Ion concentrations in nasal airway surface liquid: a prediction model for the identification of cystic fibrosis carriers.

BACKGROUND: Cystic fibrosis (CF) carriers seem to have a higher risk to develop chronic rhino-sinusitis (CRS), although the full underlying mechanisms are unknown. Ion concentrations in nasal airway surface liquid (ASL) may be influenced by the heterozygosity for CF gene mutation, with possible impacts on the development of CRS. METHODS: A cheap and feasible standardized technique was designed to measure the ion levels in nasal ASL. With this purpose we collected, under basal conditions, samples from the nasal cavity of 165 adults: 14 homozygous for CF, 83 carriers and 68 healthy controls. Sodium (Na) and Chlorine (Cl) concentrations were then evaluated among different groups. RESULTS: Statistical analysis revealed a significant difference of Na and Cl values between controls and carriers and between controls and homozygotes. Receiver operating characteristic (ROC) curves and derived indicators (Youden's index and Area Under the Curve, AUC) were used to further evaluate the diagnostic capability of Na and Cl concentrations to differentiate heterozygotes from controls. ROC curves demonstrated that the optimal diagnostic cut-off value of Na is at 124, and the optimal cut-off value of Cl is at 103,2. CONCLUSION: ASL sampling can be considered a new diagnostic tool for providing quantitative information on nasal ion composition. According to our findings, Na and Cl concentrations of nasal ASL could represent a useful tool to assess heterozygotes and healthy controls.

Listeria Monocytogenes: an uncommon pathogen of cervical necrotizing fasciitis.

The aim of this paper is to present a unique case of neck-necrotizing fasciitis caused by Listeria Monocytogenes in a young woman, successfully treated by surgery and IV antibiotic therapy. Necrotizing fasciitis is a rare, rapidly progressing and potentially life-threatening infection that infrequently occurs in the head and neck region. Pathogens involved in necrotizing fasciitis are heterogeneous and include aerobic and anaerobic bacteria. To the best of our knowledge, this is the only case of neck necrotizing fasciitis caused by Listeria Monocytogenes studied in literature so far.

Analysis of Il-10 gene sequence in patients with sinonasal polyposis.

Sinonasal polyposis (SNP) is a chronic inflammatory disease of nasal and paranasal cavities. Human leukocyte antigen-G molecules (HLA-G) are non-classic HLA-I molecules with anti-inflammatory and tolerogenic properties. HLA-G production is mainly induced by interleukin (IL)-10. IL-10 is an anti-inflammatory cytokine that inhibits the production of proinflammatory cytokines and induces HLA-class II down-modulation. Recent studies suggest that HLA-G could play a role in SNP pathogenesis; in SNP patients physiological levels of IL-10 (produced by activated peripheral blood CD14+ monocytes) are not able to induce production of HLA-G. Different mechanisms could justify these findings: genomic or amino-acidic sequence alterations in IL-10 lower IL-10 receptor expression, lower IL-10 receptor affinity, or alterations of the intracellular signal transmission. This study analyzes nucleotidic sequence of IL-10 gene in SNP patients. Sequencing of IL-10 gene shows that the lack of HLA-G production by peripheral blood CD14+ monocytes is not related to alterations in IL-10 gene nucleotidic sequence.

Preoperative assessment of salivary gland neoplasms with fine needle aspiration cytology and echography: a retrospective analysis of 357 cases.

Fine-needle aspiration cytology (FNAC) is a minimally invasive procedure usually well tolerated, easy to perform, quick, cheap and easy to repeat in case of doubts or non-diagnostic results. Echography is also a fast, cheap and non-invasive tool; however, the role of FNAC and echography in the diagnosis of salivary gland pathology is not universally recognised. Three hundred and fifty-seven patients with a cytological diagnosis at FNAC, and 247 of these who were also studied with echography, were enrolled for this retrospective study. The final histopathological diagnoses, obtained after surgery, were then compared to the preoperative FNAC diagnoses and echographic findings. From the analysis of our data, the overall FNAC specificity resulted 93 percent, sensitivity 83 percent, and diagnostic accuracy 92 percent. Echography sensibility was 57.1 percent specificity 98.2 percent, while positive and negative predictive value were respectively 80 percent and 94.8 percent. While echography can be useful in order to provide a better characterization of salivary gland lesions, FNAC can then be considered a safe diagnostic tool with reliable sensitivity and specificity for the assessment of salivary gland pathology and thus for selecting patients and indicating the best surgical treatment.

