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OBJECTIVES: This study analyzes the efficacy in myocardial protection of two types of cardioplegia solutions, namely, blood and crystalloid cardioplegia, both given intermittently in patients undergoing coronary artery bypass grafting (CABG). METHODS: Adult patients undergoing primary isolated coronary artery bypass grafting between January 1998 and January 2011 with cardiopulmonary bypass, using either blood or crystalloid cardioplegia, were identified in our database. Propensity score matching was performed to create comparable patient groups. Multivariate logistic regression analysis was performed to identify independent risk factors for perioperative myocardial damage. The primary endpoint of the study was the maximum creatine kinase-MB (CK-MB) value within 5 days postoperatively with a cut-off point of 100 U/L. Early mortality and perioperative low cardiac output syndrome in both groups were compared. RESULTS: The study included 7138 CABG patients: 3369 patients using crystalloid cardioplegia and 3769 using blood cardioplegia. After propensity score matching, 2585 patients per study group remained for the analysis. Wilcoxon signed-rank test revealed significantly higher CK-MB levels in patients operated with the use of blood cardioplegia. Multivariate regression analysis identified blood cardioplegia as an independent risk factor for elevated CK-MB levels. However, it was associated with lower aspartate aminotransferase (AST) levels. The type of cardioplegia had no influence on early mortality, postoperative low cardiac output syndrome or intensive care unit stay. CONCLUSIONS: Blood cardioplegia was identified as an independent risk factor for elevated levels of CK-MB after CABG, but was associated with lower AST levels. The authors conclude that the type of cardioplegia had no significant influence on clinical outcome.

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Atrial fibrillation occurring after cardiac surgery has been the subject of intensive research over the past decades. However, the incidence remains high, despite numerous preventive and treatment strategies. In addition, several reports show that the impact of post-operative atrial fibrillation (POAF) is high. It is an independent risk factor for mortality after several years. These findings make clear that the pathophysiology of POAF is not fully understood and POAF-associated risks to some extent might be underestimated. On the one hand, excessive triggers during the acute post operative phase after cardiac surgery might initiate AF even in atria with low vulnerability. On the other hand, many patients undergoing surgery have an atrial substrate at the time of operation promoting AF not only in the post-operative phase but also in the days and weeks thereafter. Progress in our understanding of the AF mechanisms in general has provided valuable insights into processes involved in atrial structural remodeling due to advanced age, hypertension, obesity, and congestive heart failure. These patient characteristics strongly contribute to cardiac disease, predict POAF and likely have an impact on the risk of thrombus formation in the weeks and months after cardiac surgery. For a better understanding of the mechanisms involved, it is important to not only recognize the occurrence of POAF by continuous monitoring after surgery, but also to identity the extent of atrial vulnerability to AF in these patients.

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AIM: The PAS-Port® Proximal Anastomosis System (Cardica, Inc, Redwood City, CA, USA) has been used worldwide since March 2003. The objective of the present study was to evaluate the clinical outcome of the PAS-Port® Proximal Anastomosis System. METHODS: All the patients who underwent off-pump coronary artery bypass grafting in the Catharina Hospital Eindhoven between August 2006 and April 2010 were included in a non-randomized retrospective case-control study, if they had at least one proximal vein graft anastomosis. Study end-points consisted of overall survival, coronary reintervention and postoperative stroke. RESULTS: The study included 312 patients (201 cases, 111 controls). After 36 months of follow-up there was no difference in survival between cases and controls (92.2% vs. 93.7%, P=0.52). No significant difference could be detected between cases and controls with respect to overall coronary reintervention-free survival (93% vs. 96.4%, P=0.20) and freedom from coronary reintervention due to proximal vein graft failure (98% vs. 100% P=0.14). The use of the PAS-Port system could not be identified as an independent risk factor of coronary reintervention (p=0.21). Postoperative stroke rates of cases and controls (2% vs. 0.9%, P=0.42) were comparable. CONCLUSION: The clinical outcomes in patients treated with the PAS-Port® Proximal Anastomosis System were satisfactory compared with those treated with the conventional hand-sewing technique. The use of the PAS-Port system was not associated with higher adverse outcome in terms of overall survival, stroke, coronary reintervention-free survival and freedom from reintervention due to proximal vein graft failure.

