Beneficial herb-drug interaction of rhein in Jinhongtang and Imipenem/Cilastatin mediated by organic anion transporters.

ETHNOPHARMACOLOGICAL RELEVANCE: Jinhongtang as a traditional Chinese medicine (TCM) formula, has been widely used as a clinical adjuvant in the treatment of acute abdominal diseases and sepsis. Clinical benefits of the concurrent use of Jinhongtang and antibiotics have been observed, however, the mechanism has not been fully understood. AIM OF THE STUDY: The present study aimed to explore the effect of Jinhongtang on the antibacterial activity of Imipenem/Cilastatin and to clarify the underlying mechanism of herb-drug interaction (HDI). MATERIALS AND METHODS: A mouse model of sepsis induced by Staphylococcus aureus (S. aureus) was used to evaluate the pharmacodynamic interaction in vivo. In vitro antibacterial activity of Imipenem/Cilastatin was studied by determining minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC). Pharmacokinetic interaction was investigated by pharmacokinetic studies in rats and uptake assays using OAT1/3-HEK293 cells. The main constituents ingested into blood of rats were qualitatively identified by UHPLC-Q-TOF-MS. RESULTS: Mice treated by Imipenem/Cilastatin and Jinhongtang exhibited higher survival rate, lower bacteria load and less inflammation in blood and lung tissues, compared with those treated by Imipenem/Cilastatin alone after injection of S. aureus. However, MIC and MBC of Imipenem/Cilastatin against S. aureus in vitro were not significantly changed in the presence of Jinhongtang. On the contrary, Jinhongtang increased the plasma concentration of Imipenem and decreased its urinary excretion in rats. CLr of Imipenem was reduced by 58.5%, while its half-life (t1/2) was prolonged for approximate 1.2 times after coadministered Jinhongtang. Furthermore, the extracts of Jinhongtang, single herb in the prescription, and main absorbable constituents inhibited cellular uptake of probe substrates and Imipenem by OAT1/3-HEK293 cells to different extents. Among them, rhein exhibited the strongest inhibition capacity with IC50 values of 0.08 ± 0.01 µM (OAT1) and 2.86 ± 0.28 µM (OAT3). Moreover, coadministration of rhein also significantly enhanced the antibacterial activity of Imipenem/Cilastatin in sepsis mice. CONCLUSION: Concomitant administration of Jinhongtang enhanced antibacterial activity of Imipenem/Cilastatin in sepsis mice induced by S. aureus through reducing renal elimination of Imipenem via inhibition of OATs. Our investigation provided the insight of Jinhongtang as an effective supplement to enhance the antibacterial activity of Imipenem/Cilastatin and can be useful for future clinical studies.

Kidney-Protector Lipidic Cilastatin Derivatives as Structure-Directing Agents for the Synthesis of Mesoporous Silica Nanoparticles for Drug Delivery.

Mesoporous silica nanomaterials have emerged as promising vehicles in controlled drug delivery systems due to their ability to selectively transport, protect, and release pharmaceuticals in a controlled and sustained manner. One drawback of these drug delivery systems is their preparation procedure that usually requires several steps including the removal of the structure-directing agent (surfactant) and the later loading of the drug into the porous structure. Herein, we describe the preparation of mesoporous silica nanoparticles, as drug delivery systems from structure-directing agents based on the kidney-protector drug cilastatin in a simple, fast, and one-step process. The concept of drug-structure-directing agent (DSDA) allows the use of lipidic derivatives of cilastatin to direct the successful formation of mesoporous silica nanoparticles (MSNs). The inherent pharmacological activity of the surfactant DSDA cilastatin-based template permits that the MSNs can be directly employed as drug delivery nanocarriers, without the need of extra steps. MSNs thus synthesized have shown good sphericity and remarkable textural properties. The size of the nanoparticles can be adjusted by simply selecting the stirring speed, time, and aging temperature during the synthesis procedure. Moreover, the release experiments performed on these materials afforded a slow and sustained drug release over several days, which illustrates the MSNs potential utility as drug delivery system for the cilastatin cargo kidney protector. While most nanotechnology strategies focused on combating the different illnesses this methodology emphasizes on reducing the kidney toxicity associated to cancer chemotherapy.

[The clinical efficacy of imipenem/cilastatin sodium in orthopedic infections and drug levels in the bone tissue].