Dynamic changes of live/apoptotic circulating tumour cells as predictive marker of response to sunitinib in metastatic renal cancer.

BACKGROUND: Recently, we developed an apoptotic assay for expanding the monitoring capabilities of the circulating tumour cells (CTC) test during therapy. An automated platform for computing CTCs was integrated with a mAb (M30) targeting a neoepitope disclosed by caspase cleavage at cytokeratin 18 in early apoptosis; we showed that live CTCs were associated with progression, consistent with enhanced cell migration and invasion. The test was first applied here to mRCC. METHODS: Live/apoptotic CTCs changes were measured in mRCC patients receiving first-line Sunitinib and compared with circulating endothelial cell (CEC) levels. RESULTS: The presence of EpCAM-positive, live CTCs predicts progression in individual mRCC patient, being associated with distant metastasis under first-line Sunitinib. Synchronous detection of CTCs and CEC levels discloses for the first time an association between their dynamic changes and outcome: a rapid increase of the CEC number as early as the first cycle of therapy is associated with CTC decrease in non-progressed patients, whereas a delayed response of CECs is related to higher CTC values in the progressed group indicating treatment failure. CONCLUSION: We demonstrated that a delayed response to antiangiogenic treatment indicated by persistent detection of CECs correlates with persistent live CTCs and more aggressive disease.

Diabetes, cardiovascular risk factors and idiopathic sudden sensorineural hearing loss: a case-control study.

AIMS/HYPOTHESIS: Idiopathic sudden sensorineural hearing loss (ISSNHL) represents an acute inner ear disorder with an overall incidence of 5-20/100000 individuals per year in western countries. No clear causes for this disease have been found so far, but cochlear ischemia has been hypothesized as one of the etiopathological mechanisms. The aim of our study was to assess the role of diabetes and traditional cardiovascular risk factors in the pathogenesis of ISSNHL. MATERIALS/METHODS: Case-control study of 141 patients (75 males/66 females) matched for age and gender. Cases were affected by ISSNHL, defined as a sudden hearing loss > or =30 dB, within 3 frequencies, developing over 72 h. The control group was composed of 271 sex- and age-matched subjects (142 males/129 females) who agreed to participate in this observational study and provided blood samples for laboratory investigations. Cardiovascular risk factors examined were: diabetes mellitus, smoking history, hypercholesterolemia, hypertriglyceridemia and hypertension. RESULTS: On the univariate analysis, diabetes prevalence was higher in the ISSNHL group (15.6%) compared to controls (8.5%) (p = 0.03). Also hypercholesterolemia was significantly more frequent in the ISSNHL group compared to the control population. There were no statistically significant differences between the 2 populations concerning other cardiovascular risk factors. The risk of ISSNHL tended to increase as the number of cardiovascular risk factors increased (p for linear trend = 0.018). CONCLUSIONS: Our findings suggest that diabetes mellitus, hypercholesterolemia and a high burden of cardiovascular risk factors are associated with the risk of ISSNHL.

Enhanced in vitro and in vivo antioxidant activity and mobilization of free phenolic compounds of soybean flour fermented with different beta-glucosidase-producing fungi.

