Pharmacokinetics of cefradine, sulfamethoxazole and trimethoprim and their metabolites in a patient with peritonitis undergoing continuous ambulatory peritoneal dialysis

Cefradine and co-trimoxazole pharmacokinetics were studied in a patient with peritonitis that complicated continuous ambulatory peritoneal dialysis (CAPD). Concentrations in the plasma reached after oral administration of 500 mg cefradine four times daily and 400/80 mg co-trimoxazole four times daily were for cefradine 100g/ml, for trimethoprim 15g/ml, and for sulfamethoxazole 100/ml, respectively. In the dialysate concentrations were reached of 35–70/ml cefradine, 2–5/ml trimethoprim and 8–17g/ml sulfamethoxazole. The values for sulfamethoxazole are regarded too low to be clinically effective. Half-lives protein binding values and CAPD clearances are presented. Low CAPD clearances were obtained during the night and high values during the day. The dosage yielded too high plasma trimethoprim concentrations, while sulfamethoxazole dialysate concentrations were too low. It seems questionable therefore whether co-trimoxazole can be used orally for the treatment of CAPD peritonitis.     

Effects of hydroxypropyl-beta-cyclodextrin on the chemical stability and the aqueous solubility of thalidomide enantiomers

The aim of this work was to study the effect of hydroxypropyl-beta-cyclodextrin on the solubility and stability of thalidomide enantiomers in aqueous solutions for clinical oral administration to be used in HIV-infected children. For this reason racemic thalidomide was added to solutions containing different concentrations of hydroxypropyl-beta-cyclodextrin. True complexes were obtained by using hydroxypropyl-beta-cyclodextrin and the solubility of both thalidomide enantiomers was increased directly depending on the amount of hydroxylpropyl-beta-cyclodextrin in the medium although no enantioselective differences were observed at 37 degrees C. The chemical stability of thalidomide enantiomers is clearly improved by hydroxypropyl-beta-cyclodextrin. No enantioselective degradation of thalidomide was observed in sodium chloride solution (0.9%) samples stored at 6 degrees C for nine days when hydroxypropyl-beta-cyclodextrin was employed as excipient. Therefore a thalidomide solution suitable for oral administration can be prepared by adding hydroxypropyl-beta-cyclodextrin at 10% (w/v).     

Penetration of trimethoprim and sulfamethoxazole into skin blister fluid

In 32 patients the concentrations of sulfamethoxazole and trimethoprim in whole blood, plasma and skin blister fluid were studied in the course of treatment with co-trimoxazole and trimethoprim alone. Measurements were taken on the fourth day of treatment, 3 h after administration of the morning dose of the drug. The blood contained a lower concentration of sulfamethoxazole than plasma. About 70% of the sulfonamide penetrated into the exudate from plasma. Trimethoprim administered conjointly with sulfamethoxazole to a higher degree penetrated skin blister fluid to a greater extent than when given alone.     

Effect of hydroxypropyl-beta-cyclodextrin on the solubility, stability and in-vitro release of ciprofloxacin for ocular drug delivery

Eye drops in the form of an aqueous solution with a lower viscosity are preferred for local administrations in ophthalmology. In ophthalmic formulations, cyclodextrins (CDs) are frequently used in recent years in order to increase water solubility, stability and bioavailability of an active substance and decrease an irritation to the eye. The scope of the present study was to investigate the influence of hydroxypropyl-beta-cyclodextrin (HPCD) on the solubility, stability and in vitro release of ciprofloxacin (CIP). According to the phase solubility studies, A(L) type solubility curve was obtained. HPCD improved the solubility of CIP 3 times at pH 5.5 and 2 times at pH 7.4. The two month stability studies indicated that CIP was more stable at pH 5.5 than at pH 7.4 and the stability of CIP was significantly increased by HPCD. The stability constant of the HPCD:CIP complex was increased further by a-ddition of 0.1% (w/v) polymer (HPMC and PVP) to the aqueous medium including HPCD. Stability constant of solutions prepared in an ultrasonic water bath was higher than solutions prepared by heating in an autoclave. The results indicated that the CIP:HPCD complex increased in vitro release of CIP and the addition of polymer promoted this increase even more.     