We evaluated the clinical efficacy of imipenem/cilastatin sodium (IPM/CS--a carbapenem antibiotic) against orthopedic infections, and the drug levels of the bone tissues were determined. The clinical efficacies for 6 patients in the infection group were good in 3 cases, and fair in the other 3; giving an efficacy rate of 50%. Bacteriologically, 8 strains were isolated from patients with the infection and an eradication rate of 87.5% was obtained upon the treatment. In 39 patients that were given the drug prophylactically, no postoperative infections occurred. Mean IPM levels in the bone and the bone marrow at 1 hour after administration in 5 patients of the prophylactic group were 17.3 micrograms/ml and 5.9 micrograms/g, respectively. The ratio of concentrations the bone to those in the bone marrow was 34.6%. The results of this study suggest that IMP/CS reaches to the bone tissue providing sufficient concentrations and that the drug is efficacious for the prophylaxis and the treatment of orthopedic infections.

Mucosal pharmacokinetics and pilot study of short course of parenteral imipenem in the eradication of Helicobacter pylori.

Eradication of Helicobacter pylori infection is known to reduce the incidence of duodenal ulcer recurrence. The most commonly used regimen for H. pylori infection is triple antimicrobial therapy for 1-2 weeks. This treatment is associated with frequent side effects and hence unsatisfactory compliance. As in vitro data showed that H. pylori is sensitive to imipenem, the pharmacokinetics of this drug in the gastric milieu, and the clinical efficacy of imipenem with omeprazole in eradicating H. pylori infection were studied. Imipenem/cilastatin levels in serum, gastric secretion and gastric mucosa were assayed in four patients after intravenous injection of a bolus dose of 500 mg. The serum and gastric secretion levels of imipenem achieved were more than 10 times the minimum inhibitory concentration of the drug for H. pylori. Gastric mucosal levels of imipenem vary considerably with time, which probably indicates rapid elimination of the drug into the gastric lumen. In the second part of this study, imipenem/cilastatin was given intravenously for the first 2 days after diagnosis of H. pylori infection in patients with endoscopically confirmed duodenal ulcers. The patients were also treated with 4 weeks of omeprazole. Clearance of H. pylori was initially achieved at the end of 2 days in 20 out of 22 (91%) patients. However, when the biopsies were repeated at 8 weeks, recurrence of H. pylori infection was evident in 19 cases (86.3%) indicating a failure of eradication. It was concluded that imipenem/cilastatin in combination with omeprazole failed to eradicate H. pylori infection.

Pharmacokinetic evaluation of imipenem combined with cilastatin in cystic fibrosis.

The pharmacokinetics of imipenem (MK-787) and cilastatin (MK-791) were studied in 30 patients with cystic fibrosis (CF) receiving the drug for therapeutic purposes at doses of 11 mg/kg given as a 30-min infusion. The serum concentrations and urine elimination were studied after the first dose and during steady state. The concentrations were assayed by high-pressure liquid chromatography. The total areas under the imipenem serum concentration curves (AUCs) to infinity were 30.4 +/- 6.8 mg.h/l after the first dose compared with 29.1 +/- 7.1 mg.h/l during steady state (NS). The cilastatin AUCs on the 2 days were 40.3 +/- 9.3 and 38.3 +/- 0.4 mg.h/l (NS), respectively. The urinary recovery of imipenem was 47.8 +/- 17.8% after the first dose and 57.8 +/- 24.2% during steady state (NS). The amounts of cilastatin eliminated in the urine during 6 h were 6/7.3 +/- 22.9% after the first dose and 60.5 +/- 17.0% of the dose during steady state (NS). The mean half-life of imipenem in these CF patients was 1.2 +/- 0.4 h on the first day of the examination and within the same range during steady state. The distribution volume (Vd beta) was in the range of 28 liters, the total body clearance was 16.3 liters/h (285 ml/min) on the first day. The t1/2 of cilastatin was 0.59 +/- 0.14 h after the first dose and 0.61 +/- 0.14 h during steady state. Thus patients with CF eliminated cilastatin more quickly than imipenem.

[Chemotherapy with imipenem/cilastatin for severe infections accompanied by malignant hematological disorders].

