Sustained release of metformin via red blood cell accumulated sulfenamide prodrug.

Metformin is a first-line antidiabetic drug to treat type 2 diabetes. It is rapidly eliminated from plasma but also accumulated into red blood cells (RBCs) from which it is slowly released back into plasma. The aim of the study was to evaluate whether the amount of metformin in the RBCs could be increased by a sulfenamide prodrug approach, which could provide longer duration of metformin in systemic circulation. Pharmacokinetic properties of metformin and its cyclohexyl sulfenamide prodrug were evaluated in plasma and in whole blood after intravenous and oral administration in rats. Once the sulfenamide prodrug reached the bloodstream, it was rapidly and efficiently accumulated into the RBCs, where it was converted to metformin by free thiols. The RBC-whole blood ratio of metformin was increased approximately from 42% to 96% when metformin was administered intravenously as its sulfenamide prodrug, and the proportion of metformin in the RBCs was found to be concentration and time independent. Because metformin was slowly liberated into plasma, the prodrug showed a sustained-release pharmacokinetic profile and longer plasma half-life for metformin after oral administration. Therefore, this sulfenamide prodrug has great potential to improve metformin therapy as the daily doses could be reduced.

Characterization, inclusion mode, phase-solubility and in vitro release studies of inclusion binary complexes with cyclodextrins and meglumine using sulfamerazine as model drug.

In order to investigate the effect on the aqueous solubility and release rate of sulfamerazine (SMR) as model drug, inclusion complexes with ß-cyclodextrin (ßCD), methyl-ß-cyclodextrin (MßCD) and hydroxypropyl-ß-cyclodextrin (HPßCD) and a binary system with meglumine (MEG) were developed. The formation of 1:1 inclusion complexes of SMR with the CDs and a SMR:MEG binary system in solution and in solid state was revealed by phase solubility studies (PSS), nuclear magnetic resonance (NMR), Fourier-transform infrared spectroscopy (FT-IR), thermal analysis and X-Ray diffractometry (XRD) studies. The CDs solubilization of SMR could be improved by ionization of the drug molecule through pH adjustments. The higher apparent stability constants of SMR:CDs complexes were obtained in pH 2.00, demonstrating that CDs present more affinity for the unionized drug. The best approach for SMR solubility enhancement results from the combination of MEG and pH adjustment, with a 34-fold increment and a Smax of 54.8 mg/ml. The permeability of the drug was reduced due to the presence of ßCD, MßCD, HPßCD and MEG when used as solubilizers. The study then suggests interesting applications of CD or MEG complexes for modulating the release rate of SMR through semipermeable membranes.

Randomised double-blind trial of the effect of vitamin C on dyspareunia and vaginal discharge in women receiving doxycycline and triple sulfa for chlamydial cervicitis.

BACKGROUND: Chlamydia trachomatis is the most common bacterial cause of cervicitis. AIM: The aim of this randomised, double-blind trial was to compare the effect of vitamin C on dyspareunia and vaginal discharge in women receiving doxycycline and triple sulfa for chlamydial cervicitis. METHODS: Eighty women with increased anti-C. trachomatis IgM, reporting abnormal vaginal discharge and dyspareunia, demonstrating signs of cervical oedema and erythema and friability of cervix were included. Thirty-nine women received doxycycline capsules 100 mg twice daily plus triple sulfa vaginal cream once daily for ten days, and 41 received doxycycline capsules 100 mg twice-daily and triple sulfa vaginal cream once daily plus vitamin C tablets 250 mg once daily for ten days. Women were evaluated at follow-up visit, eleventh day, following completion of intervention. ANALYSIS: The effect of treatment was assessed regarding clinical criteria (presence of endocervical mucopus and cervical severity score) and presence of dyspareunia. Statistical analysis was carried out using spss version 11.5. RESULTS: The mean age of women was 30.6 +/- 8.4 years. There was no relationship between demographics and dyspareunia and discharge (P > 0.05). There was statistically significant difference between the effect of 'doxycycline plus triple sulfa' and 'doxycycline, triple sulfa plus vitamin C' on discharge and dyspareunia (P = 0.005, P < 0.001, respectively). Most frequently reported drug-related adverse event in both groups was heartburn. CONCLUSION: Adding vitamin C to doxycycline and triple sulfa was more efficient than standard regimen (doxycycline and triple sulfa without vitamin C) in treating chlamydial cervicitis.

Preparation, characterization and in vivo conversion of new water-soluble sulfenamide prodrugs of carbamazepine.