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A previously healthy 28-year-old woman presented to the emergency clinic with acute severe abdominal pain and high fever. A diagnostic laparoscopy was performed, during which a large retroperitoneal tumour was found. A CT-scan of the abdomen and thorax confirmed the presence of a retroperitoneal mass but also revealed multiple renal angiomyolipomas and extensive cystic lesions in all lung fields. Based on these findings, the diagnosis lymphangioleiomyomatosis (LAM) was suspected, and later confirmed by histological examination of a biopsy specimen. The acute abdomen and fever appeared to have been caused by a Streptococcus agalactiae infection of the retroperitoneal lymphangiomyoma, which was treated with intravenous antibiotics. LAM is a very rare disease affecting mostly women of childbearing age and presenting almost exclusively with pulmonary symptoms. This is the first description of LAM presenting with an acute surgical abdomen and fever due to infection of a lymphangiomyoma.

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(207)Pb solid-state NMR studies have been conducted on binary lead-group 16 and mixed transition-metal/lead group 16 materials, correlating the NMR chemical shifts of the materials with their structures. The experimental results show that the (207)Pb chemical shifts are strongly influenced by the local electronic structure. Data are reported for lead selenide, lead selenate, calcium plumbate, strontium plumbite, barium plumbite, lead borate, lead zirconate, lead tungstate, lead meta-tantalate, lead niobate, lead molybdate, lead meta-vanadate, lead sulfite, and lead sulfate.

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Hypoglossal nerve palsy following intubation is a rare complication that can be reversible depending on the extent of nerve damage. A 63-year-old male with a sigma carcinoma was repeatedly intubated orotracheally due to postoperative complications. After the fourth intubation, bilateral, complete hypoglossal nerve palsy with severe dysarthria and swallowing disability was observed. A percutaneous endoscopic gastrostomy tube was inserted for nutrition and to prevent aspiration. Cerebral MRI showed no pathological findings, particularly in the brainstem. Electromyographic studies revealed pathological spontaneous activity of both glossal muscles without any motor unit potential consistent with an axonal lesion of both hypoglossal nerves. Nevertheless, complete clinical and electromyographical recovery occurred within 7 months. The bilateral hypoglossal nerve palsy in our patient was probably due to mechanical alteration during intubation, leading to axonotmesis. Hypoglossal nerve palsy following intubation might have a favourable prognosis as long as continuity of the nerve sheath is maintained.

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OBJECTIVE: To detect perfusion reductions in patients with acute cerebral infarcts using near-infrared spectroscopy (NIRS) with indocyanine green (ICG) as tracer. METHODS: Kinetics of an intravenous bolus of ICG were monitored by NIRS in 13 patients with acute infarction in the territory of the middle cerebral artery (mean (SD) age, 62.2 (13.0) years) and 12 controls (64.2 (9.1) years) at 2.8 (2.8) days after onset. NIRS optodes were placed bitemporally, with an interoptode distance of 4-5 cm. Absolute concentration changes in ICG were calculated. The following were assessed: time to peak, maximum ICG concentration, time interval between 0% and 100% maximum ICG concentration (interval), rise time (time between 10% and 90% ICG maximum), slope (maximum Delta ICG/interval), and blood flow index (BFI = maximum Delta ICG/rise time) of each hemisphere. Intraindividual differences were calculated between the two hemispheres. RESULTS: Patients with ischaemic stroke had increased time to peak (p<0.01), interval (p<0.01), and rise time (p<0.01), while maximum ICG concentration (p<0.03), slope (p<0.01), and BFI (p<0.01) were diminished at the site of infarction compared with the unaffected hemisphere. In stroke patients, intraindividual differences in time to peak (p<0.001), interval (p<0.001), rise time (p = 0.001), maximum ICG concentration (p<0.02), slope (p<0.001), and BFI (p<0.001) were greater than in the controls, with excellent sensitivity and specificity for Delta time to peak (100% and 100%, respectively) and Delta time interval (100% and 91.7%). CONCLUSIONS: Measurement of interhemispheric differences in ICG kinetics by NIRS detects perfusion reductions in patients with acute middle cerebral artery infarction. This non-invasive bedside test is rapid, repeatable, without major side effects, and avoids transportation of critically ill patients.

