Association of CCND1 rs9344 polymorphism with lung cancer susceptibility and clinical outcomes: a case-control study.

BACKGROUND: Cyclin D1 (CCND1) plays a pivotal role in cancer susceptibility and the platinum-based chemotherapy response. This study aims to assess the relationship between a common polymorphism (rs9344 G > A) in CCND1 gene with cancer susceptibility, platinum-based chemotherapy response, toxicities and prognosis of patients with lung cancer. METHODS: This study involved 498 lung cancer patients and 213 healthy controls. Among them, 467 patients received at least two cycles of platinum-based chemotherapy. Unconditional logistical regression analysis and meta-analysis were performed to evaluate the associations. RESULTS: The lung adenocarcinoma risk was significantly higher in patients with AA than GG + GA genotype (adjusted OR = 1.755, 95%CI = 1.057-2.912, P = 0.030). CCND1 rs9344 was significantly correlated with platinum-based therapy response in patients receiving PP regimen (additive model: adjusted OR = 1.926, 95%CI = 1.029-3.605, P = 0.040; recessive model: adjusted OR = 11.340, 95%CI = 1.428-90.100, P = 0.022) and in the ADC subgroups (recessive model: adjusted OR = 3.345, 95%CI = 1.276-8.765, P = 0.014). Furthermore, an increased risk of overall toxicity was found in NSCLC patients (additive model: adjusted OR = 1.395, 95%CI = 1.025-1.897, P = 0.034; recessive model: adjusted OR = 1.852, 95%CI = 1.088-3.152, P = 0.023), especially ADC subgroups (additive model: adjusted OR = 1.547, 95%CI = 1.015-2.359, P = 0.043; recessive model: adjusted OR = 2.030, 95%CI = 1.017-4.052, P = 0.045). Additionally, CCND1 rs9344 was associated with an increased risk of gastrointestinal toxicity in non-smokers (recessive model: adjusted OR = 2.620, 95%CI = 1.083-6.336, P = 0.035). Non-significant differences were observed in the 5-year overall survival rate between CCND1 rs9344 genotypes. A meta-analysis of 5432 cases and 6452 control samples did not find a significant association between lung cancer risk and CCND1 rs9344 polymorphism. CONCLUSION: This study suggests that in the Chinese population, CCND1 rs9344 could potentially serve as a candidate biomarker for cancer susceptibility and treatment outcomes in specific subgroups of patients.

Efficacy, mechanism, and safety of melatonin-loaded on thermosensitive nanogels for rabbit VX2 tumor embolization: A novel design.

Transarterial chemoembolization (TACE) has been widely used for hepatocellular carcinoma. Reducing hypoxia in the tumor microenvironment after TACE remains a challenge as tumor progression is common in post-TACE patients due to the hypoxic tumor microenvironment. In this study, melatonin loaded on p(N-isopropyl-acrylamide-co-butyl methylacrylate) (PIB-M) was used for tumor embolism. Two types of human hepatoma cell lines were used to explore the mechanism by which melatonin prevents the growth and metastasis of cancer cells in vitro. A VX2 rabbit tumor model was used to evaluate the efficacy, mechanism, and safety of PIB-M in vivo. We found that under hypoxic condition, melatonin could inhibit tumor cell proliferation and migration by targeting hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (VEGF-A) in vitro. In vivo, PIB-M inhibited tumor growth and metastasis in rabbit VX2 tumors by promoting apoptosis of tumor cells and targeting related angiogenic proteins and vascular permeability proteins. A high concentration of melatonin in the PIB-M group could be maintained in tumor tissue for 72 h after embolization. The liver and kidney functions were most damaged on the first day but recovered to normal on the seventh day after embolization in the PIB-M group. This novel method may open avenues for reduction of tumor growth and metastasis after TACE and is efficacy and safety, which may be used for treatment for other solid tumors and clinical translation.

A pharmacokinetics interaction study of antiplatelet agents aspirin and clopidogrel combined with dl-3-n-butylphthalide in rats by liquid chromatography-tandem mass spectrometry.

