Physiologically Based Pharmacokinetic Modeling of Renally Cleared Drugs in Pregnant Women.

BACKGROUND: Since pregnant women are considerably underrepresented in clinical trials, information on optimal dosing in pregnancy is widely lacking. Physiologically based pharmacokinetic (PBPK) modeling may provide a method for predicting pharmacokinetic changes in pregnancy to guide subsequent in vivo pharmacokinetic trials in pregnant women, minimizing associated risks. OBJECTIVES: The goal of this study was to build and verify a population PBPK model that predicts the maternal pharmacokinetics of three predominantly renally cleared drugs (namely cefazolin, cefuroxime, and cefradine) at different stages of pregnancy. It was further evaluated whether the fraction unbound (f u) could be estimated in pregnant women using a proposed scaling approach. METHODS: Based on a recent literature review on anatomical and physiological changes during pregnancy, a pregnancy population PBPK model was built using the software PK-Sim®/MoBi®. This model comprised 27 compartments, including nine pregnancy-specific compartments. The PBPK model was verified by comparing the predicted maternal pharmacokinetics of cefazolin, cefuroxime, and cefradine with observed in vivo data taken from the literature. The proposed scaling approach for estimating the f u in pregnancy was evaluated by comparing the predicted f u with experimentally observed f u values of 32 drugs taken from the literature. RESULTS: The pregnancy population PBPK model successfully predicted the pharmacokinetics of cefazolin, cefuroxime, and cefradine at all tested stages of pregnancy. All predicted plasma concentrations fell within a 2-fold error range and 85% of the predicted concentrations within a 1.25-fold error range. The f u in pregnancy could be adequately predicted using the proposed scaling approach, although a slight underestimation was evident in case of drugs bound to α1-acidic glycoprotein. CONCLUSION: Pregnancy population PBPK models can provide a valuable tool to predict a priori the pharmacokinetics of predominantly renally cleared drugs in pregnant women. These models can ultimately support informed decision making regarding optimal dosing regimens in this vulnerable special population.

A medusa-like ß-cyclodextrin with 1-methyl-2-(2'-carboxyethyl) maleic anhydrides, a potential carrier for pH-sensitive drug delivery.

We developed a new pH-sensitive drug delivery carrier based on ß-cyclodextrin (ß-CD) and 1-methyl-2-(2'-carboxyethyl) maleic anhydrides (MCM). The primary hydroxyl groups of ß-CD were successfully attached to MCM residues to produce a medusa-like ß-CD-MCM. The MCM residue was conjugated with cephradine (CP) with high efficiency ( > 90%). More importantly, ß-CD-MCM-CP responded to the small pH drop from 7.4 to 5.5 and released greater than 80% of the drugs within 0.5 h at pH 5.5. In addition, the inclusion complex between ß-CD-MCM-CP and the adamantane derivative was formed by simple mixing to show the possibility of introducing multi-functionality. Based on these results, ß-CD-MCM can target weakly acidic tissues or organelles, such as tumours, inflammatory tissues, abscesses or endosomes, and be easily modified with various functional moieties, such as ligands for cell binding or penetration, enabling more efficient and specific drug delivery.

Preparation and characterization of electrospun PLGA/gelatin nanofibers as a drug delivery system by emulsion electrospinning.

Novel biocompatible poly(lactide-co-glycolide) (PLGA) nanofiber mats with favorable biocompatibility and good mechanical strength were prepared, which could serve as an innovative type of tissue engineering scaffold or an ideal controllable drug delivery system. Both hydrophobic and hydrophilic drugs, Cefradine and 5-fluorouracil were successfully loaded into PLGA nanofiber mats by emulsion electrospinning. The natural bioactive protein gelatin (GE) was incorporated into the nanofiber mats to improve the surface properties of the materials for cell adhesion. Nanofibrous scaffolds were characterized by scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, contact angle and tensile measurements. Emulsion electrospun fibers with GE had perfect hydrophilic and good mechanical property. The in vitro release test showed thedrugs released from emulsion electrospun fibers, which achieved lower burst release. The cells cytotoxicity experiment indicated that emulsion electrospun fibers were less toxic and tended to promote fibroblasts cells attachment and proliferation, which implied that the electrospun fibers had promising potential application in tissue engineering or drug delivery.