AIMS: To evaluate the soybean polyphenol glucosides bioconversion to aglycone forms by different beta-glucosidases-producing filamentous fungi to enhance their antioxidant activity. METHODS AND RESULTS: Soybean defatted flour was submitted to solid-state fermentation with Aspergillus niger, Aspergillus niveus and Aspergillus awamori. The fungi studied produced approximately the same beta-glucosidase activity units amount when p-nitrophenyl-beta-d-glucopyranoside was used as substrate for the assay. However, electrophoretic analysis, using 4-methylumbellipheryl-beta-d-glucopyranoside as substrate, showed that beta-glucosidase produced by A. niveus was more active. Fermented methanolic extracts showed an increase in polyphenol and genistein contents and antioxidant activities. The highest genistein content was found in soybean fermented by A. niveus. Methanolic extracts of the soybean fermented by the different fungi showed a similar capacity of scavenging H(2)O(2) generated in vivo by the tumour promoter 12-O-tetradecanoyl phorbol-13-acetate. CONCLUSIONS: A. niveus synthesized a beta-glucosidase with higher specificity to hydrolyse genistin beta-glycosidic bond than those produced by A. awamori and A. niger. SIGNIFICANCE AND IMPACT OF THE STUDY: The utilization of these beta-glucosidases-producing fungi in soybean fermentation processes resulted in the obtaining of methanolic extracts with different antioxidant potentials that could be used either therapeutically or as an antioxidant in nonphysiological oxidative stress conditions, as the one induced in skin by UV radiation.

Performance evaluation of the automated nucleated red blood cell count of five commercial hematological analyzers.

INTRODUCTION: Recent automated hematology analyzers (HAs) can identify and report nucleated red blood cells (NRBC) count as a separate population out of white blood cells (WBC). The aim of this study was to investigate the analytical performances of NRBC enumeration on five top of the range HAs. METHODS: We evaluated the within-run and between-day precision, limit of blank (LoB), limit of detection (LoD), and limit of quantitation (LoQ) of XE-2100 and XN-module (Sysmex), ADVIA 2120i (Siemens), BC-6800 (Mindray), and UniCel DxH 800 (Beckman Coulter). Automated NRBC counts were also compared with optical microscopy (OM). RESULTS: The limits of detection for NRBC of the BC-6800, XN-module, XE-2100, UniCel DxH 800, and ADVIA 2120i are 0.035×109 /L, 0.019×109 /L, 0.067×109 /L, 0.038×109 /L, and 0.167×109 /L, respectively. Our data indicated excellent performance in terms of precision. The agreement with OM was excellent for BC-6800, XN-module, and XE-2100 (Bias 0.023, 0.019, and 0.033×109 /L, respectively). ADVIA 2120i displayed a significant constant error and UniCel DxH 800 both proportional and small constant error. CONCLUSION: Regards to NRBC counting, the performances shown by BC-6800, XN-module, and XE-2100 are excellent also a low count, ADVIA 2120i and UniCel DxH 800 need to be improved.

Comparing the performance of three panels rules of blood smear review criteria on an Italian multicenter evaluation.

BACKGROUND: The aims of this study were to compare the diagnostic accuracy of blood smear review criteria, by means of three different panel rules, those proposed by: the International Consensus Group for Hematology [41-ICGH rules], the Italian Survey [IS rules] and the Working Group on Hematology-SIBioC (WGH) consensus rules (WGH rules). METHODS: This study is based on 2707 peripheral blood (PB) samples referred for routine hematological testing to the WGH-associated laboratories displaced all over the Italian territory. The PB samples were processed on seven different hematology analyzers (HAs): Advia 2120i, XE-2100, BC-6800, ABX Pentra, XN-1000, Cell-DYN Sapphire, and DxH800, respectively. All the results provided by the HAs were analyzed through the application of three different blood smear review criteria: that is, the 41-ICGH, IS, and WGH rules. Finally, data were compared with those obtained by optical microscopy (OM), as the current gold standard. RESULTS: The overall the agreement OM classification with ICGH, IS, and WGH panel rules is 0.83, 0.83, and 0.85, respectively. The false negatives are 2.1%, 3.0%, and 2.9%, while false positives are 15.1%, 13.7%, and 11.7%, respectively. All the seven HAs showed variable interinstrument performance, as three different criteria for OM review were adopted on each of them from time to time. CONCLUSION: These results presented show that the customization of validation rules is necessary for enhancing the quality of hematological testing and optimizing workflow.