Improved synthetic methods are reported for the preparation of sulfenamide derivatives of carbamazepine (CBZ) for evaluation as prodrugs. These sulfenamide prodrugs were designed to rapidly release CBZ in vivo by cleavage of the sulfenamide bond by chemical reaction with glutathione and other sulfhydryl compounds. Physicochemical characterization and in vivo conversion of a new prodrug of CBZ was evaluated to further establish the proof of concept of the sulfenamide prodrug approach.

A new concept for interpretation of first-order release from albumin microspheres.

A release mechanism from a microsphere that consisted of a water-swellable polymer and a uniformly dispersed, relatively small number of very slightly soluble large-core particles was considered. When the microsphere is dipped in release media the polymer swells instantly, and every core particle dissolves in the release media in the space between the core particles and the swollen polymer to make a saturated solution. It is assumed that Fickian diffusion of dissolved core substance between all spaces filled with saturated solution and outer sink occurs independent of each other, and release from one entire microsphere is the sum of diffusion from all spaces in the microsphere. Then, derived theoretical release kinetics is found to be first-order, and the derived first-order release rate constant is expressed as a function of the following parameters: radius of core particle, radius of the microsphere, solubility of core substance to media solution, density of the core particle, and permeability constant of core substance in swollen polymer. When rate constants were measured from release tests, varying each parameter, the relation between constants and each parameter follows the function. The permeability constant, which was calculated applying the function on measured rate constants and other known parameters, was in good agreement with the permeability constant measured from permeation study of planar membrane prepared in similar conditions to when preparing microspheres. These results are thought to show the validity of the mechanism and function proposed.

[Comparative studies of the effectiveness of 1-day treatment and 7-day treatment with sulfamerazine/trimethoprim (Berlocombin) of patients with urinary tract infection]. / Vergleichende Untersuchungen zur Wirksamkeit einer Ein-Tages-Behandlung und einer Sieben-Tage-Behandlung mit Sulfamerazin/Trimethoprim (Berlocombin) bei Patienten mit einer Harnwegsinfektion.

Insights into the pathogenesis of urinary tract infections warrant reflections on new therapeutic strategies. Of particular interest is the phenomenon of bacterial adherence to cells, as the adhesion of microorganisms to uroepithelial cells plays an important role in the development of the disease. In 21 women with an acute episode of lower urinary tract infection who were known of having chronic pyelonephritis, we studied the influence of a one-day (n = 7) and a seven-day treatment by administering the regular sulfamerazine/trimethoprime (Berlocombin) dose (2 X 2 tablets from the 2nd day, n = 7) or a reduced amount (2 X 1 tablet from the 2nd day, n = 7). All treatment regimes led to a disappearance of the clinical symptoms; however, in one case of the group receiving one-day treatment, dysuric complaints recurred as early as on day 3 after therapy. Only when employing the regular schedule of therapy, the controls of the urine cultures revealed sterility of the urine for all cases still on the 21st day after treatment. This treatment regimen most clearly influenced the ability of the microorganisms to adhere to the uroepithelial cells of the probands (in-vivo adherence). The one-day treatment was not able to reduce the rates of bacterial adherence to the cells. In all patients, the acute disease resulted in an increase in microorganisms coated with antibodies; on day 21 following therapy, however, the findings registered were as before onset of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Selective decontamination of the digestive tract and fungal infection in acute leukemia patients.

For prevention of infection we used an SD design including antibacterial (trimethoprim 480 mg/daily, sulfamerazine 720 mg/daily, and polymyxin 0.25 mg/daily) and antifungal (4-6 million IU nystatin/daily) components. We analyzed retrospectively 138 treatment periods in 108 patients. The intensified chemotherapy resulted in severe granulocytopenia below 0.1 x 10(9)/liter over 25.2 days. In 19 patients there was suspicion of major fungal infection; therefore they were given amphotericin B and 5-fluocytosine. Fourteen of them died; major fungal infections were documented in 5 cases. In 18% of all the deceased we found major fungal infections. There was a correlation between fungal infection, the late stages of the hematological malignancy, and the lesions on the oropharyngeal mucosa. However, in terms of the serological and culture findings no correlation appeared to exist between the group with and the group without fungal infection. The SD regime is meant to suppress the Candida cell concentration in the digestive tract but has no influence on Aspergillus in the respiratory tract.

[Value of the preventive use of antibiotics following vaginal obstetric operations]. / Zur Zweckmässigkeit einer Antibiotikaprophylaxe nach vaginalen geburtshilflichen Operationen.