双波长倍增差示法测定复方新诺明片含量

分别测定标准溶液和样品溶液在265及275 nm处的吸收度,根据标准溶液的吸收系数可同时计算出样品中 SMZ 和 TMP 的含量。SMZ 平均回收率与变异系数分别为100.8%,0.95%;TMP 为99.16%,0.82%。方法简便、快速。结果令人满意。     

Studies of the pharmacokinetics and bioavailability of a new trimethoprim/sulfamethoxazole preparation in healthy volunteers

The objective of this study was to determine both the pharmacokinetic parameters and the bioavailability of a newly developed trimethoprim/sulfamethoxazole preparation (cotrimoxazole, Kepinol forte, 160 mg of trimethoprim/800 mg of sulfamethoxazole) in comparison with a reference preparation customary in trade and registered according to the AMG 1976, after single oral administration. For this purpose the test and the reference preparation were examined in a randomized 2-way crossover design (Latin square) in 12 volunteers each. Both dosage forms led to maximum plasma levels of approx. 1250 ng/ml of trimethoprim and about 40 micrograms/ml of sulfamethoxazole 1.5-2 h after application; the plasma half-lives were about 9 h for trimethoprim and around 8.5 h for sulfamethoxazole. The statistical comparison (ANOVA, confidence intervals according to Westlake, Pratt-Wilcoxon test) of the pharmacokinetic parameters found in the study resulted in bioequivalence of the newly developed trimethoprim/sulfamethoxazole preparation and the reference preparation. Furthermore, after the administration of both preparations no marked side effects worth mentioning were observed, suggesting a good and comparable clinical tolerability of the two preparations.     

The influence of polyvinylpyrrolidone on naproxen complexation with hydroxypropyl-beta-cyclodextrin.

The combined effect of hydroxypropyl-beta-cyclodextrin (HPbetaCD) and polyvinylpyrrolidone (PVP) on the solubility of naproxen (NAP) was studied. Phase-solubility analysis at different temperatures was used to investigate interactions in aqueous solution between NAP and the carriers, either alone or in combination. Equimolar NAP-HPbetaCD solid systems, in the presence or the absence of 15% (w/w) PVP, were prepared by cogrinding, kneading, coevaporation or freeze-drying, and characterized by differential scanning calorimetry, X-ray powder diffraction analysis, infrared spectroscopy and dissolution rates. The combined use of PVP and HPbetaCD resulted in a synergistic increasing effect of the aqueous solubility of NAP (120 times that of the pure drug). The phenomenon was interpreted in terms of the strongest complexation capacity of HPbetaCD towards NAP, which was reflected by an about 65% increase in the apparent stability constant of the NAP-HPbetaCD complex in the presence of only 0.1% (w/v) PVP. Variations in thermodynamic parameters accounted for a PVP role in the formation of a NAP-HPbetaCD-PVP ternary complex. The positive effect of PVP also reflected on NAP dissolution rates from solid preparations, because all ternary systems, with the exception of physical mixtures, dissolved faster than the corresponding NAP-HPbetaCD binary systems. The results of solid state studies accounted for the occurrence of mechanically- and/or thermally-induced stronger interactions in ternary than in binary systems, that in some cases led to a complete loss of NAP crystallinity.     