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In our previous study, healthy volunteers showed considerable short-term dynamics and patterns of the coherence of high time resolution between respiratory movements (RESP), heart rate fluctuations (HRF), and arterial blood pressure fluctuations (BPF). These are physiological indicators of autonomic short-term coordination mediated mainly by the brainstem which could be impaired in severe brain disorders. We hypothesized a direct or indirect impairment of these functions by these disorders and examined these patterns in 16 patients suffering from severe brain disorders. We calculated partial and ordinary coherence sequences and found almost the same patterns of coherence sequences as in healthy volunteers, but a distinctly reduced frequency of pattern incidence in patients (2.8+/-1.5/10 min/patient and 9.5+/-2.8/10 min/subject, P<0.05). Furthermore, there is a significantly smaller frequency of HRF-related patterns in patients with poor outcome, compared with those in patients with good outcome (1.8+/-0.8/10 min/patient and 4.5+/-2.7/10 min/patient, P<0.05). We conclude that severe brain disorders reduce physiological short-term dynamics of autonomic coordination patterns in the mean values of patients, but not in every patient.

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An LC/MS/MS method for the simultaneous determination of cilostazol, a quinolinone derivative, and three active metabolites, OPC-13015, OPC-13213, and OPC-13217, in human plasma was developed and validated. Cilostazol, its metabolites, and the internal standard, OPC-3930 were extracted from human plasma by liquid-liquid partitioning followed by solid-phase extraction (SPE) on a Sep-Pak silica column. The eluent from the SPE column was then evaporated and the residue reconstituted in a mixture of methanol/ammonium acetate buffer (pH 6.5) (2:8 v/v). The analytes in the reconstituted solution were resolved using reversed-phase chromatography on a Supelcosil LC-18-DB HPLC column by an 17.5-min gradient elution. Cilostazol, its metabolites, and the internal standard were detected by tandem mass spectrometry with a Turbo Ionspray interface in the positive ion mode. The method was validated over a linear range of 5.0-1200.0 ng/ml for all the analytes. This method was demonstrated to be specific for the analytes of interest with no interference from endogenous substances in human plasma or from several potential concomitant medications. For cilostazol and its metabolites, the accuracy (relative recovery) of this method was between 92.1 and 106.4%, and the precision (%CV) was between 4.6 and 6.5%. During the validation, standard curve correlation coefficients equalled or exceeded 0.999 for cilostazol and its metabolites. These data demonstrate the reliability and precision of the method. The method was successfully cross-validated with an established HPLC method.

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The possible linear short-term coordination between respiratory movements (RESP), heart rate fluctuations (HRF), and arterial blood pressure fluctuations (BPF) in conscious human beings has not yet been investigated because of the restricted time resolution of conventional time series analysis. At present, this short-term dynamics as an expression of relative coordination can be quantified by newly developed adaptive autoregressive modeling of time series using Kalman filtering. Thus, in 6 conscious healthy volunteers, RESP, HRF, and BPF were recorded during 10 min in the supine position, at rest and during paced breathing. A considerable part of calculated ordinary and partial coherence sequences of short-term resolution between RESP and HRF, RESP and BPF, and partially between HRF and BPF showed patterns varying in time that could be correlated to changes between gradual coordinations (coherence changing between 0.40 and 0.95). They were more seldom complete or absent. There were mostly opposite changes between partial coherence sequences RESP-HRF/BPF and RESP-BPF/HRF demonstrating competitive behavior between these coordinations. Paced breathing did not essentially affect any observed characteristics. Therefore, these coherence dynamics are not essentially dependent on voluntary breathing movements. We conclude that to a different extent these linear and changing couplings between RESP, HRF, and BPF in conscious human beings exhibit properties of short-term complete and more frequently gradual coordinations showing dynamics that can not be determined by conventional methods.