A study of the chemiluminescence behavior of cephalosporins with luminol and its analytical application.

The chemiluminescence intensity of luminol-dissolved oxygen was decreased when cephalosporins were mixed with luminol. The decrease chemiluminescence intensity was linear with the logarithm of cephalosporins concentration over the range from nanogram to microgramme level, with the limits of detection at nanogram level. The sensitivities of determination for cephalosporins were in the order of cefoperazone > ceftriaxone > cefuroxime > cefaclor > cefalexin > cefradine. The proposed method was applied to monitor the excretion of cefradine in human urine after taken cefradine capsules. The possible chemiluminescence mechanism and relationship between the determination sensitivities and generations of cephalosporins were also discussed.

[Microcalorimetric investigation of two cephalosporins on colon bacteria activity].

The effects of cephradinum and ceftazidime on the metabolism of Escherichia coli (E. coli) DH5alpha was determined by microcalorimetry. The microbial activity was recorded as power-time curves through an ampoule method with a TAM Air Isothermal Microcalorimeter at 37 degrees C. The parameters such as the growth rate constant (k), inhibitory ratio (I), the maximum power output (Pm) and the time (tm) corresponding to the maximum power output were calculated. The results show that the ceftazidime has a better inhibitory effect on E. coli DH5alpha than cephradinum.

Pharmacokinetic study of cephradine in Pakistani healthy male volunteers.

To observe and discuss the difference in the pharmacokinetics of cephradine in Pakistani population with the reported data of other ethnic origins. A Single group pharmacokinetic study was conducted having six healthy male volunteers of 20-24 years of age. Blood samples were collected at appropriate times up to 7 hours. Plasma concentrations of cephradine was determined by HPLC technique and pharmacokinetic parameters were determined by both compartmental and noncompartmental methods using Kinetica ver 4.4.1 and Winnonlin ver 5.01. Peak plasma concentration was 11.49+/-1.73 microg/ ml achieved at 0.76+/-0.12 hr, after the administration of 250 mg cephradine to fasting volunteers. Area under the serum concentration-time curve was found to be 16.4+/-1.71 g.hr/ ml. Absorption, distribution, disposition and elimination half lives were calculated as 0.183 +/- 0.038 hr, 0.248 +/- 0.143 hr, 2.126 +/- 0.341 hr and 0.441+/-0.193 hr respectively where as the volume of central compartment and total body clearance were found to be 9.65+/-3.78 L and 15.4+/-1.89 L/hr. The plasma concentration time curves showed the absorption rate constant was 3.968 +/- 0.05 hr(-1), disposition rate constant was 0.333+/-0.05 hr(-1), distribution rate constant was 3.64+/-2.18 hr(-1) and elimination rate constant was 1.738+/-0.468 hr(-1). The value of micro-constants i.e. K(12) (central to peripheral compartment) and K(21) (peripheral to central compartment) were found to be 1.529+/- 1.499 hr(-1) and 0.704 +/- 0.44 hr(-1) respectively, where as MRT and AUMC were calculated as 2.04+/-0.09 hr and 35.92+/-1.86 hr(2) microg/ ml. The findings showed that the results of Pakistani subjects are slightly different when compared with the reported data of other ethnic origin.

Properties and active substance release kinetics from gelatin-alginate matrices.

The aim of the study was to evaluate the effect of composition and technological processing on pharmaceutical availability of active substance as well as on the properties of porous gelatin-alginate matrices. The active substance carrier included glycerol or peanut oil apart from gelatin and sodium alginate, and some matrices were additionally modified with calcium lactate. The obtained matrices were characterized by good sorption properties and high resistance to proteolytic enzymes. The release of the model antibiotic followed the pattern of first order kinetics, while half-release time in vitro (in the experimental conditions) was 1.5 to 3 hrs.

Controlled drug delivery system based on magnetic hollow spheres/polyelectrolyte multilayer core-shell structure.