A sensitive and specific high-performance liquid chromatography-tandem mass spectrometry method has been developed to determine the pharmacokinetic interactions of the antiplatelet agents aspirin and clopidogrel combined with dl-3-n-butylphthalide. For the determination of aspirin metabolite salicylic acid, clopidogrel inactive metabolite SR26334 and NBP prototype drug in rat plasma, plasma samples were prepared by precipitation of proteins using methanol containing 0.1% formic acid, followed by centrifugation. Chromatography was performed on a C18 column, eluting with a gradient of acetonitrile (with 0.1% formic acid)-water (with 0.1% formic acid). The detection adopted electrospray ion source and positive ion multiple reaction monitoring modes. The linear detection response range of salicylic acid is 80-80,000 ng/ml, and the linear detection response range of SR26334 and dl-3-n-butylphthalide is 10-10,000 ng/ml. Our study revealed that dl-3-n-butylphthalide affected the pharmacokinetics of aspirin and clopidogrel when administered to rats.

A retrospective analysis of clinical efficacy of ribavirin in adults hospitalized with severe COVID-19.

INTRODUCTION: Coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) swept rapidly throughout the world. So far, no therapeutics have yet proven to be effective. Ribavirin was recommended for the treatment of COVID-19 in China because of its in vitro activity. However, evidence supporting its clinical use with good efficacy is still lacking. METHODS: A total of 208 confirmed severe COVID-19 patients who were hospitalized in Wuhan Union West Campus between 1 February 2020 and 10 March 2020 were enrolled in the retrospective study. Patients were divided into two groups based on the use of ribavirin. The primary endpoint was the time to clinical improvement. The secondary endpoints included mortality, survival time, time to throat swab SARS-CoV-2 nucleic acid negative conversion, and the length of hospital stay. RESULTS: 68 patients were treated with ribavirin while 140 not. There were no significant between-group differences in demographic characteristics, baseline laboratory test results, treatment, and distribution of ordinal scale scores at enrollment, except for coexisting diseases especially cancer (ribavirin group vs no ribavirin group, P = 0.01). Treatment with ribavirin was not associated with a difference in the time to clinical improvement (P = 0.48, HR = 0.88, 95% CI = 0.63-1.25). There were also no significant differences between-group in SARS-CoV-2 nucleic acid negative conversion, mortality, survival time, and the length of hospital stay. CONCLUSIONS: In hospitalized adult patients with severe COVID-19, no significant benefit was observed with ribavirin treatment.

STAT3 rs4796793 contributes to lung cancer risk and clinical outcomes of platinum-based chemotherapy.

BACKGROUND: Signal transducer and activator of transcription (STAT) 3 plays a vital role in carcinogenesis and drug response. Platinum-based chemotherapy is the first-line treatment for lung cancer patients, especially those in advanced stages. In the present study, we investigated the association of STAT3 polymorphism rs4796793 with lung cancer susceptibility, platinum-based chemotherapy response, and toxicity. METHODS: A total of 498 lung cancer patients and 213 healthy controls were enrolled in the study. 467 of them received at least 2-cycle platinum-based chemotherapy. Unconditional logistical regression analysis was used to assess the associations. RESULTS: STAT3 rs4769793 G allele carriers had an increased susceptibility of lung cancer [additive model: adjusted OR (95% CI) 1.376 (1.058-1.789), P = 0.017; recessive model: adjusted OR (95% CI) 1.734 (1.007-2.985), P = 0.047]. Rs4769793 was not significantly associated with platinum-based chemotherapy response in lung cancer patients. STAT3 rs4796793 was associated with an increased risk of severe overall toxicity [additive model: adjusted OR (95% CI) 1.410 (1.076-1.850), P = 0.013; dominant model: adjusted OR (95% CI) 1.638 (1.091-2.459), P = 0.017], especially hematological toxicity [additive model: adjusted OR (95% CI) 1.352 (1.001-1.826), P = 0.049]. CONCLUSIONS: STAT3 rs4796793 may be considered as a potential candidate biomarker for the prediction of susceptibility and prognosis in Chinese lung cancer patients. However, well-designed studies with larger sample sizes are required to verify the results.

Synergistic effects and molecular mechanisms of DL-3-n-butylphthalide combined with dual antiplatelet therapy in acute ischemic stroke.