For a period of 6 years 838 puerperal cases after vaginal obstetric operations (forceps delivery, vacuum extraction, delivery with speculum, manual placenta separation, palpation of the uterus) were critically analysed. The result of the studies suggest that an antibiotic or chemoprophylaxis after vaginal obstetric operations is not successful because of the relatively low infectious morbidity. In obstetrics this prophylaxis is indicated only in delivery by caesarean section as a perioperative short-time prophylaxis.

Pectin-gelatin complex coacervates II: Effect of microencapsulated sulfamerazine on size, morphology, recovery, and extraction of water-dispersible microglobules.

Spherical medicated microglobules were prepared by complex coacervation of Type A gelatin with pectin, having nominal diameters of 5, 10, and 25 micron and containing 37.3, 44.9, and 45.2% (w/w) sulfamerazine, respectively. They were recovered as water-insoluble powders and were spontaneously revertible to highly disperse systems when reconstituted in water or physiological electrolyte solution. The conditions affecting microglobule formation were studied. For complete formation, the crystals must be dispersed at greater than or equal to pH 5. The effect of the sulfamerazine mass added on microglobule morphology, yield, and contents were investigated. As much as 37.3, 44.5, and 69.1% (w/w) sulfamerazine in 5-, 10- and 25-micron microglobules could be formed without loss of spherical shape. The microglobule yield versus drug-to-colloid ratio curves were nonlinear below the critical drug-to-colloid ratio for loss of sphericity. Addition of sulfamerazine suppressed coacervation by 10-15% but it had no significant effect on microglobule size. The extraction of medicated microglobules in various media demonstrated the existence of a porous matrix that required hydration to facilitate extraction of the microglobular drug. Fifteen percent of the encapsulated sulfamerazine was extracted from 25-micron microglobules as opposed to 9% from 10-micron microglobules after equilibration for 24 h in replacement electrolyte solution.

[The influence of galenic and biologic factors on the bioavailability of Berlocombin]. / Der Einfluss galenischer und biologischer Faktoren auf die Bioverfügbarkeit von Berlocombin.

The analysis of the influence of galenical and biological factors on the biological availability of Berlocombin (sulfamerazin and trimethoprim combination) has been performed by a single Berlocombin juice administration compared to tablets and by a tablet administration combined with nourishment. In case of the juice administration, the biological availability of trimethoprim and sulfamerazin has been reduced. The tablet administration at an empty stomach and a subsequent 5-h waiting period revealed a more complete trimethoprim resorption, which compared to an administration immediately after the standard breakfast is expressed by a significantly greater area under the concentration-time curve (AUC) in serum. In tablet application subsequent to a fatty breakfast, the trimethoprim and sulfamerazin resorption is compared to the relative group some increased; the differences, however, were insignificant ones. The results of this study failed to be of practical consequences, because the dosage applied and recommended by the producer significantly exceeded the minimum inhibition concentrations in serum and urine 3 h after administration. The required therapeutic level in no case fell short of up to the 12. hour.

Pharmacokinetics of sulfamerazine and antipyrine in neonatal and young lambs.

The disposition of sulfamerazine after oral and after IV administrations was studied in lambs at different times after birth. There was a gradual increase in systemic clearance and plasma binding until the 9th week. After sulfamerazine was given orally, there was a marked evolution in the shape of the concentration-time curves in function of age, strongly suggesting a defective absorption rate in the first weeks after birth. For antipyrine, too, the clearance increased gradually during the period of study, but absorption seemed to be rapid in the very young animals.

[Pharmacokinetic findings following the oral application of granulated Mebacid in cattle, calves and sheep]. / Pharmakokinetische Untersuchungsergebnisse nach oraler Applikation von Mebacidgranulat beim Rind, Kalb und schaf.

The pharmacokinetic properties of sulphamerazine, following oral application of granulated Mebacid to cattle, calf, and sheep, were compared with results obtained from the use of Mebacid tablets. Elimination half-life was higher in cattle, calf, and sheep, following oral application of Mebacid tablets. Different pharmacokinetic properties of sulphamerazine were found to exist between the two modes of preparation. Sulphonamide was eliminated more rapidly by cattle, calf, and sheep, when granulated Mebacid was used. When granulate is used, higher sulphamerazine doses have to be applied to calf and sheep to obtain the sulphonamide levels required for effective therapy. No intolerance was recorded from the above species, following oral application of granulated Mebacid.

[Pharmacokinetic model studies of sulfamerazine in domestic mammals. 2. Elimination of Mebacid 200 and Mebacid tablets following oral, subcutaneous and intramuscular administration]. / Pharmakokinetische Modelluntersuchungen an Sulfamerazin bei Haussäugetieren. 2. Mitteilung: Die Elimination von Mebacid 200 und Mebacid-Tabletten nach oraler, subkutaner und intramuskulärer Applikation.

