Administration Of Ticlopidine Research Articles

Antibiotic prophylaxis of infective endocarditis in dental procedures: challenges, certainties, and perspectives

Antibiotic prophylaxis against infective endocarditis (IE) before dental procedures is currently limited to high-risk patients, yet there is no evidence of its efficacy/inefficacy in humans, and it is unlikely there will be for organizational and economic reasons. Most cases of endocarditis from oral streptococci are due to bacteremias associated with chewing and oral hygiene habits, which could be reduced by regular oral hygiene. Data from studies conducted after the most recent guidelines are not sufficient to establish a relationship between the reduction in patient groups to which antibiotic prophylaxis is given and the incidence trend of endocarditis from oral streptococci. This is mainly attributed to study limitations and lack of data on physicians' adherence to official recommendations. Patients at risk of IE should be made aware of the lack of firm evidence of the benefits of antibiotic prophylaxis for IE in humans and be involved in the decision to receive it or not. According to some studies, the administration of aspirin and ticlopidine to experimental animals followed by the induction of low-grade bacteremia has prevented IE in most cases. However, the possible use of these drugs in humans requires further clinical studies.

Ticlopidine, a Cholestatic Liver Injury-Inducible Drug, Causes Dysfunction of Bile Formation via Diminished Biliary Secretion of Phospholipids: Involvement of Biliary-Excreted Glutathione-Conjugated Ticlopidine Metabolites

The antiplatelet drug, ticlopidine (TIC), reportedly causes cholestatic liver injuries. The present study analyzed the effect of TIC on bile formation, revealing that the biliary secretion of phospholipids was significantly decreased in TIC-administered Sprague Dawley (SD) rats. However, the effect of TIC on biliary phospholipids was not observed in SD rats pretreated with diethylaminoethyl diphenylpropylacetate that inhibits cytochrome P450s (P450), or in Eisai hyperbilirubinemic rats (EHBR) lacking functional multidrug resistance-associated protein 2 (MRP2/ABCC2). These results suggest that glutathione-conjugated TIC metabolites (TIC-SGs), which were formed in the liver after P450s-mediated metabolism and were excreted extensively into bile by MRP2, mediated the observed alterations of the bile composition. Administration of TIC caused significant liver injuries in SD rats, with decreased biliary phospholipids, but not in EHBR, consistent with the in vitro observation that phospholipid-bile acid-mixed micelles moderated the cytotoxic effects of bile acids. Further analyses revealed that TIC-SGs did not directly inhibit multidrug resistance 3 P-glycoprotein (MDR3/ABCB4)-mediated phosphatidylcholine efflux in vitro. Because the diminished biliary secretion of phospholipids with TIC administration was restored by taurocholate infusion in SD rats, the decreased biliary concentration of bile acids, due to the stimulation of bile acid-independent bile flow driven by TIC-SGs, might have indirectly attenuated phospholipid secretion. In conclusion, extensive biliary excretion of TIC-SGs decreased the biliary secretion of phospholipids, which might have increased the risk of TIC-induced cholestatic liver injury.

Ticlopidine-induced hepatotoxicity in a GSH-depleted rat model

We investigated hepatotoxicity induced by ticlopidine (TIC) in glutathione (GSH)-depleted rats by pre-treatment of a well-known GSH synthesis inhibitor, L-buthionine-S,R-sulfoxinine (BSO). Although sole administration of either TIC or BSO showed no signs of hepatotoxicity, combined administration of TIC with BSO induced hepatotoxicity, which was characterized by centrilobular necrosis of the hepatocytes and an elevation of plasma alanine aminotransferase activity. Administration of radio-labeled TIC in combination with BSO resulted in significantly higher covalent binding to rat liver proteins than that observed after sole dosing of radio-labeled TIC. Pre-treatment of 1-aminobenzotriazole, a non-specific inhibitor of P450s, completely suppressed both hepatotoxicity and the increased hepatic covalent binding caused by TIC co-treatment with BSO. The results obtained in this animal model suggest that GSH depletion and covalent binding may be involved in hepatotoxicity induced by TIC. These observations may help to understand the risk factors and the mechanism of hepatotoxicity of TIC in humans.