DL-3-n-butylphthalide (NBP) is isolated from the seeds of Apium graveolens L., and has been recently used as a neuroprotective agent for acute ischemic stroke. The present study aimed to determine the efficacy and safety of the combined use of dual antiplatelet therapy (DAPT) and NBP for treating of acute ischemic stroke in rats and to explore the synergistic mechanism of this treatment strategy in rat middle cerebral artery occlusion models. The efficacy of DAPT combined with NBP was evaluated by determining neurological deficits, infarction status, and histological changes. Changes in body weight, blood glucose level, blood count, and serum biochemical parameters were detected to evaluate the safety. To explore the synergistic pharmacological mechanism, the mRNA expression and protein levels of key proteins in the pyroptosis-inflammatory pathway, and the pyroptosis ratio of microglias were examined. Compared with the administration of NBP or DAPT alone, combination of them significantly improved neurological deficits, reduced infarct area, and repaired tissue injury and inflammation after cerebral ischemia. No hepatorenal toxicity was observed. The mRNA expression and protein levels of key proteins in the pyroptosis-inflammation pathway, and the pyroptosis ratio of microglias were significantly downregulated in the combined administration group than in the monotherapy group. We demonstrated that the combined use of NBP and DAPT exhibits better efficacy and high safety and plays a synergistic role by inhibiting the pyroptosis-inflammation pathway in the brain tissues, particularly in microglial cells.

Anti-angiogenic therapy in ovarian cancer: Current understandings and prospects of precision medicine.

Ovarian cancer (OC) remains the most fatal disease of gynecologic malignant tumors. Angiogenesis refers to the development of new vessels from pre-existing ones, which is responsible for supplying nutrients and removing metabolic waste. Although not yet completely understood, tumor vascularization is orchestrated by multiple secreted factors and signaling pathways. The most central proangiogenic signal, vascular endothelial growth factor (VEGF)/VEGFR signaling, is also the primary target of initial clinical anti-angiogenic effort. However, the efficiency of therapy has so far been modest due to the low response rate and rapidly emerging acquiring resistance. This review focused on the current understanding of the in-depth mechanisms of tumor angiogenesis, together with the newest reports of clinical trial outcomes and resistance mechanism of anti-angiogenic agents in OC. We also emphatically summarized and analyzed previously reported biomarkers and predictive models to describe the prospect of precision therapy of anti-angiogenic drugs in OC.

Factors affecting the medication literacy of older adults and targeted initiatives for improvement: a cross-sectional study in central China.

Introduction: This study explored the state of rational drug use among older adults in central China, aiming to unveil factors influencing their medication literacy and proposing targeted improvement measures. Methods: A cross-sectional study involving 454 participants aged 60 and above was conducted in Hubei province between February 1 and May 30, 2023, with data collected through face-to-face interviews by pharmacists. Multiple logistic regression analysis was conducted to determine factors that affected medication literacy. Results: Of the 412 valid questionnaires, findings revealed inadequate knowledge of rational drug use among older adults in central China. Those who fully understood (105, 25.49%, OR = 9.349, p < 0.001, 95%CI = 3.884-22.502) or partially understood (228, 55.34%, OR = 3.295, p = 0.002, 95%CI = 1.548-7.013) drug instructions exhibited significantly higher medication literacy than those who did not understand (79, 19.17%). Subsequent research revealed a lack of awareness in reading drug instructions or difficulty in understanding them. Most older adults seldom heard of but exhibited high acceptance of medication guidance services. Discussion: In conclusion, the ability to comprehend drug instructions significantly influenced the medication literacy of older adults. Initiatives such as revising age-appropriate drug instructions could effectively enhance rational drug use among this demographic.

Naringenin prevents non-alcoholic steatohepatitis by modulating the host metabolome and intestinal microbiome in MCD diet-fed mice.