The mathematical foundations underlying pharmacokinetic testing and acceptance of medicaments for domestic mammals are expounded and discussed, with reference being made to examples of intramuscular, subcutaneous, and oral application of Mebacid 200 and Mebacid tablets. Elimination of sulphamerazine may be mathematically described by means of the following bi-exponential function: c = B x e-k2 x t -- A x e-k1 x t The concepts of the mono-compartmental model "Extravasal Application" can be claimed as being of basic validity. Blood levels established after intramuscular and subcutaneous application of sulphamerazine-sodium (Mebacid 200) were lower than those recorded after oral application of Mebacid tablets. The half-lives of elimination, following oral application to big animals of Mebacid tablets, were longer than those following intravenous application of comparable injection solution.

[Pharmacokinetic model studies of sulfamerazine in domestic mammals. 5. Resorption of Mebacid tablets in large animals]. / Pharmakokinetische Modelluntersuchungen and Sulfamerazin bei Haussäugetieren. 5. Mitteilung: Zur Problematik der Resorption von Mebacid-Tabletten beim Grosstier.

The formula proposed by RITSCHEL (1973) for calculation of rates of resorption is explained and modified for use of the monocompartment model. Resorption rates were calculated for cattle, calf, horse, and sheep, with reference being made to the example of Mebacid tablets. The most favourable rate of resorption was established for calf.

[Pharmacokinetic model studies of sulfamerazine in domestic mammals. 1. Elimination of Mebacid 200 following intravenous administration to large animals]. / Pharmakokinetische Modelluntersuchungen an Sulfamerazin bei Haussäugetieren. 1. Mitteilung: Die Elimination von Mebacid 200 nach intravenöser Applikation beim Grosstier.

Pharmacokinetic data of sulphamerazine were recorded from eight heads each of calf, adult cattle, horse, and sheep, following intravenous application of Mebacid 200, and mathematical implications were discussed. Exponential excretion was recorded from all species, according to the following equation: c = B x e-k2 x t The most favourable pharmacokinetic parameters were recorded from calf.

[Pharmacokinetic model studies of sulfamerazine in domestic mammals. 4. Mebacid tablet and Mebacid 200 dosage calculation problems]. / Pharmakokinetische Modelluntersuchungen an Sulfamerazin bei Haussäugetieren. 4. Mitteilung: Zur Problematik von Dosisberechnungen an Mebacid-Tabletten und Mebacid 200.

The highly variegated complex of aspects relating to dosage calculation for veterinary drugs is explained and discussed by examples of Mebacid 200 and Mebacid tablets. For domestic mammals, a dosage interval of 24 hours is desirable for reasons of economy. Therefore, due allowance must be made, by means of unilateral confidence, of the most unfavourable case of high protein fixation, low half-life for elimination, and high coefficient of distribution. The following equation, proposed by DETTLI and SPRING (1966) was used for dosage calculation: AD = c . delta' . ek2 . t or ED = c . delta' . (ek2 . t -1) The dosage will now be in a twelve-hour rhythm, because of the low half-life for elimination of sulphamerazine-Na. A pharmacokinetically founded dosage interval of 24 hours will be feasible only by oral application of Mebacid tablets. The difference between the calculated initial and maintenance doses was found to be negligible.

[Pharmacokinetic model studies of sulfamerazine in domestic mammals. 6. Absence of drug residues]. / Pharmakokinetische Modelluntersuchungen an Sulfamerazin bei Haussäugetieren. 6. Mitteilung: Zur Problematik der Rückstandsfreiheit.

The problem of no residues is elucidated and discussed under pharmacokinetic aspects. An equation with due consideration confidence by which to calculate the absence of residues in drugs is given under the assumption that elimination of such residues should follow the concepts of the monocompartment model. The time is calculated by which all residues of sulphamerazine have disappeared, following application of Mebacid 200 and Mebacid tablets to farm animals.

[Pharmacokinetic studies of sulfamerazine-Na, sulfaperine-Na and sulfadimidine-Na in the hen]. / Pharmakokinetische Untersuchungen von Sulfamerazin-Na, Sulfaperin-Na und Sulfadimidin-Na beim Huhn.

The pharmacokinetic properties of sulphaperine-sodium, Mebacid 200, and sulphadimidine-sodium were experimentally established from fowl and mathematically objectivated. The highest half-life for elimination, coupled with low protein fixation, was recorded from sulphadimidine, by comparison of the above three sulphonamides. These data were used in dosage calculations for clinical testing.