复方新诺明片的溶出度测定

采用双波长法和吸收度加和性原理,直接测定复方新诺明片中磺胺甲基异(口恶)唑和甲氧苄氨嘧啶的溶出度。此法快速、简便。磺胺甲基异(口恶)唑平均回收率为100.9%,甲氧苄氨嘧啶平均回收率为99.69%。变异系数分别为0.76%和1.90%。     

Double-blind co-operative trial to compare trimethoprim-sulfalene and co-trimoxazole in the treatment of lower respiratory tract infections

Two fixed trimethoprim-sulfonamide combinations were compared in a clinical trial for their effectiveness and safety in the treatment of patients with acute lower respiratory tract infections (pneumonia, bronchopenumonia, purulent tracheobronchitis, ect.). 46 in-patients were randomly allocated to Kelfiprim (trimethoprim 250 mg + sulfalene (sulfamethopyrazine) 200 mg) or to co-trimoxazole (trimethoprim 320 mg + sulfamethoxazole 1600 mg) and were treated for 1-2 weeks under double-blind conditions. Assessment of effectiveness was based on daily follow-up of subjective and objective signs and symptoms, on changes in X-ray picture, and on microbiological and laboratory findings. Response to therapy was excellent or good in 86% of patients receiving Kelfiprim and in 79% of those given cotrimoxazole. Transient side-effects were observed in three patients under Kelfiprim (two allergic reactions and one G.I. complaint) and in one under co-trimoxazole (altered kidney function).     

Stability of concentrated trimethoprim-sulfamethoxazole admixtures

The stability of trimethoprim-sulfamethoxazole (TMP-SMX) at various concentrations in 5% dextrose injection or 0.9% sodium chloride injection was studied. Appropriate volumes of TMP-SMX formulation (80 mg TMP and 400 mg SMX/5 mL) were mixed with 5% dextrose injection or 0.9% sodium chloride injection to provide dilutions of 1:25 v/v, 1:20 v/v, 1:15 v/v, and 1:10 v/v. Aliquots were removed at 0, 0.5, 1, 2, 4, 8, 14, 24, and 48 hours and filtered. The pH of the samples was determined, and the samples were assayed for trimethoprim and sulfamethoxazole content by high-performance liquid chromatography. Admixtures were visually inspected for precipitate before each sample was removed. The concentration of SMX in all admixtures did not change during the study period. The stability of TMP was dependent on concentration and vehicle. At a 1:25 v/v dilution, TMP was stable for 48 hours in 5% dextrose injection and 0.9% sodium chloride injection. At a 1:20 v/v dilution, TMP was stable for 24 hours in 5% dextrose injection and 14 hours in 0.9% sodium chloride injection. At a 1:15 v/v dilution, TMP was stable for four hours in 5% dextrose injection and two hours in 0.9% sodium chloride injection. At a 1:10 v/v dilution, TMP was stable for one hour in 5% dextrose injection and 0.9% sodium chloride injection. Concentrated solutions of TMP-SMX should be prepared in 5% dextrose injection, infused within one hour of preparation, and visually inspected for precipitation before and during infusion.     

A case-control analysis of the teratogenic effects of co-trimoxazole

The possible teratogenic effect of co-trimoxazole (sulfamethoxazole and trimethoprim, Bactrim® [Roche], Septrin® or Septra® [Burroughs-Wellcome], Sumetrolim® [EGIS]) was evaluated using the data set of the Hungarian Case-Control Surveillance of Congenital Anomalies. In the study period of 1980 through 1984, 1.25% of pregnant women who had healthy babies (negative control group) were treated with co-trimoxazole during pregnancy. In those who had babies with congenital anomalies the rate of co-trimoxazole use was 2.31%. The case-control analysis showed a significant increase of co-trimoxazole use only in the groups of cleft lip ± cleft palate and hypospadias. However, drug use was not higher during the critical period in either of the congenital anomaly groups. The distribution of component congenital anomalies in 13 cases affected by multiple congenital anomalies did not show any characteristic pattern. Respiratory and urinary system diseases were mentioned significantly more frequently in pregnancies of index patients' mothers. This analysis did not indicate any teratogenicity of co-trimoxazole. The higher drug use can probably be explained by maternal disorders.     