Non-alcoholic steatohepatitis (NASH) is a severe inflammatory phase of the non-alcoholic fatty liver disease (NAFLD) spectrum and can progress to advanced stages of NAFLD if left untreated. This study uses multi-omics data to elucidate the underlying mechanism of naringenin's reported benefit in alleviating (NASH). Male mice were fed a NASH-inducing (methionine-choline-deficient) MCD diet with or without naringenin supplementation for 6 weeks. Naringenin prevented NASH-induced histopathological liver damage and reversed the abnormal levels of hepatic triglyceride (TG)/total cholesterol (TC), serum TG/TC, serum alanine aminotransferase/aspartate transaminase, and hepatic malondialdehyde and glutathione. Importantly, naringenin intervention significantly modulated the relative abundance of gut microbiota and the host metabolomic profile. We detected more than 700 metabolites in the serum and found that the gut genus levels of Anaeroplasma and the [Eubacterium] nodatum group were closely associated with xanthine, 2-picoline, and securinine, respectively. Tuzzerella alterations showed the highest number of associations with host endogenous metabolites such as FAHFA (8:0/10:0), FFA (20:2), carnitine C8:1, tridecanedioic acid, securinine, acetylvaline, DL-O-tyrosine, and Phe-Asn. This study indicates that the interplay between host serum metabolites and gut microbiota may contribute to the therapeutic effect of naringenin against NASH.

A simple and sensitive liquid chromatographic technique for the determination of cefotetan disodium in human plasma and its application in a pharmacokinetic study.

A simple and sensitive liquid chromatographic method was developed for quantification of cefotetan disodium (CTT), a semi-synthetic cephamycin antibiotic, in human plasma. CTT and the internal standard chloramphenicol were extracted from plasma by a simple one-step protein precipitation with 35% (v/v) perchloric acid. Separation was carried out on a reverse-phase C18 column with a mobile phase of acetonitile-water containing 0.5% (v/v) phosphoric acids (20:80, v/v) at a flow rate of 1.0 mL/min. The column effluent was monitored by UV detection at 300 nm. The column temperature was maintained at 40°C. This method demonstrated good linearity in the range of 0.525-300.0 µg/mL, with correlation coefficients greater than 0.99. The limit of quantification (LOQ) was 0.525 µg/mL in human plasma. Intra- and inter-day precisions were less than 6.63% in terms of relative standard deviation (RSD). The accuracy, when expressed by the bias, ranged from 0.57% to 4.04%. The mean extraction recovery of CTT was higher than 40.94%. The method was found to be precise, accurate, and specific for CTT quantitative analysis, and was successfully applied for a pharmacokinetic study of CTT after a single intravenous dose of 1.0 g of CTT in healthy Chinese subjects.

Resistin increases cisplatin-induced cytotoxicity in lung adenocarcinoma A549 cells via a mitochondria-mediated pathway.

Lung cancer is the most commonly diagnosed cancer with a high mortality rate. Cisplatin is one of the most important chemotherapeutic agents for the treatment of lung cancer patients, especially in advanced stages. Recent studies show that cisplatin may interact with mitochondria to induce apoptosis, which may partly account for its cytotoxicity. In the study, we explored the effect of resistin on cisplatin-induced cytotoxicity in A549 cells and assessed whether mitochondria-dependent apoptosis was involved. Our results found that 25 ng/ml resistin could significantly increase cisplatin-induced apoptosis and G2/M phase arrest, enhance reactive oxygen species generation, exacerbate the collapse of mitochondrial membrane potential, promote the distribution of cytochrome C in the cytoplasm from mitochondria, and activate caspase 3. Therefore, the results suggested that resistin might increase cisplatin-induced cytotoxicity via a mitochondria-mediated pathway in A549 cells. However, the precise mechanism remains to be explored in the future.

A novel immune-related ceRNA network that predicts prognosis and immunotherapy response in lung adenocarcinoma.

BACKGROUND: The tumor microenvironment plays an important role in the progression and malignancy of lung adenocarcinoma and affects the immunotherapy response. There is increasing evidence that long non-coding RNAs (lncRNAs) as competing endogenous RNAs (ceRNAs) have significant functions in the development and treatment response of various kinds of cancer. This study aimed to explore the association between immune-related lncRNA-microRNA (miRNA)-messenger RNA (mRNA)-ceRNA networks, and the prognosis of and immunotherapy response in lung adenocarcinoma. METHODS: RNA-sequencing (RNA-seq) and miRNA-seq data from The Cancer Genome Atlas (TCGA) were used to evaluate the infiltration of immune cells in lung adenocarcinoma samples by undertaking a single-sample gene set enrichment analysis (ssGSEA) to divide the cells into high and low immune cell infiltration groups. The differentially expressed mRNA (DEmRNA) was further analyzed by a weighted gene co-expression network analysis (WGCNA), search tool for recurring instances of neighboring genes (STRING), and Cytoscape to select hub genes. The ceRNA network was constructed using Cytoscape. Additionally, survival analyses were conducted to screen out prognostic candidate genes. RESULTS: Seven thousand five hundred and thirty-eight mRNAs, 540 lncRNAs, and 138 miRNAs were found to be differentially expressed between the high and low immune cell infiltration groups. The two DEmRNA modules most significantly associated with immune cell infiltration were further analyzed, and four clusters, including 179 DEmRNAs, were selected based on Molecular Complex Detection (MCODE) scores. The selected DEmRNAs in the four clusters were mainly enriched in pathways involved in regulating the immune response. Ultimately, a ceRNA network of SNHG6-hsa-miR-30e-5p-CYSLTR1 was identified as being associated with the prognosis of and immunotherapy response in lung adenocarcinoma. CONCLUSIONS: The present study extends understandings of immune-related lncRNA-miRNA-mRNA-ceRNA networks and identifies novel targets and a regulatory pathway for anti-tumor immunotherapy.