The clinical and bacteriological efficacy of imipenem/cilastatin (IPM/CS) was evaluated in 30 cases of serious infections associated with hematological malignancies. 1. Among 28 evaluable cases, excellent efficacy was obtained in 6 cases and good effectiveness in 10 cases, resulting in a high clinical efficacy rate (57.1%). The clinical effectiveness of IPM/CS was not dependent on neutrophil count in peripheral blood. A 53.8% efficacy rate was observed in 26 cases which had received pretreatment with other antibiotics. 2. Antibacterial activities of IPM/CS have so far been evaluated against organisms isolated in 20 of 28 cases: 2 strains of coagulase-negative Staphylococcus, 2 strains of methicillin-resistant Staphylococcus aureus, 2 strains of Enterococcus faecalis, 9 strains of Enterobacter cloacae, and 8 other strains. 3. Among 3 evaluable cases treated with IPM/CS alone, response was good in 1 case. Among 25 patients receiving IPM/CS in combination with an aminoglycoside or a penicillin, the efficacy rate was 60%. 4. Five patients had IPM/CS-related adverse events; nausea and vomiting in 2 cases, seizures in 1 case, small increases in GOT and GPT in 2 cases, and the appearance of casts in urine sediment in 1 case. These patients, however, tolerated the complete course of therapy with IPM/CS except the 2 cases with nausea and vomiting. These results indicate that chemotherapy with IPM/CS is effective for the treatment of severe infectious diseases accompanied by hematological disorders.

Imipenem/cilastatin. A reappraisal of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy.

Imipenem is an antibacterial agent of the carbapenem class of beta-lactams, with a very broad spectrum of activity that includes most Gram-negative and Gram-positive pathogens, aerobes and anaerobes, and with marked activity against species producing beta-lactamases. It is coadministered with cilastatin, a renal dehydropeptidase inhibitor that prevents renal metabolism of imipenem. As initial monotherapy, imipenem/cilastatin provides effective and well-tolerated treatment of moderate to severe infections in various body systems, including intra-abdominal, obstetric and gynaecological, lower respiratory tract, skin and soft tissue, and urinary tract infections, and also in bacteraemia and septicaemia, and in patients with malignancy-related febrile neutropenia. It is likely to be of particular benefit in cases where bacterial pathogens have not yet been identified, such as in the treatment of serious infections in immunocompromised patients, or in an intensive care setting. Thus, imipenem/cilastatin is effective as initial monotherapy of a variety of infections, including infections in neutropenic patients, with a clear role in empirical treatment of mixed infection.

Intramuscular imipenem as adjuvant therapy for acute cholecystitis and perforated or gangrenous appendicitis.

An open-label prospective study was performed employing intramuscularly administered imipenem as an adjunct to surgery in 20 patients with acute cholecystitis and 24 patients with perforated or gangrenous appendicitis. Three (12.5%) septic failures occurred in appendicitis patients and 2 (10%) failures in cholecystitis patients. There were no deaths. Adverse effects were minor, and there was no toxicity. Although failures were not associated with in vitro resistance, Pseudomonas spp. were recovered from 2 of 3 appendicitis failures. Intramuscular imipenem appeared to be an effective single-drug antimicrobial when used as an adjunct to surgery in patients with acute cholecystitis or perforated appendicitis. It should be a more cost-effective alternative to the current multiple-drug therapy frequently employed in patients with intra-abdominal sepsis.

Pharmacokinetics of imipenem in patients undergoing major colon surgery.

Ten patients about to undergo a colorectal operation lasting an average of three hours received 500 mg each of imipenem and cilastatin i.v. preoperatively. During the operation blood and tissue samples were taken in order to determine the serum kinetics of the substances as well as the levels of imipenem in the cutis, subcutis, fascia, muscle, parietal peritoneum and colon. The imipenem concentrations were measured by HPLC. The mean peak serum concentration was 26 mg/l, the mean half-life 55 min and the AUC 40 mg/l/h-1. The serum pharmacokinetics of imipenem was subject to substantially larger fluctuations in this patient group than in subjects or patients without surgery. Imipenem rapidly penetrates into tissue, with peak concentrations being reached after 10-25 min. The highest imipenem concentrations were found in the colon, the lowest in the cutis and subcutis. After 1 h a level of 8 mg/kg imipenem was still found in the colon. The concentrations were greater than 1 mg/kg in all tissues for more than 3 h p. a. and thus within this period exceeded the MICs of Escherichia coli and Bacteroides fragilis, the indicator organisms of intraabdominal infections.