Clinical pharmacokinetics of co-trimazine

The clinical pharmacokinetics of co-trimazine (trimethoprim plus sulphadiazine) are reviewed and compared with those of co-trimoxazole (trimethoprim plus sulphamethoxazole). Both combination drugs have similar serum half-life values in persons with normal renal function (half-life of 8 to 12 hours), but the sulphamethoxazole metabolites are retained more than trimethoprim in reduced renal function. Sulphadiazine is less metabolised and the total sulphonamide load of therapeutic doses of co-trimazine is therefore less than for co-trimoxazole. Both co-trimazine and co-trimoxazole have high bioavailability. A suspension of co-trimazine gives serum concentrations comparable with those of tablets. The extravascular penetration of the co-trimazine components is reflected by the total area under the lymph concentration curve in comparison with serum. This measure shows a penetration into peripheral human lymph of 68% for sulphadiazine and 59% for trimethoprim. The proportions eliminated in urine are about 55% for sulphadiazine, 30% for its acetylated metabolite and 75% for trimethoprim. In comparison, for co-trimoxazole, the proportion of sulphamethoxazole eliminated in urine is 15%, that of the acetylated derivative 47%, and that of trimethoprim is also 75%. Urine concentrations of both combinations have similar bioactivity against urinary pathogens after 500 mg of co-trimazine and 960 mg of co-trimoxazole.     

Solubilization of tropicamide by hydroxypropyl-beta-cyclodextrin and water-soluble polymers: in vitro/in vivo studies

1% (w/v) aqueous solutions of tropicamide (TR), a poorly water-soluble mydriatic-cycloplegic drug, are usually obtained by adjusting the pH to approximately 5.0, at the expense, however, of ocular tolerance and bioavailability. The capacity of hydroxypropyl-beta-cyclodextrin (HP-beta-CD) to solubilize TR in pH 7.4 0.02 M phosphate buffer was investigated in the absence and presence of hydrophilic polymers (PVP, CMC and HPMC). Approximately 3.5% (w/v) HP-beta-CD was required to solubilize 1% (w/v) TR in pH 7.4 buffer at room temperature. The required amount was reduced to 0.9% (w/v) by heating at 120 degrees C in the presence of 0.1% (w/v) HPMC. Mydriatic activity tests in rabbits showed an improved bioavailability and maximal mydriatic response for two CD formulations, with and without HPMC, when compared to standard 1% (w/v) TR eyedrops, buffered at pH 5.0. The improved in vivo behaviour of the CD formulations are likely due to their physiological pH, resulting in a reduced irritant effect, although an effect of HP-beta-CD on corneal permeability cannot be dismissed a priori.     

Simultaneous solubility and dissolution rate of sulfamethoxazole and trimethoprim in binary mixture

The solubilities of trimethoprim in solutions with different pH values decreased in the presence of sulfamethoxazole, while that of the latter increased in the presence of the first. The dissolution rate of trimethoprim in HCl (0.1 mol/1) was the same in the presence and absence of sulfamethoxazole. That of sulfamethoxazole however, decreased in the presence of trimethoprim. The different reasons were explained.     

The effect of formulation variables on the stability of nebulized aviscumine

The pulmonary drug delivery of proteins present an alternative to parenteral and oral administration. Nebulization of aqueous protein solutions is an ideal method for pulmonary application of therapeutic proteins considering the difficulties of their formulation as MDIs or DPIs. This research presents the effect of variable excipients on the stability of freeze-dried aviscumine after reconstitution and nebulization. Formulations containing different lyoprotectants have been lyophilized and reconstituted with isotonic salt solution. The loss of aviscumine activity in the nebulizer reservoir and after nebulization with a PariBoy air-jet nebulizer, a Multisonic ultrasonic nebulizer and a Systam ultrasonic nebulizer was determined by a binding assay. The effect of variable lyoprotectants such as 8% (w/v) Dextran T1, HES130, HES450, HP-beta-CD and 6% (w/v) HES450 plus 2% (w/v) mannitol on the stability of aviscumine to air-jet and ultrasonic nebulization has been evaluated. Only 50% of aviscumine activity was retained after 20 min nebulization, where 8% (w/v) HES450 was shown to be the best stabilizer. Stabilization of aviscumine by the addition of variable surfactants as 0.01 and 0.1% (w/v) Poloxamer 188, 0.03 and 0.1% (w/v) PEG 8000, 0.03 and 0.1% (w/v) Solutol HS15 and 0.03 and 0.1% (w/v) octanoyl-N-methyl-glucamide to the reconstitution solution has also been studied. By the addition of 0.03% (w/v) octanoyl-N-methyl-glucamide, 70% of the activity was retained after 20 min nebulization.     