Activity and in vivo tracking of Amphotericin B loaded PLGA nanoparticles.

The development of biocompatible polymeric nanoparticles has become an important strategy for optimizing the therapeutic efficacy of many classical drugs, as it may expand their activities, reduce their toxicity, increase their bioactivity and improve biodistribution. In this study, nanoparticles of Amphotericin B entrapped within poly (lactic-co-glycolic) acid and incorporated with dimercaptosuccinic acid (NANO-D-AMB) as a target molecule were evaluated for their physic-chemical characteristics, pharmacokinetics, biocompatibility and antifungal activity. We found high plasma concentrations of Amphotericin B upon treatment with NANO-D-AMB and a high uptake of nanoparticles in the lungs, liver and spleen. NANO-D-AMB exhibited antifungal efficacy against Paracoccidioides brasiliensis and induced much lower cytotoxicity levels compared to D-AMB formulation in vivo and in vitro. Together, these results confirm that NANO-D-AMB improves Amphotericin B delivery and suggest this delivery system as a potential alternative to the use of Amphotericin B sodium deoxycholate.

Use of La3+ to distinguish activity of the plasmalemmal Ca2+ pump from Na+/Ca2+ exchange in arterial myocytes.

La3+ was tested for its ability to distinguish external Na+ (Nao)-independent Ca2+ efflux via the plasma membrane (PM) Ca2+ pump from Nao-dependent Ca2+ efflux via Na+/Ca2+ exchange. Fura-2 loaded cultured rat aortic myocytes were used with digital imaging to measure the cytosolic free Ca2+ concentration ([Ca2+]cyt) and to monitor La3+ entry. At a La3+ concentration ([La3+]o) of 0.25 mM, but not at lower concentrations, La3+ entered the cells; 0.01 mM verapamil blocked this entry. Transient increases in [Ca2+]cyt were evoked by unloading the sarcoplasmic reticulum with cyclopiazonic acid (CPA)+caffeine (CAF) in Na,Ca-free medium (to inhibit Ca2+ extrusion via Na+/Ca2+ exchange and Ca2+ influx). La3+ (0.03-0.25 mM with verapamil) augmented the Ca2+ transients and slowed Nao-independent [Ca2+]cyt recovery in a dose-dependent manner (IC50 approximately 0.01 mM La3+). This La(3+)-sensitive recovery was apparently mediated by the PM Ca2+ pump. The effects of La3+ were reversible: [Ca2+]cyt returned promptly toward base line when La3+ was washed out in Na,Ca-free medium containing CPA + CAF. Reintroduction of extracellular Na+ during [Ca2+]cyt recovery ([La3+]o = 0.06-0.25 mM) significantly speeded recovery, indicating that the Na+/Ca2+ exchanger was not inhibited by [La3+]o < or = 0.25 mM. The La(3+)-sensitive (Nao-independent) and Nao-dependent [Ca2+]cyt recovery rates were comparable. In Na(+)-loaded cells, < or = 0.25 mM La3+ also did not affect Na+/Ca2+ exchange mediated Ca2+ influx. In medium containing Na+ and Ca2+, 0.125 mM La3+ abolished the serotonin (5-HT) evoked plateau responses that resulted from Ca2+ entry via Ca2+ channels. In Na,Ca-free medium, but not Ca-free medium, however, La3+ converted 5-HT evoked Ca2+ transients into sustained responses. We conclude that low [La3+]o (0.06-0.25 mM) inhibits the PM Ca2+ pump, but spares Na+/Ca2+ exchanger mediated Ca2+ influx and efflux in arterial myocytes.

Pharmacokinetic study of the interaction between rifampin and delavirdine mesylate.