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A high performance liquid chromatography (HPLC) method with ultraviolet detection for the simultaneous quantification of cilostazol, and its known metabolites in human urine was developed and validated. Cilostazol, its metabolites and the internal standard OPC-3930 (structural analogue of cilostazol) were extracted from human urine using liquid-liquid extraction with chloroform. The organic extract was then evaporated and the residue was reconstituted in 8% acetonitrile in ammonium acetate buffer (pH 6.5). The reconstituted solution was injected onto an HPLC system and was subjected to reverse-phase HPLC on a 5-microm ODS column. A gradient mobile phase with different percentages of acetonitrile in acetate buffer (pH 6.5) was used for the resolution of analytes. Cilostazol, its metabolites and the internal standard were well resolved at baseline with adequate resolution from constituents of human urine. The lower limit of quantification was 100 ng/ml for cilostazol and all metabolites. The method was validated for a linear range of 100-3000 ng/ml for all the metabolites and cilostazol. The overall accuracy (% relative recovery) of this method ranged from 86.1 to 116.8% for all the analytes with overall precision (%CV) being 0.8-19.7%. The long-term stability of clinical urine samples was established for at least 3 months at -20 degrees C in a storage freezer. During validation, calibration curves had correlation coefficients greater than or equal to 0.995 for cilostazol and the seven tested metabolites. The method was successfully used for the analysis of cilostazol and its metabolites in urine samples from clinical studies, demonstrating the reliability and robustness of the method.

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1. Cilostazol (OPC-13013) undergoes extensive hepatic metabolism. The hydroxylation of the quinone moiety of cilostazol to OPC-13326 was the predominant route in all the liver preparations studies. The hydroxylation of the hexane moiety to OPC-13217 was the second most predominant route in vitro. 2. Ketoconazole (1 microM) was the most potent inhibitor of both quinone and hexane hydroxylation. Both the CYP2D6 inhibitor quinidine (0.1 microM) and the CYP2C19 inhibitor omeprazole (10 microM) failed to consistently inhibit metabolism of cilostazol via either of these two predominant routes. 3. Data obtained from a bank of pre-characterized human liver microsomes demonstrated a stronger correlation (r2=0.68, P < 0.01) between metabolism of cilostazol to OPC-13326 and metabolism of felodipine, a CYP3A probe, that with probes for any other isoform. Cimetidine demonstrated concentration-dependent competitive inhibition of the metabolism of cilostazol by both routes. 4. Kinetic data demonstrated a Km value of 101 microM for cilostazol, suggesting a relatively low affinity of cilostazol for CYP3A. While recombinant CYP1A2, CYP2D6 and CYP2C19 were also able to catalyze formation of specific cilostazol metabolites, they did not appear to contribute significantly to cilostazol metabolism in whole human liver microsomes.

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Clinical doses are developed for the oral coadministration of radiolabeled and nonlabeled forms of a poorly soluble investigational compound: OPC-41061. The release rates of the labeled and nonlabeled forms are equated and matched to the release rate of the polymer spray-dried form of the drug in the proposed market product. The study involves the physicochemical characterization of the powders using thermal analysis and dissolution testing, development and extemporaneous manufacture of liquid-filled soft gelatin capsules, and dissolution and stability testing of the final dosage form. Thermal analysis indicated that the labeled powder was amorphous and that the nonlabeled powder, which had been jet-milled, was crystalline. Dissolution testing of the jet-milled and spray-dried powders indicated that the former was released at a significantly slower rate. A liquid formulation containing 25% dimethyl acetamide and 75% polyethylene glycol 400 (PEG 400) solubilized the desired dose of 60 mg and exhibited a drug profile that was similar to the spray-dried formulation. The final formulation was a soft gelatin capsule containing 60 mg of drug, including 100 microCi radioactivity, dissolved in 0.8 ml of a 25% dimethyl acetamide/75% PEG 400 solution. The formulation was chemically and physically stable for a period greater than the duration of the study.

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Vesnarinone is an orally administered inotropic agent that is metabolized in vitro by the cytochrome P450 (CYP) isozymes CYP3A4 and CYP2E1. The purpose of this study was to assess the contribution of CYP2E1 activity to the disposition of vesnarinone in humans by characterizing the pharmacokinetics before and after disulfiram-mediated CYP2E1 inhibition. The pharmacokinetics of vesnarinone 60 mg were determined in normal healthy volunteers (N = 7) before and after daily disulfiram administration (250 mg). Chlorzoxazone 250 mg was also administered before, during, and after disulfiram administration to serve as a positive control for CYP2E1 inhibition. Disulfiram treatment decreased 6-hydroxychlorzoxazone formation clearance by nearly 95% but effected only a modest decrease in vesnarinone apparent oral clearance (5.7 +/- 1.0 vs. 5.0 +/- 0.5 ml/min; p = 0.022). In contrast to the modest effect on the parent drug, disulfiram treatment substantially increased plasma concentrations of the primary metabolite OPC-18692. The Cmax of OPC-18692 was increased approximately 7-fold, and the area under the plasma concentration-time curve was increased 18-fold (2.9 +/- 0.9 vs. 53.7 +/- 33.2 micrograms.h/ml; p = 0.006). The results indicate that CYP2E1 inhibition has only a modest, clinically insignificant effect on vesnarinone disposition but markedly increases plasma concentrations of the OPC-18692 metabolite. The pharmacological properties of this metabolite have not been fully defined; thus, the clinical importance of this observation depends on whether this metabolite contributes to any of the toxicity associated with vesnarinone administration.