Effect of 2-hydroxypropyl-beta-cyclodextrin on the solubility, stability, and pharmacological activity of the chemical delivery system of TRH analogs

To improve the aqueous solubility and stability of the chemical delivery system (CDS) of the thyrotropin-releasing hormone (TRH) analogs, 2-hydroxypropyl-beta-cyclodextrin (HPBCD) has been attempted. TRH analogs were [Leu2]-TRH, [Nva2]-TRH and [Nva2, Pip3]-TRH. Excess amount of CDS was added in various HPBCD in water solutions (0%-50%, pH 6.5). The mixture was saturated by ultra-sonication for 1 h at 15 degrees C and filtered. The concentration of CDS in the filtrate (solubility) was determined with UV detector, and subsequently the stability was investigated. By HPBCD complexation, the aqueous solubility and stability (half-life) of CDS were significantly improved from undetectable levels to about 15 mg/ml and 30 h, respectively. In pH 6.5 and 7.4 HPBCD solution, the degradation of CDS was mainly via acid catalyzed water addition reaction, thus, e.g. [Leu2]-TRH-CDS was more stable in pH 7.4 than in pH 6.5 aqueous solutions. After lyophilizing the saturated CDSs in 50% HPBCD complex solutions, the amount of CDS in the complex was determined as 26.22, 26.79, and 30.34 mg/g for [Leu2]-TRH, [Nva2]-TRH and [Nva2, Pip3]-TRH, respectively. The half-life of [Leu2]-TRH-CDS/HPBCD solid complex at 25 degrees C, 4 degrees C and -15 degrees C was about 100 days, 440 days and no detectable change in three months, respectively. Argon protected condition did not improve the stability of lyophilized [Leu2]-TRH-CDS/HPBCD complex. Dimethyl sulfoxide although increased the solubility of [Leu2]-TRH-CDS in the 50% HPBCD solution by 1.3 times, significantly decreased its stability by 6.6 times. After intravenous administration of CDS (in 30% HPBCD) at a dose of 10 mumole/kg in mice, compared to the vehicle control or the same dose of [Leu2]-TRH (in 30% HPBCD), a significant increase in pharmacological effect (decrease in barbiturate-induced sleeping time) was observed. These results demonstrate the usefulness of cyclodextrin in the formulation of the CDSs of TRH analogs.     

Oversaturated solutions of drug in hydroxypropylcyclodextrins: parenteral preparation of pancratistatin

The effect of 15 cyclodextrin derivatives (polar-electroneutral, cationic, anionic, and lipophilic) and of three 2-hydroxypropyldigitonins on the solubility of pancratistatin, an anticancer drug, was evaluated. The direct solubilizations into aqueous solutions were invariably low (0.1-1.2 mg/mL compared with 50 micrograms/mL in water). Complexes of pancratistatin with hydroxypropyl-beta-cyclodextrin were more stable (Kapp 153 M-1) than those with hydroxypropyl-gamma-cyclodextrin (Kapp 108 M-1). Acceptable preparations were made by dissolution of pancratistatin in a large excess (50x) of hydroxypropylcyclodextrin by ammonia and then freeze drying to ammonia-free preparations. In these preparations, both the inclusion and interdispersion phenomena were operative, and the preparations dissolved rapidly forming clear solutions of pancratistatin of concentrations up to 9 mg/mL. These solutions were oversaturated and while those based on hydroxypropyl-beta-cyclodextrin precipitated within 1 h; those based on hydroxypropyl-gamma-cyclodextrin were stable for at least 4 h when kept in a plastic container (i.e., time sufficient for potential use in parenteral preparations).     