Pharmacokinetics and tolerability of oral dosage forms of huperzine a in healthy Chinese male volunteers: a randomized, single dose, three-period, six-sequence crossover study.

Huperzine A is a potent, reversible, and blood-brain barrier permeable acetylcholinesterase inhibitor. The aim of this study was to compare the pharmacokinetics, tolerability, and bioavailability of two formulations with the established reference formulation of huperzine A in a fasting, healthy Chinese male population. This was a randomized, single-dose, 3-period, 6-sequence crossover study. The plasma concentrations of huperzine A were determined by liquid chromatography tandem mass spectrometry. Tolerability was assessed based on subject interview, vital sign monitoring, physical examination, and routine blood and urine tests. The mean (SD) pharmacokinetic parameters of the reference drug were Cmax, 1.550 (0.528) ng/mL; t1/2, 12.092 (1.898) h; AUC0-72h, 17.550 (3.794) ng·h/mL. Those of the test formulation A and test formulation B were Cmax, 1.412 (0.467), 1.521 (0.608) ng/mL; t1/2, 12.073 (2.068), 12.271 (1.678) h; AUC0-72h, 15.286 (3.434) ng·h/mL, 15.673 (3.586) ng·h/mL. The 90% confidence intervals for the AUC0-72h and Cmax were between 0.80 and 1.25. No adverse events were reported by the subjects or found with results of clinical laboratory test. The test and reference products met the regulatory criteria for bioequivalence in these fasting, healthy Chinese male volunteers. All three formulations appeared to be well tolerated.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of recombinant human parathyroid hormone (1-34) in healthy Chinese subjects.

BACKGROUND: The recombinant human parathyroid hormone (1-34) (rhPTH[1-34]) teriparatide is the first anabolic agent approved by the US Food and Drug Administration for the treatment of osteoporosis in men and women. This study was conducted to provide support for marketing authorization of an agent biosimilar to teriparatide in China. OBJECTIVE: The main aim of the present study was to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic parameters of rhPTH(1-34) after single and multiple subcutaneous doses in healthy Chinese subjects. METHODS: Two open-label, randomized, single-center, dose-escalation studies were performed. In study 1, subjects were randomized to receive a single dose of rhPTH(1-34) (10, 20, 30, 40, 50, or 60 µg) or a multiple dose of rhPTH(1-34) (10 and 20 µg once daily for 7 consecutive days) to determine the safety profile and tolerability, as reflected by the incidence, intensity, and seriousness of the observed adverse events. In study 2, a single dose of rhPTH(1-34) (10, 20, or 40 µg) and a multiple dose of rhPTH(1-34) (20 µg) were administrated subcutaneously to investigate the pharmacokinetic and pharmacodynamic parameters. RESULTS: Forty-two subjects completed study 1, and 30 subjects completed study 2. rhPTH(1-34) was well tolerated during the investigated single (10-60 µg) and multiple (10-20 µg once daily for 7 consecutive days) dose ranges. The most generally reported adverse events were erythema at the injection site and gastrointestinal reactions. After single and multiple subcutaneous administration of rhPTH(1-34), the drug was rapidly absorbed, with a Tmax of 20 to 30 minutes, and rapidly cleared from the plasma, with a t½ of 47.2 to 60.6 minutes. The mean Cmax, AUC0-t, and AUC0-∞ increased in proportion to the doses, whereas the t½, total clearance, and Tmax values were independent of the administered dose. No significant differences in pharmacokinetic parameters were noted by sex except for Tmax in the 10-µg and 20-µg single-dose groups. Compared with the baseline levels, no significant changes or dose-related significant effects were observed in serum calcium and phosphate levels. CONCLUSIONS: All rhPTH(1-34) doses appeared to be well tolerated in the population studied. Linear pharmacokinetic characteristics were displayed in the dose range studied. Chinese ClinicalTrials.gov identifier: ChiCTR-ONC-12002874.