OBJECTIVE: To study the effect of rifampin (INN, rifampicin), a potent inducer of cytochrome P450, on the steady-state pharmacokinetics of delavirdine. METHODS: Twelve patients who were positive for human immunodeficiency virus, with CD4 counts ranging from 110 to 483/mm3, were randomized to two groups and studied in parallel. Both the control group (n = 5) and the rifampin group (n = 7) received 400 mg delavirdine mesylate every 8 hours for 30 days; subjects in the rifampin group took a 600 mg once-daily dose of rifampin on days 16 through 30. Harvested plasma from serial blood samples collected after dosing on days 15, 16, and 30 was assayed for delavirdine and its N-desalkyl metabolite concentrations with a reversed-phase HPLC method. Blood samples obtained on days 16 and 30 were also assayed for rifampin by HPLC. RESULTS: Delavirdine mesylate alone and in combination with rifampin was well tolerated. On day 30, statistically significant differences between groups were observed for all delavirdine pharmacokinetic parameters (p < 0.049). In the rifampin group, delavirdine oral clearance increased by about 27-fold (p = 0.022), resulting in virtually negligible (< 0.09 mumol/L) steady-state through drug concentrations in all patients after 2 weeks of concurrent dosing of delavirdine mesylate and rifampin. The ratio of metabolite formation to elimination clearance for desalkyldelavirdine was significantly higher (3.9 +/- 1.2 versus 0.23 +/- 0.10) and delavirdine elimination half-life was significantly shorter (1.7 +/- 1.4 versus 4.3 +/- 1.3 hours) when delavirdine mesylate was taken with rifampin. Rifampin pharmacokinetic parameters on days 16 and 30 were similar to those previously reported for normal volunteers. CONCLUSIONS: The findings of this study indicate that rifampin induces the metabolism of delavirdine. Therefore therapy with rifampin is contraindicated in patients receiving delavirdine mesylate.

Blockade of ADP-induced Ca2+-signal and platelet aggregation by lipoxygenase inhibitors.

Stimulation of platelets results in the liberation of arachidonic acid (AA) which is further metabolized via the cyclooxygenase or lipoxygenase (LPG) pathway. We have examined the effect of inhibition of LPG on (i) the ADP-induced increase of cytoplasmic Ca2+ concentration and (ii) platelet aggregation. Lipoxygenase inhibitors, nordigidroguaiaretic acid (NDGA) and BW-755C, both suppressed ADP-induced Ca2+-signals and aggregation in a dose-dependent manner, with an IC50 value of 1 2 microM for NDGA. Qualitatively the same effect was obtained with 4-bromophenylacyl bromide, the inhibitor of phospholipases A2 and C. By contrast, cyclooxygenase inhibitor indomethacin had only a negligible effect on Ca2+-signals and suppressed only the second phase of ADP-induced aggregation. It is concluded that the LPG pathway of AA metabolism in platelets might play a crucial role in ADP-induced Ca2+-signal generation and platelet aggregation.

A review of the pharmacokinetics of cefpodoxime proxetil.

Cefpodoxime proxetil is an orally absorbed broad spectrum third generation cephalosporin antibacterial. It is a prodrug that is de-esterified in vivo to its active metabolite, cefpodoxime. After single- and multiple-dose (12-hourly) administration of cefpodoxime proxetil in the therapeutic dose range of 100 to 400mg of cefpodoxime equivalents, average peak plasma concentrations of cefpodoxime range from 1.0 to 4.5 mg/L and occur between 1.9 and 3.1 hours after administration. The half-life of cefpodoxime ranges from 1.9 to 2.8 hours. The absolute bio-availability of cefpodoxime proxetil tablets is 50%, and absorption is enhanced by concomitant administration of food. Raising gastric pH by pretreatment with antacids or H2-receptor antagonists results in reduced absorption. Binding of cefpodoxime to human plasma or serum protein is low (18 to 23%), suggesting that cefpodoxime should readily transfer across the capillary lining into tissues. Cefpodoxime undergoes minimal metabolism in humans. Drug not absorbed is degraded in the gastrointestinal tract and excreted in the faeces. As expected for a drug eliminated primarily by renal excretion, the disposition of cefpodoxime is altered in patients with impaired renal function; the half-life increases, while apparent plasma clearance and renal clearance decrease. The pharmacokinetics of cefpodoxime after oral administration of cefpodoxime proxetil are not affected by age.