Effect of pH and complexation on transdermal permeation of gliquidone

Gliquidone, a second generation sulfonylurea has been investigated for transdermal delivery. The poor aqueous solubility of the drug prompted the use of hydroxypropyl-beta-cyclodextrin (HP-beta-CD), a cyclic oligosaccharide, which is known to facilitate transdermal permeation of many drugs by enhancing the solubility and thus improving the diffusible species of the drug molecules at the skin-vehicle interface. In order to optimize the transdermal delivery of gliquidone, the effect of pH along with complexation on the solubility and permeation has been investigated. The solubility profiles of the drug, on increasing the concentration of HP-beta-CD were of Higuchi's AL type at the three pH values evaluated. However, the solubilization slope of the drug at pH 7.0 was 22 times that at pH 3.0 as a result of greater intrinsic solubility of the ionized form of the drug at pH 7.0. Transdermal flux of gliquidone at pH 7.0 was significantly greater than the flux at pH 3.0 in the presence of 15% w/v HP-beta-CD, attributable to the better solubility of the drug at pH 7.0 in the presence of HP-beta-CD. The effect of increasing concentrations of HP-beta-CD investigated at variable drug loading in the donor phase at pH 7.4 endorsed the earlier observations from studies on other drugs, that the drug has to be present at saturation in HP-beta-CD aqueous vehicle to achieve an optimized flux. While at saturation, the steady state flux of gliquidone from the aqueous HP-beta-CD (25% w/v) vehicle was enhanced 31 times compared to pure drug suspension at pH 7.4, unsaturation in the donor phase resulted in the decreased flux of gliquidone. It was concluded from the present study that enhanced transdermal flux of gliquidone can be achieved by adjusting the pH and the concentration of HP-beta-CD to achieve a better solubility of the drug.     

Quinolones in the treatment of uncomplicated urinary tract infections

In comparative clinical studies the quinolones have been shown to be effective in a short-course (3-5 days) or a single dose therapy in uncomplicated urinary tract infections. Comparative clinical trials of single dose therapy with the fluoroquinolones and trimethoprim or co-trimoxazole (trimethoprim/ sulfamethoxazole) for acute bacterial cystitis have shown equivalent efficacy. Studies on the use of quinolones for the treatment of uncomplicated acute pyelonephritis have also been reviewed. The results from several comparative trials which compared the fluoroquinolones with netilmicin, co-trimoxazole, cefadroxil, or ceftazidime have been comparable. Some of the fluoroquinolones can be administered in parenteral and oral forms enabling the patient to be discharged from hospital earlier, a more cost-effective option. The fluoroquinolones, in particular norfloxacin, have also been shown to be effective as prophylactic agents for patients with recurrent symptomatic urinary tract infections. The optimal dosage and length of prophylactic treatment have not yet been clearly defined.     

Effects of 2-hydroxypropyl-beta-cyclodextrin on pharmacokinetics of digoxin in rabbits and humans

Considering the narrow therapeutic index of digoxin and the low range between the safe and toxic serum concentrations of this drug, to evaluate the relative bioavailability of tablets and oral solution is necessary. The pharmacokinetic properties of digoxin after oral administration of its hydroxypropyl-beta-cyclodextrin (HPCD) inclusion complex to rabbits and human volunteers were investigated in comparison with those of commercially available tablets. The aqueous solubility of digoxin was enhanced by HPCD for about 2000 times at HPCD concentration of 50% (w/v). But in a human bioavailability study no significant difference was observed in the extent of absorption (AUC(0-t)) and Cmax between the two formulations. Time to reach peak was significantly shorter for the solution than for the tablets (p < 0.01). The pharmacokinetic results from the rabbit study were similar to human studies and no significant difference was observed for AUC, Cmax and Tmax. As the bioavailability of both tablets and solution is equivalent HPCD based oral digoxin solution could serve as an alternative to tablets.