchial asthma by the extracorporeal connection of a donor spleen]. / Lechenie infektsionno-allergicheskoi bronkhial'noi astmy metodom ékstrakorporal'nogo podkliucheniia donorskoi selezenki.

A total of 25 patients suffering from infective allergic bronchial asthma underwent extracorporeal connection of the donor's spleen (ECCDS). Before ECCDS was made the health status was unstable in all the patients, with asphyxia attacks occurring fairly often, namely up to 12 times a day. Nine patients received the maintenance therapy with steroid hormones. After ECCDS 23 persons (92%) manifested complete disappearance of asphyxia attacks or considerable abatement of their severity and rate. In all the steroid-dependent patients, the daily dosage of steroids could be lowered, while in 3 patients, hormonal drugs were afterwards discontinued. Examination of external respiratory function demonstrated the improvement of bronchial patency at the level of large, medium-size and small bronchi. There was a decrease of the concentration of the circulating immune complexes and IgE in the blood plasma. During 2 years of the follow up, 16 patients did not show any disease relapses, whereas the remainder demonstrated less gravity of attacks as compared to the period preceding the use of ECCDS. It is concluded that the use of ECCDS is desirable in the multimodality treatment of infective allergic bronchial asthma.

[Effect of halogen aerosol therapy on resistance parameters of the respiratory tract]. / Vliianie galoaérozol'noi terapii na zashchitnye svoistva respiratornogo trakta.

AIM: Assessment of the efficacy of dry high-dispersive aerosol of sodium chloride--the main acting factor of haloaerosol therapy--on defense system of the respiratory tract. MATERIAL AND METHODS: 188 patients with respiratory disease and at risk of pulmonary pathology received course of haloaerosol therapy. 49 matched patients were given placebo. The effect of the treatment was assessed by clinicoendoscopic picture, cytomorphological and bacteriological characteristics of the bronchoalveolar lavage, contamination activity of the microflora, activity of local humoral immunity in pharyngeal brush-biopsies and saliva, rheological indices of the sputum. RESULTS: Dry aerosol of sodium chloride demonstrated antiinflammatory activity in the respiratory tract, mucoregulating action. It enhances drainage of the bronchi, activates alveolar macrophages, improves biocenosis and local humoral immunity. CONCLUSION: Haloaerosol therapy has positive effect on the defense system, improves function of the respiratory tracts.

Radioimmunoassay of oxfendazole in sheep fat.

Oxfendazole (methyl 5-(phenylsulfinyl)-2-benzimidazole-carbamate) is a broad spectrum anthelmintic agent designed for use in food-producing animals. A simple radioimmunoassay (RIA) for determination of oxfendazole in plasma was modified for determining oxfendazole in sheep fat. Fat tissue was enzymatically hydrolyzed to an oily residue with collagenase-hyaluronidase, and oxfendazole was then extracted into an acidified aqueous phase. An aliquot of this phase was used directly for RIA. Bound radioactivity was separated from free by using polyethylene glycol-bovine gamma globulin because oils and other components in the aqueous aliquot preclude the use of charcoal for the separation. The lower limit of sensitivity of the assay is 0.003 ppm. Accuracy experiments carried out in the range 0.01-0.5 ppm gave a regression line of y (ng/g) = 0.91 x (ng/g) + 2.89, with r = 0.99. Fat tissue derived from sheep given an oral dose of 6.0 mg/kg was analyzed by this method and by a high pressure liquid chromatographic (HPLC) method. Values obtained by the 2 methods agreed well.

Liquid chromatography of codeine in plasma with fluorescence detection.

This analytical method for easier determination of codeine in human plasma is based on "high-performance" liquid chromatography for separation and the natural fluorescence of codeine for detection. Codeine is extracted from alkalinized plasma with a mixture of hexane and dichloromethane, and the extract is further purified and chromatographed. The method can be used for routine assay of codeine at the concentrations of 10 micrograms/L or greater in human plasma. As little as 4 micrograms/L can be detected. Coefficients of variation for the assay of codeine in the concentration range of 10 to 100 micrograms/L were 2.2-7.4% (n = 6). We used this method to establish a concentration/time profile for plasma from a human volunteer after a 60-mg oral dose of codeine sulfate.

High-performance liquid chromatographic method for the determination of mycophenolate mofetil in human plasma.

A method for the quantification of mycophenolate mofetil (MMF, CellCept) in plasma using solid-phase extraction and HPLC is described here. A solution of internal standard is added to a 0.5-ml plasma aliquot. The resulting sample is treated with water and dilute HCl and applied to a C18 solid-phase extraction column. After a water wash, the MMF and internal standard are eluted with methanol-0.1 M citrate-phosphate buffer, pH 2.6 (80:20, v/v). A 20-microliters aliquot of the eluate is injected onto a C18 column (5 microns particle size, 150 x 4.6 mm I.D.) and eluted at ambient temperature with acetonitrile-0.05 M citrate-phosphate buffer, pH 3.6, containing 0.02 M heptanesulfonic acid (41:59, v/v). Quantification is achieved by UV detection at 254 nm. The method is reproducible, accurate and specific for MMF. Using 0.5 ml of plasma for analysis, the quantification limit is 0.400 microgram/ml and the range is 0.400-20 micrograms/ml. Based on the stability profile of MMF in plasma, it is recommended that blood samples collected following intravenous infusion be immediately stored on ice and that plasma be prepared rapidly, immediately stored frozen at -80 degrees C and analyzed within four months of collection.

Selection of a derivative of the antiviral agent 9-[(1,3-dihydroxy-2-propoxy)-methyl]guanine (DHPG) with improved oral absorption.

Various diesters of 9-[(1,3-dihydroxy-2-propoxy)-methyl]guanine (DHPG) were screened in order to identify a derivative with improved oral absorption. The solubilities and dissolution rates decreased with increasing chain length and branching of the ester group. However, the dipropionate ester showed an anomalously faster dissolution rate. The rates of hydrolysis to DHPG in the presence of intestinal homogenates were found to increase with increasing carbon number for the straight-chain alkyl esters and decreased with branching. The shorter-chain alkyl esters were relatively more stable in intestinal homogenates than in liver homogenates. Therefore they may have a better membrane permeability than DHPG due to their intact ester group. The hydrolysis rates in human blood increased with increasing carbon number for the straight-chain alkyl esters. The dipropionate ester appeared to be the most promising derivative because of its rapid dissolution rate, slower hydrolysis in the intestine, and rapid conversion to DHPG in liver and blood.

Manual and automated (robotic) high-performance liquid chromatography methods for the determination of mycophenolic acid and its glucuronide conjugate in human plasma.

A manual and an automated (Zymark PyTechnology robot) HPLC method for simultaneous determination of plasma mycophenolic acid (MPA) and its glucuronide conjugate (MPAG) are described here. Both methods are reproducible and accurate, and both are equivalent in all respects, including quantification limits (MPA, 0.100 microgram/ml; MPAG, 4.00 micrograms/ml), range (using 0.05-0.5 ml of plasma: MPA, 0.0500-20.0 micrograms/aliquot; MPAG, 2.00-200 micrograms/aliquot), precision, and accuracy. MPA and MPAG were stable under the conditions used with both methods. Results from aliquots of paired control samples, analyzed by the manual method over three years at six analytical laboratories, showed excellent agreement in precision and accuracy.