A novel controlled drug delivery system was fabricated by coating chitosan/PAA multilayer onto magnetic hollow spheres via a "Layer-by-Layer" (LBL) assembly approach. Cefradine was used as a model drug to evaluate the drug release characteristics of this core-shell hollow structure and the results show that it exhibits a sustained release of the drug and the release rate can be regulated by the pH environment of release medium. It is believed that this core-shell hollow structure, which combines the advantage of controlled delivery as well as magnetic targeting, has commendable potential in drug delivery therapeutics.

Preparation and characterization of uniform nanosized cephradine by combination of reactive precipitation and liquid anti-solvent precipitation under high gravity environment.

In this work, a novel direct method, which was combined with reactive precipitation and liquid anti-solvent precipitation under high gravity environment, had been developed to prepare nanosized cephradine with narrow particle size distribution. Compared with commercial crude cephradine, the prepared cephradine showed a significant decrease in particle size, a significant increase in the specific surface area and shorter dissolving time when used for injection. The characteristic particle size was between 200-400 nm. The specific surface area increased from 2.95 to 10.87 m2/g after micronization. When the amount of L-arginin decreased from 0.25 to 0.18 g, the mixture of nanosized cephradine and L-arginine could still dissolve in 1 min. The X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR) analysis indicated that the physical characteristics and molecular states remained unchanged after the recrystallization process. This method had potential application in industrial fields because of its low cost, efficient processing and the ease of scaling-up.

Preparation and characterization of porous hollow silica nanoparticles for drug delivery application.

Porous hollow silica nanoparticles (PHSNP) with a diameter of 60-70 nm and wall thickness of approximately 10nm were synthesized by using CaCO(3) nano-particles as the inorganic template. The characterization of PHSNP by TEM and BET indicated that PHSNP were uniform spherical particles with good dispersion, and had a specific surface area of 867 m(2)/g. The as-synthesized PHSNP were subsequently employed as drug carrier to investigate in vitro release behavior of cefradine in simulated body fluid. UV-spectrometry and TG analyses were performed to determine the amount of cefradine entrapped in the carrier. The BJH pore size distribution of PHSNP before and after entrapping cefradine was examined. Cefradine release profile from PHSNP followed a three-stage pattern and exhibited a delayed release effect.

An interrupted time series analysis of parenteral antibiotic use in Colombia.

A University-based hospital in Bogotá, Colombia, developed and implemented an educational intervention to complement a new structured antibiotic order form. This intervention was performed after assessing the appropriateness of the observed antibiotic prescribing practices using a quasi-experimental study. An application of interrupted time series intervention analysis was conducted in three antibiotic groups (aminoglycosides, cephradine/cephalothin, and ceftazidime/cefotaxime) and their hospital weekly rate of incorrect prescriptions before and after the intervention. A fourth time series was defined on prophylactic antibiotic use in elective surgery. Preintervention models were used in the postintervention series to test for pre-post series level differences. An abrupt constant change was significant in the first, third, and fourth time series indicating a 47, 7.3, and 20% reduction of incorrect prescriptions after the intervention. We conclude that a structured antibiotic order form, coupled with graphic and educational interventions can improve antibiotic use in a university hospital.

Treatment of breast abscesses with sonographically guided aspiration, irrigation, and instillation of antibiotics.

OBJECTIVE: We studied the feasibility of treating breast abscesses with sonographically guided aspiration, irrigation, and local instillation of antibiotics without placing indwelling catheters. MATERIALS AND METHODS: Seventy-three patients with breast abscesses were seen from 1995 to 2001. Aspiration and irrigation were performed under sonographic guidance. Repeated aspiration was performed when deemed necessary. One gram of cephradine was injected into 29 abscesses measuring more than 25 mm. RESULTS: Six patients refused further treatment after failure of the first aspiration and elected surgical drainage. Of the remaining 67 patients who completed treatment, 38 required one aspiration for cure, 18 required two aspirations, and eight required more than two aspirations. The treatment failed and surgical drainage was required in only three of the 67 patients completing treatment. CONCLUSION: Ninety-six percent of patients completing treatment were cured with this procedure. Local instillation of antibiotics is probably beneficial.

A recirculatory model with enterohepatic circulation by measuring portal and systemic blood concentration difference.