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A high-performance liquid chromatographic (HPLC) method for the simultaneous determination of cilostazol, a quinolinone derivative, and its known metabolites OPC-13015, OPC-13213, OPC-13217, OPC-13366, OPC-13269, OPC-13326 and OPC-13388 in human plasma was developed and validated. Cilostazol, its metabolites and two internal standards, OPC-3930 and OPC-13112, were extracted from human plasma by a combination of liquid-liquid and liquid-solid phase extractions, with combined organic solvents of n-butanol, methanol, chloroform, methyl-tert.-butyl ether, and a Sep-Pak silica column. The combined extract was then evaporated and the residue was reconstituted in ammonium acetate buffer (pH 6.5). The reconstituted solution was injected onto a HPLC system and was subjected to reversed-phase HPLC on a 5 microm ODS-80TM column to obtain quality chromatograph and good peak resolution. A gradient mobile phase with different percentages of acetonitrile in acetate buffer (pH 6.5) was used for the resolution of analytes. Cilostazol, its metabolites and the two internal standards were well separated at baseline from each other with resolution factor being 74 and 138. This HPLC method was demonstrated to be specific for all analytes of interest with no significant interference from the endogenous substances of human plasma. The lower limit of quantitation was 20 ng/ml for cilostazol and all metabolites. The method was validated initially for an extended linear range of 20-600 ng/ml for all metabolites and cilostazol, and has been revised later for a linear range of 20-1200 ng/ml for cilostazol and two major and active metabolites OPC-13015 and OPC-13213. The overall accuracy (relative recovery) of this method was established to be 98.5% to 104.9% for analytes with overall precision (CV) being 1.5% to 9.0%. The long-term stability of clinical plasma samples was established for at least one year at -20 degrees C. Two internal standards of OPC-3930 and OPC-13112 were evaluated and validated. However, the data indicated that there was no significant difference for all accuracy and precision obtained by using either OPC-3930 or OPC-13112. OPC-3930 was chosen as the internal standard for the analysis of plasma samples from clinical studies due to its shorter retention time. During the validation standard curves had correlation coefficients greater than or equal to 0.998 for cilostazol and the seven metabolites. These data clearly demonstrate the reliability and reproducibility of the method.

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An LC/MS/MS assay was developed and successfully used to quantitate vesnarinone and its principal metabolites (OPC-8230, OPC-18136, and OPC-18137) in human plasma and urine. Samples were pre-treated with liquid-solid extraction followed by simultaneous monitoring of primary and daughter ions which were used for the identification and quantitation of the analytes on LC/MS/MS. This assay offers advantages of specificity, speed and greater sensitivity over the previously developed HPLC-UV assay. The lower limit of quantitation is 500 ng x ml(-1) for vesnarinone and 20 ng x ml(-1) for OPC-8230, OPC-18137, and OPC-18136 in plasma. Methodology is similar for the estimation of these analytes in urine with the lower limit of quantitation being 500 ng x ml(-1) for vesnarinone and 100 ng x ml(-1) for each metabolite. Ascorbic acid was added to stabilize the analytes from degradation. This LC/MS/MS method was developed to overcome many practical problems associated with the HPLC method. The LC/MS/MS method offers the flexibility of analyzing additional metabolites and changing the linearity range to accommodate the differences in linear range (200-10000 ng x ml(-1) for vesnarinone and 20-1000 for metabolites) for the analytes.