Cefpodoxime pharmacokinetics in children: effect of food.

BACKGROUND: Cefpodoxime, an oral third generation cephalosporin antibiotic, is used for the treatment of acute upper respiratory tract infection caused by susceptible bacteria in children 5 months to 12 years of age. We report the results of a randomized two-way crossover study designed to characterize the disposition of a single dose (10 mg/kg) of cefpodoxime proxetil oral suspension in children, under fed and fasted conditions. METHODS: Seventeen children (8.4 months to 12.2 years old, seven female) participated in this study. Each subject received a single 10-mg/kg dose of cefpodoxime proxetil oral suspension, after a predose fast and again coadministered with food. Repeated blood samples (n=10) were obtained during 12 h postdose and cefpodoxime was quantified from plasma by high performance liquid chromatography. Plasma concentration vs. time data were curve fit for each subject with a nonlinear weighted least squares algorithm, and pharmacokinetic parameters were determined from the polyexponential estimates. RESULTS: Cefpodoxime disposition was best characterized using a one-compartment open model with first order absorption. The area under the plasma concentration vs. time curve, Cmax and Ke were not significantly different between fed and fasted conditions. However, Tmax was significantly prolonged (fed=2.79+/-1.10 h vs. fasted=1.93+/-0.54 h) and Ka was significantly smaller (fed=0.42+/-0.14 h(-1) vs. fasted=0.81+/-0.72 h(-1)) in the fed state. CONCLUSIONS: Administration of cefpodoxime in the presence of food affected the rate but not the extent of absorption. Cefpodoxime proxetil oral suspension can be administered without regard to meals in children 6 months to 12 years of age.

Pharmacokinetic study of the interaction between rifabutin and delavirdine mesylate in HIV-1 infected patients.

The oxidative metabolism of delavirdine, a non-nucleoside inhibitor of HIV-1 reverse transcriptase, is mediated in part by cytochrome P450 3A. The influence of rifabutin, an inducer of certain human cytochrome P450 isozymes, on the steady-state pharmacokinetics of delavirdine was investigated in 12 HIV-positive patients with CD4 counts ranging from 75 to 671/mm3. Both the control group (n = 5) and the rifabutin group (n = 7) received 400 mg delavirdine mesylate every 8 h for 30 days; subjects in the rifabutin group took a 300 mg, once-daily dose of rifabutin on study days 16-30. Harvested plasma from serial blood samples collected after dosing on days 15, 16, and 30 was assayed for delavirdine and its N-desalkyl metabolite concentrations using a reversed-phase HPLC method. Blood samples obtained on days 16 and 30 were also assayed for rifabutin by HPLC. Delavirdine mesylate alone or in combination with rifabutin was well-tolerated. On day 30, statistically significant differences between groups were observed for all delavirdine pharmacokinetic parameters (P < 0.046). After coadministration of rifabutin and delavirdine mesylate for 2 weeks, oral clearance of delavirdine increased five-fold, resulting in lower steady-state plasma delavirdine concentrations. Rifabutin pharmacokinetic parameters were similar to those previously reported. Concomitant use of delavirdine and rifabutin at the recommended dose for each drug is discouraged. Maintaining therapeutic concentrations of delavirdine in patients on both medications may require dose modification.

Systemic absorption of clindamycin following intravaginal application of clindamycin phosphate 1% cream.