The present study describes a recirculatory model for the evaluation of pharmacokinetic characteristics of drugs possessing enterohepatic circulation (EHC). The advantage of the model is to separately define the extent and rate of absorption for the dosage and EHC after oral administration. Cephradine was used as a model drug and was intravenously or orally administered to rats. Portal and systemic bloods were simultaneously collected in order to estimate various local moments after defining the global moments obtained by non-compartment analysis. For the zero-order moments, bioavailability (BA), the hepatic recovery ratio (Fh), the sum of the local absorption ratio for the dosage and recirculatory local absorption ratio for EHC (F(a)po), and the recirculatory local absorption ratio for EHC (F(a)ehc) after oral administration were estimated to be 95.6, 77.9, 172, and 71.5%, respectively. These data indicate that a complete absorption and substantial EHC contribute high oral exposure of cephradine. For the first-order moments, the sum of the mean local absorption times for the dosage and EHC (t(a)po) and the mean transit time for a single pass of EHC (tc) were 2.50 and 0.117 hr, suggesting a rapid EHC of cephradine compared with the absorption from the dosage. With this model, the absorption rate-time profiles for the dosage and EHC were separately simulated by using a program of nonlinear least squares (MULTI) with fast inverse Laplace transform (FILT). The cumulative biliary excretion ratio (Fbile) calculated by the model was in good agreement with the experimental value obtained in the bile ductcannulated rats. These results suggest that the model proposed in this study would be useful for evaluating the extent and rate of ECH along with absorption from the dosage after oral administration of drugs.

Prolonged intestinal absorption of cephradine with chitosan-coated ethylcellulose microparticles in rats.

Cephradine-containing ethylcellulose microparticles (MPC) were prepared by the solvent evaporation method. Chitosan-coated MPC (Chi-MPC) were prepared by doping MPC with viscous chitosan solution and subsequently drying. When fluorescein isothiocyanate (FITC)-labeled chitosan-coated ethylcellulose microparticles without drug were administered intraduodenally, they moved slowly in the intestine, that is, most of them were retained at the upper and middle parts of the small intestine for more than 8 h, which is considered due to mucoadhesive properties of coated chitosan. When MPC and Chi-MPC was incubated at 37 degrees C in the JP 14 second fluid, pH 6.8, both released the drug slowly with similar release rates. Cephradine solution and suspension, MPC and Chi-MPC were administered intraduodenally to investigate intestinal drug absorption. Only Chi-MPC suppressed the initial plasma level and maintained the plasma concentration for a long time up to 24 h, suggesting Chi-MPC would be useful for prolonged intestinal absorption of cephradine.

Update on prosthetic joints, dental treatment, and antibiotic prophylaxis.

At this time, all dentists and physicians should be very familiar with the 1997 ADA/AAOS antibiotic prophylaxis recommendations for joint prosthesis patients who are undergoing dental treatment. The guidelines identify physical conditions that place joint replacement patients at the highest risk for joint sepsis. They also stratify dental procedures into higher-risk and lower-risk categories. Combining these two groupings clarifies the dentist's strategy for antibiotic prophylaxis protocols, which are greatly simplified over previous practices. Of notable importance is the elimination of posttreatment antibiotic dosing, the reduction of the loading dose of antibiotic, and the identification of a large group of joint replacement patients who do not require antibiotic prophylaxis prior to dental treatment. Every dentist must use clinical judgment, knowledge of the patient, and consultation with the attending physician to determine the appropriate treatment plan.

Comparison of local povidone-iodine antisepsis with parenteral antibacterial prophylaxis for prevention of infective complications of TURP: a prospective randomized controlled study.