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OBJECTIVE: To study the pharmacokinetics of cilostazol following single oral administration of 50 to 200 mg in healthy young males, and after repeated oral administration of 100 mg every 12 hours to patients with peripheral arterial disease (PAD). DESIGN: The healthy male single dose study was a single-centre, randomised sequence, open-label, incomplete block, 3-period, 4-treatment, crossover design. The patient study was a single-centre, multiple dose, open-label study. STUDY PARTICIPANTS: 20 healthy nonsmoking male volunteers were enrolled and successfully completed the single dose study. 26 patients (21 males, 5 females) with intermittent claudication resulting from PAD were enrolled and completed the single/multiple dose study. MAIN OUTCOME MEASURES: Noncompartmental pharmacokinetic parameters, the area under the plasma concentration-time curve from zero to the time of last measurable plasma concentration, and maximum plasma concentration. RESULTS: Peak plasma concentrations of cilostazol occurred about 3 hours after drug administration and then declined biexponentially with concentrations detectable (> 20 micrograms/L) in the plasma for at least 36 hours postdose. The apparent elimination half-life of cilostazol (approximately 11 hours) was similar after a single dose or after multiple doses, with steady state being reached within 4 days. Cilostazol accumulated 1.7-fold following multiple dose administration. The apparent volume of distribution (Vz/F; 2.76 L/kg) suggested extensive distribution of cilostazol in the tissues. The oral clearance of cilostazol (CL/F; 0.18 L/h/kg) was much lower than liver blood flow, indicating a low extraction ratio drug, and hence low probability of a significant first-pass effect. None of the administered doses were recovered in the urine as unchanged cilostazol, suggesting that metabolism, rather than urinary excretion, is the major elimination route. Following single oral doses of 50 to 200 mg, the plasma concentrations of cilostazol and its metabolites increased less than proportionally to the dose. The pharmacokinetics of cilostazol in normal healthy volunteers are predictive of those in patients with PAD. Single oral doses of 50 to 200 mg cilostazol as well as 100 mg cilostazol every 12 hours were well tolerated. CONCLUSION: The plasma concentration of cilostazol and its metabolites increased less than proportionally with increasing doses. The relatively low plasma clearance and high volume of distribution of cilostazol suggest a low first-pass effect and extensive distribution. The pharmacokinetics of cilostazol in normal volunteers is predictive of that in patients with PAD. Cilostazol was well tolerated in healthy volunteers and patients with intermittent claudication resulting from PAD.

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OBJECTIVES: The objectives of this research were to (1) assess the relative bioavailability following administration of a 100 mg cilostazol suspension versus 100 mg tablet; (2) assess dosage form equivalency (2 x 50 mg compared with 1 x 100 mg); (3) compare the relative bioavailability following a single 50 mg dose of cilostazol administered as an ethanolic solution versus a 50 mg tablet; and (4) determine the effects of high fat diet on the pharmacokinetics of cilostazol following a single dose of 100 mg cilostazol in the fed or fasted state. Results were compiled from 3 separate studies to address these objectives. DESIGN: All studies involved healthy adult males receiving single oral doses of cilostazol in the fed or fasted state. The fed state consisted of administering cilostazol after ingestion of a high fat meal. One study compared the relative bioavailability of 100 mg suspension and 2 x 50 mg tablet versus 100 mg tablet in a randomised crossover design. The study involving administration of a 50 mg cilostazol ethanolic solution was a single treatment study. The effects of food on the pharmacokinetics of cilostazol after administration of 100 mg cilostazol in the fed or fasted state as well as the pharmacokinetic profile following administration of a single 50 mg oral dose of cilostazol were assessed in a randomised crossover design. STUDY PARTICIPANTS: All participants were healthy nonsmoking males aged between 19 and 48 years whose bodyweight was within 15% of ideal bodyweight. MAIN OUTCOME MEASURES: Noncompartmental pharmacokinetic parameters were determined for each study participant. RESULTS: The area under the plasma concentration-time curve (AUC) parameters were within the 80 to 125% criterion for bioequivalence for the cilostazol and its primary metabolite, OPC-13015. The maximum observed plasma concentrations (Cmax) for these formulations were not equivalent and indicated that the absorption of cilostazol from a suspension is more rapid than from a tablet. The apparent terminal half-lives (t1/2z) of cilostazol and OPC-13015 were shorter after administration of the suspension compared with the tablet. Cmax and AUC following administration of a single 50 mg cilostazol tablet were approximately 80% of that from the same dose administered as an ethanolic solution. The t1/2z of cilostazol decreased from 15.5 hours after a tablet to 2.5 hours after an ethanolic solution. Upon coadministration with a high fat meal, the Cmax of cilostazol increased 90% and AUC infinity increased 25% (p < 0.05). The t1/2z decreased from 15.1 +/- 14.5 hours (mean +/- SD) in the fasted state to 5.4 +/- 2.0 hours in the fed state. Single oral doses of 50 and 100 mg cilostazol were well tolerated. CONCLUSIONS: The relative bioavailability of the 100 mg cilostazol tablet versus an oral 100 mg cilostazol suspension is 100%. The 2 x 50 mg and 1 x 100 mg tablets are considered to be bioequivalent. The absorption following administration of 50 mg cilostazol ethanolic solution is faster and appears to be greater than that after administration of the 50 mg tablet. Coadministration of food increases the rate and extent of cilostazol absorption. The oral pharmacokinetics of cilostazol and metabolites are absorption-rate limited. The significant differences in the t1/2z observed when comparing cilostazol tablet, suspension, and solution as well as the effects of food suggest 'flip-flop' pharmacokinetics.