Pharmacokinetics and tolerability of intravenous cefotetan disodium for injection in healthy Chinese volunteers: A randomized, open-label, single- and multiple-dose study.

BACKGROUND: Cefotetan disodium for injection is a semisynthetic cephamycin antibiotic that exerts its bactericidal effects by inhibition of cell-wall synthesis. Despite being widely used in the treatment of various infections, little information is available on the pharmacokinetic properties of cefotetan disodium in Chinese subjects. OBJECTIVES: This study evaluated the pharmacokinetics of single and multiple intravenous doses of a generic formulation of cefotetan disodium in healthy Chinese volunteers. The effect of sex on the pharmacokinetics of cefotetan disodium was evaluated as a secondary objective. METHODS: In this open-label, dose-escalating study, subjects were randomized to receive a single dose of cefotetan disodium 0.5, 1.0, or 2.0 g administered as a 1-hour intravenous infusion. Those allocated to the 1.0-g dose continued into the multiple-dose phase, in which they received 1.0 g BID for 7 consecutive days. During the single-dose phase, blood samples were collected at regular intervals from 0 to 15 hours after drug administration and were analyzed using a validated HPLC method. During the multiple-dose phase, blood samples were obtained before drug administration on days 5, 6, and 7 to determine the C(min) at steady state; on day 7, blood samples were also collected from 0 to 15 hours after drug administration. Tolerability was assessed based on physical examinations, vital signs, laboratory tests (hematology, biochemistry, hepatic and renal function, and urinalysis), and subject interviews. RESULTS: Three groups, each consisting of 5 men and 5 women, were enrolled in the single-dose phase. The mean (SD) age of subjects was 23.2 (2.2) years (range, 19-30 years). Their mean weight was 57.0 (6.3) kg (range, 46.4-72.0 kg), and their mean height was 1.66 (0.08) m (range, 1.48-1.81 m). After intravenous administration of single doses of 0.5, 1.0, and 2.0 g, the cefotetan disodium C(max) was 35.01 (6.98), 76.67 (10.52), and 154.33 (27.17) mg/L, respectively; the AUC0₋15(h) was 145.35 (18.36), 307.45 (33.07), and 746.09 (103.07) mg · h/L; the AUC0₋(∞) was 171.51 (20.61), 347.25 (44.20), and 843.84 (131.13) mg · h/L; the t(1/2) was 5.80 (1.29), 4.91 (1.15), and 5.04 (1.26) hours; the CL was 2.96 (0.41), 2.92 (0.39), and 2.42 (0.39) L/h; and the V(d) was 24.55 (5.19), 20.37 (3.66), and 17.30 (3.52) L. After administration of multiple doses, the cefotetan disodium C(max,ss) was 80.53 (10.04) mg/L; the C(mix,ss) was 11.00 (4.04) mg/L; the AUC(ss) was 347.92 (50.04) mg · h/L; the steady-state plasma concentration was 28.99 (4.17) mg/L; the t(1/2) was 6.24 (2.52) hours; the CL was 2.32 (0.64) L/h; and the Vd was 19.19 (4.58) L. No significant differences in pharmacokinetic parameters were noted by sex in the multiple-dose phase. Cefotetan disodium appeared to be well tolerated. CONCLUSIONS: In these healthy Chinese subjects, the cefotetan disodium AUC and C(max) increased in a dose-proportional manner, whereas the t(1/2) was independent of dose. The pharmacokinetic properties of cefotetan disodium were linear at doses of 0.5 to 2.0 g. After multiple doses, the pharmacokinetic parameters of cefotetan disodium were consistent with those after single doses. At the doses studied, cefotetan disodium appeared to be well tolerated in these healthy volunteers.