[Study of the intraperitoneal penetration of imipenem/cilastatin in acute peritonitis with perforation]. / Etude de la pénétration intrapéritonéale de l'imipénème/cilastatine au cours de péritonites aiguës avec perforation.

A study was performed to investigate the intraperitoneal penetration of Imipenem/cilastatin into inflammatory peritoneal fluid. Six patients undergoing abdominal surgery (acute peritonitis), were treated with Imipenem/cilastatin (4 perfusions of 0.5 g/day) during 5 days after the intervention. Plasma samples were obtained on day 1 and 4 at the pic and at the valley; peritoneal samples were obtained every days for 4 days, 1, 3 and 6 hours after the end of a perfusion. The samples were immediately stabilised following the manufacturer instructions and quick freezed at -80 degrees C. Dosages were performed using a microbiological assay. The mean peritoneal levels are above the MIC 90 of the more frequent bacteria which cause infection in abdominal surgery. Moreover none of the patients showed relapse of infection or complication during this treatment.

Pharmacokinetics of imipenem/cilastatin in neutropenic patients with haematological malignancies.

The pharmacokinetics of imipenem/cilastatin were studied in febrile neutropenic patients with haematological malignancies. The peak plasma concentrations (36.4 +/- 4.96 mg/l), plasma half-life (60 min), volume of distribution (0.28 +/- 0.02 l/kg) and plasma clearance (3.23 +/- 0.38 ml/min/kg) were comparable with those in normal healthy volunteers suggesting that the drug handling is not appreciably altered in this group of patients. The administration of 12.5 mg/kg (max 1 g), 6-hourly achieved levels that were up to 3.5 times MICs of most relevant bacteria. The drug therefore has a potential use as empirical monotherapy in febrile neutropenic patients.

Antimicrobial agents in pediatrics.

For proper use of antimicrobial agents in infants and children, special precautions should be taken. These include knowledge of the pharmacokinetic properties of these agents, especially in neonates, and of host factors related to gestational and chronological ages of the patient. Failure to recognize such factors can result in either lack of therapeutic response of drug-related adverse effects. In this article, special aspects of the pharmacokinetics of antibiotics and the clinical pharmacology and indications for use of the beta-lactam antibiotics in infants and children are presented.

[Pharmacokinetics and clinical evaluation of imipenem/cilastatin sodium in pediatric surgery].

Pharmacokinetic and clinical studies on imipenem/cilastatin sodium (IPM/CS) in pediatric surgery were performed and the results obtained are summarized below. 1. Plasma and urinary levels of IPM/CS were measured in 9 neonate patients following drip-infusion for 1 hour of IPM/CS (dose of IPM 10 mg/kg for 5 patients, 20 mg/kg for 4 patients). In the 10 mg/kg group, peak plasma levels were observed at the end of infusion or after 1 hour of it. IPM 9.95-14.2 micrograms/ml, CS 7.7-30.1 micrograms/ml. In the 20 mg/kg group, peak levels were found at the end of the infusion, IPM 39.2-41.7 micrograms/ml, CS 48.1-58.8 micrograms/ml. In both groups, plasma levels of IPM/CS decreased rapidly, and plasma half-lives (T 1/2) in the 20 mg/kg group were 0.9-1.2 hours (IPM) and 0.8-1.1 hours (CS). Urinary recovery rates were 17.7-28.7% (10 mg/kg), 21.1-36.9% (20 mg/kg) for IPM and 27.1-43.8% (10 mg/kg) and 21.5-76.5% (20 mg/kg) for CS. 2. Bile levels of IPM/CS were measured in 3 patients with congenital biliary atresia and 1 patient with neonatal hepatitis. Peak levels of IPM/CS in bile were noted 1 hour after the end of infusion, and they were 3.01-12.3 micrograms/ml for IPM, and 2.5-13.1 micrograms/ml for CS. Recovery rates in bile in 7 hours after the end of infusion were 0.03-0.12% (IPM), 0.01-0.12% (CS). 3. IPM/CS was administered to 9 patients as prophylaxis against postoperative infections and to 2 patients with postoperative cholangitis. No infectious complications were observed in patients after the prophylactic use. In 1 patient with cholangitis, clinical effect was good and organisms were eradicated. No clinical or laboratory adverse reactions due to the administration of IPM/CS were noted. It is concluded that IPM/CS is an effective and safe antibiotic in pediatric surgery.