The extent to which clindamycin is absorbed systemically following intravaginal application of clindamycin phosphate 1% cream was assessed in 12 healthy female volunteers. Each subject received a single intravenous dose of clindamycin phosphate sterile solution (48 mg). A week later, each subject received 50 mg (5 mL) doses of intravaginal cream according to one of two dosage regimens: once daily (qd) for seven consecutive doses or twice daily (q12hr) for 13 consecutive doses. Steady state was achieved on or before day 4 for both regimens. The absolute bioavailabilities of the two intravaginal treatments were 6% for qd dosing and 13% for q12hr dosing, indicating that only a small fraction of the intravaginal dose is absorbed systemically.

Effect of timing of food on absorption of cefpodoxime proxetil.

The effect of a high-fat meal and the timing of this meal on the absorption of a 400-mg oral dose of cefpodoxime proxetil was evaluated in 20 healthy, adult, male volunteers in a four-way crossover study. The area under the plasma concentration-time curve, peak plasma concentration, and urinary recovery were significantly greater (P = .0001) after administration of cefpodoxime proxetil tablets with and 2 hours after a meal relative to dosing under fasted conditions or 1 hour before a meal. The time to peak concentration did not differ significantly among treatments, which suggests that food did not affect the rate of drug absorption. These results indicate that absorption of cefpodoxime proxetil is enhanced when tablets are taken with food or shortly after a meal.

Systemic absorption of clindamycin after intravaginal administration of clindamycin phosphate ovule or cream.

The absolute bioavailability of clindamycin phosphate vaginal ovule with comparison to a reference treatment of clindamycin phosphate sterile solution, as well as the relative bioavailability of the ovule compared to clindamycin phosphate vaginal cream, was evaluated in 12 healthy adult female volunteers. Subjects were randomly assigned to receive either the ovule or cream formulation intravaginally for 3 consecutive days during the two-way crossover portion of the study. During a third treatment period, all subjects received 100 mg of clindamycin as a 4-minute intravenous infusion of clindamycin phosphate sterile solution (10 mg/mL). Clindamycin concentrations in serum were assayed by a high-performance liquid chromatography method with detection by mass spectrometry. Pharmacokinetic analyses of the serum data indicated low systemic absorption of clindamycin from the vaginal cream (about 4%), consistent with results of previous bioavailability studies. Following intravaginal administration of the clindamycin phosphate ovule, systemic absorption averaged 30%, which was approximately sevenfold greater than after dosing with the vaginal cream. The higher drug absorption for the ovule may be related to differences in formulation effects on the vaginal membrane. Nevertheless, systemic exposure to clindamycin from the ovule is still considerably lower than from a therapeutic oral dose.

Pharmacokinetic and tolerance studies of cefpodoxime after single- and multiple-dose oral administration of cefpodoxime proxetil.

Cefpodoxime proxetil, a third generation, broad-spectrum, oral cephalosporin, was administered in single doses of 100, 200, 400, 600, and 800 mg (dose expressed as cefpodoxime equivalents) and multiple doses of 100, 200, and 400 mg twice daily to healthy volunteers. The pharmacokinetics of the active metabolite, cefpodoxime, and tolerance of cefpodoxime proxetil were determined. Results from the single-dose study indicate that cefpodoxime exhibits nonlinear pharmacokinetics over the dose range of 100 to 800 mg. This nonlinearity is primarily due to differences in dose-normalized AUC and Cmax, urinary recovery, and half-life between one or more of the higher-dose treatment groups and the 100-mg dosing group. After multiple-dose (twice daily) administration for 15 days, steady state is achieved on the second day of dosing, and there is no drug accumulation. Cefpodoxime pharmacokinetics are linear with dose over the clinically relevant dosing range of 100 to 400 mg. Microbiologic and HPLC plasma assay results are highly correlated, with close agreement between HPLC- and microbiologic-determined pharmacokinetic parameter estimates. Cefpodoxime proxetil was well tolerated in both studies. The most frequent medical events were related to gastrointestinal problems and consisted of transient loose stools in three subjects in the single-dose study and antibiotic-associated diarrhea in one subject in the multiple-dose study.