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OBJECTIVE: The pharmacokinetic profiles of cilostazol and its metabolites following a single oral dose of cilostazol 100 mg were compared between individuals with impaired and normal liver function. DESIGN: The study was conducted as a single-centre, open-label, single dose pharmacokinetic and tolerability trial. STUDY PARTICIPANTS: 12 patients with impaired and compensated liver function were compared with 12 volunteers with normal liver function. Participants in each group were matched for gender, age and weight. Of the 12 patients with hepatic impairment examined in this study, 10 had mild impairment (Child-Pugh class A) and 2 had moderate impairment (Child-Pugh class B). MAIN OUTCOME MEASURES: Blood and urine were collected up to 144 hours after drug administration. Pharmacokinetics were determined by noncompartmental methods. RESULTS: Protein binding did not differ between the groups (95.2% healthy volunteers, 94.6% hepatically impaired patients). Mean +/- SD unbound oral clearance of cilostazol decreased by 8.6% because of hepatic impairment (3380 +/- 1400 ml/min in healthy volunteers, 3260 +/- 2030 ml/min in hepatically impaired patients). Total urinary excretion of metabolites was significantly higher in healthy volunteers (26 vs 17% of dose). Overall, the pharmacokinetics of cilostazol and its metabolites, OPC-13213 and OPC-13015, were not substantially different in those with mild and moderate hepatic disease compared with values in healthy volunteers. Except for terminal-phase disposition half-life and apparent terminal-phase volume of distribution for cilostazol, the ratios of geometric means of pharmacokinetic parameters for plasma cilostazol, OPC-13213 and OPC-13015 in those with hepatic impairment versus healthy volunteers were close to 100%. CONCLUSIONS: Based on the results of the pharmacokinetic analysis, dose adjustment in patients with mild hepatic impairment is not necessary. However, caution should be exercised when cilostazol is administered to patients with moderate or severe hepatic impairment.

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OBJECTIVE: The pharmacokinetics of cilostazol were studied in patients with mild, moderate and severe renal impairment and in healthy volunteers after administration of 50 mg single and multiple doses of cilostazol. DESIGN: This was an open-label, single and multiple dose study administering 50 mg cilostazol every 12 hours to healthy volunteers and patients with varying degrees of renal impairment. PARTICIPANTS: 6 normal volunteers [creatinine clearance (CLCR) > or = 90 ml/min]; 6 patients with mild (CLCR 50 to 89 ml/min), 5 with moderate (CLCR 26 to 49 ml/min) and 6 with severe (CLCR 5 to 25 ml/min) renal impairment. OUTCOME MEASURES: Noncompartmental pharmacokinetic parameters were determined for each study participant. RESULTS: At steady state, in the severe renal disease group, cilostazol and OPC-13015 peak concentrations (Cmax) were 29 and 41% lower and the areas under the concentration-time curve over the dosage interval (AUC tau) 39 and 47% lower than in the healthy volunteers. Cmax and AUC tau of OPC-13213 were significantly higher, 173 and 209%, respectively, than those in the healthy volunteers. The accumulation ratios were not significantly different between the various renal function groups for cilostazol and its metabolites. The estimated pharmacological activity of cilostazol and its metabolites was similar between the normal volunteers and those with severe renal impairment. CONCLUSIONS: A dosage reduction in renally impaired patients is not supported by the pharmacokinetics of cilostazol and its metabolites in this patient group.

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