OBJECTIVE: To determine whether antisepsis with povidone-iodine solution applied at the external urethral meatus confers protection against infective complications following transurethral resection of the prostate (TURP) and compare that with antibacterial prophylaxis. METHODS: A total of 167 patients with sterile urine undergoing TURP for benign prostatic hyperplasia (BPH) were prospectively randomized into three groups. Group A, had gauze soaked in saline applied at the urethral meatus (control group). In group B, the gauze was soaked in povidone-iodine instead of saline and group C had a single 1 g i.v. injection of cephradine at induction of anaesthesia with no treatment for the meatus. Bacteraemia, post-operative bacteriuria and other infective complications were compared in the three groups. Associations of bacteriuria at catheter removal and intra-operative bacteraemia with infective complications and with long term bacteriuria were also studied. RESULTS: Bacteriuria rate at catheter removal was not significantly different in the three groups. However, intraoperative bacteraemia and bacterial growth at the external urethral meatus was significantly lower in group C. Bacteriuria at catheter removal was significantly associated with bacterial growth at the meatus but not with long term bacteriuria at 3 months. Bacteriuria at catheter removal could not accurately predict infective complications. CONCLUSION: Post-TURP bacteriuria appears to be preceded by bacterial growth at the external urethral meatus. Antisepsis with povidone-iodine solution application at the meatus does not confer adequate protection against meatal bacterial growth as that obtained by prophylactic antibacterials. Nonetheless, neither antibacterial prophylaxis nor local antisepsis could reduce bacteriuria rate in this study.

Intraperitoneal ciprofloxacin and rifampicin versus cephradine as initial treatment of (C)APD-related peritonitis: a prospective randomized multicenter comparison (CIPPER trial).

OBJECTIVE: The initial treatment of peritonitis has evolved from single-agent to combination regimens. The initial response rates improved with these newer regimens but relapsing peritonitis continues to occur. For biofilm-embedded or intracellularly sequestrated bacteria, a combination of intracellularly- and biofilm-active agents such as ciprofloxacin and rifampicin might be beneficial. Many Dutch centers continue to use cephradine as initial treatment, claiming clinically adequate responses with this regimen. We compared the impact of these two regimens on outcome in patients who developed a new episode of peritonitis. DESIGN: Prospective randomized open trial. SETTING: Multicenter study including 14 Dutch dialysis units. PATIENTS AND INTERVENTIONS: From October 1996 to October 1999, 367 patients from 14 centers were randomized to be treated with ciprofloxacin + rifampicin (CR; each 50 mg/L) or cephradine (C; 250 mg/L) in case of peritonitis. Of these 367 patients, 98 developed peritonitis, 44 of whom were treated with CR and 54 with C. MAIN OUTCOME MEASURES: Clinical response, divided into early (during the 2 weeks of therapy) and late (including the following 4 weeks) response. Success was defined as disappearance of all signs and symptoms by days 4-6, through day 42. Bacteriological response was either success (eradication) or failure (persistence, superinfection, or eradication with relapse/reinfection). RESULTS: The groups were comparable for age, sex, duration of continuous ambulatory/automated peritoneal dialysis, and occurrence of diabetes. Bacteriological cultures in both groups revealed predominantly gram-positive micro-organisms. Initial and late clinical successes were obtained in 27/54 and 20/54 episodes (50% and 37%) in the C group, and 33/44 and 28/44 episodes (75% and 63.6%) in the CR group (p = 0.021 and p = 0.019). Bacteriological success occurred in 29.6% in the C group, and in 59.1% in the CR group (p= 0.026), with failure in 46.3% and 18.2%, respectively. Peritonitis episodes were bacteriologically not evaluable in 24.1% of episodes in the C group and 22.7% of episodes in the CR group, due mostly to no growth in the initial culture. CONCLUSION: The CIPPER Trial showed ciprofloxacin + rifampicin to be superior to cephradine as empiric treatment of peritonitis.

Labile conjugation of a hydrophilic drug to PLA oligomers to modify a drug delivery system: cephradin in a PLAGA matrix.

The physical entrapment of a hydrophilic drug within degradable microspheres is generally difficult because of poor entrapment yield and/or fast release, depending on the microsphere fabrication method. In order to counter the effects of drug hydrophilicity, it is proposed to covalently attach the drug to lactic acid oligomers, with the aim of achieving temporary hydrophobization and slower release controlled by the separation of the drug from the degradable link within the polymer matrix. This strategy was tested on microspheres of the antibiotic cephradin. As the prodrug form, the entrapment of the drug was almost quantitative. The prodrug did degrade in an aqueous medium, modelling body fluids, but cleavage did not occur at the drug-oligomer junction and drug molecules bearing two lactyl residual units were released. When the prodrug is entrapped within a PLAGA matrix, no release was observed within the experimental time period. However, data suggest that conjugation via a bond more sensitive to hydrolysis than the main chain PLA ester bonds should make the system work as desired.