Pharmacokinetic Drug Interaction between Carvedilol and Ticlopidine in Rats

This study was designed to investigate the effects of ticlopidine on the pharmacokinetics of carvedilol after oral or intravenous administration of carvedilol in rats. Carvedilol was administered orally (3 mg/kg) or intravenously (1 mg/kg) without or with oral administration of ticlopidine (4, 12 mg/kg) to rats. The effects of ticlopidine on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 2C9 activity were also evaluated. Ticlopidine inhibited CYP2C9 activity in a concentration-dependent manner with 50% inhibition concentration (<TEX>$IC_{50}$</TEX>) of <TEX>$25.2\;{\mu}M$</TEX>. In addition, ticlopidine could not significantly enhance the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-gp. Compared with the control group (given carvedilol alone), the area under the plasma concentration-time curve (AUC) was significantly (12 mg/kg, p<0.05) increased by 14-41%, and the peak concentration (<TEX>$C_{max}$</TEX>) was significantly (12 mg/kg, p<0.05) increased by 10.7-73.3% in the presence of ticlopidine after oral administration of carvedilol. Consequently, the relative bioavailability (R.B.) of carvedilol was increased by 1.14- to 1.41-fold and the absolute bioavailability (A.B.) of carvedilol in the presence of ticlopidine was increased by 36.2-38.5%. Compared to the i.v. control, ticlopidine could not significantly change the pharmacokinetic parameters of i.v. administered carvedilol. The enhanced oral bioavailability of carvedilol may result from inhibition of CYP2C9-mediated metabolism rather than P-gpmediated efflux of carvedilol in the intestinal and/or in liver and renal eliminatin of carvedilol by ticlopidine.

Influence of Ginkgo biloba extract on the pharmacodynamic effects and pharmacokinetic properties of ticlopidine: An open-label, randomized, two-period, two-treatment, two-sequence, single-dose crossover study in healthy Korean male volunteers

Background: Ginkgo biloba extract is an herbal medicine used in the treatment of vascular disorders that may be coadministered with antiplatelet agents such as ticlopidine. Regulatory authorities requested evaluation of the pharmacodynamic and pharmacokinetic interactions between these entities, according to the drug-development guidance for fixed-dose combination formulations in Korea. Objective: This study was performed to evaluate the potential pharmacodynamic and pharmacokinetic interactions between ticlopidine and Ginkgo biloba extract. Methods: An open-label, randomized, 2-period, 2-treatment, 2-sequence, single-dose crossover study was conducted in healthy Korean male volunteers. All volunteers were randomly assigned to a sequence group for the 2 treatments, which consisted of ticlopidine 250 mg alone and ticlopidine 250 mg with Ginkgo biloba extract 80 mg, separated by a 1-week washout period between the treatments. Bleeding time was determined just before dosing and at 5, 12, and 48 hours after dosing. Platelet aggregation was evaluated before dosing and at 4, 8, 26, and 48 hours after dosing. Blood samples (8 mL) from each of the volunteers were collected from an indwelling intravenous cannula inserted into a forearm vein before dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 48 hours after dosing. Ticlopidine concentrations were determined by a validated method using HPLC and ultraviolet detection. Adverse events were identified using general health-related questions, vital signs, physical examinations, ECGs, and laboratory tests. Results: A total of 24 healthy men participated in the study (mean [SD] age, 24.1 [4.3] years; weight, 66.6 [7.4] kg; height, 174.7 [5.0] cm). The baselinecorrected bleeding times were not significantly different between the ticlopidine-alone and ticlopidine/ Ginkgo biloba groups, and changes in platelet aggregation were not significantly different between the groups. Likewise, the pharmacokinetic parameters of ticlopidine were not significantly different between the groups; the geometric mean ratios of the ticlopidine/ Ginkgo biloba group to the ticlopidine-alone group were 1.03 (90% CI, 0.92–1.16) for C max, 1.08 (90% CI, 0.98–1.19) for AUC 0-last, and 1.10 (90% CI, 1.00–1.20) for AUC 0–∞. A total of 28 adverse events were reported: 11 in the ticlopidine-alone group and 17 in the ticlopidine/ Ginkgo biloba group. The adverse events judged to be possibly related to ticlopidine in the ticlopidine-alone group were epigastric discomfort (2 cases), diarrhea (1), skin eruption (1), and a feeling of being cold (1) or hot (1). The adverse events judged to be related to ticlopidine or Ginkgo biloba in the ticlopidine/ Ginkgo biloba group were epigastric discomfort (2), diarrhea (2), nausea (2), and headache (1). Conclusions: In this small group of healthy Korean men, the addition of a single dose of Ginkgo biloba extract did not prolong the bleeding time and was not associated with additional antiplatelet effects compared with the administration of ticlopidine alone. The coadministration of Ginkgo biloba extract with ticlopidine was not associated with any significant changes in the pharmacokinetic profile of ticlopidine compared with ticlopidine administered alone.

Comparison of the pharmacokinetics of ticlopidine between administration of a combined fixed-dose tablet formulation of ticlopidine 250 mg/Ginkgo extract 80 mg, and concomitant administration of ticlopidine 250-mg and ginkgo extract 80-mg tablets: An open-label, two-treatment, single-dose, randomized-sequence crossover study in healthy Korean male volunteers

Background: Ticlopidine is an antiplatelet agent used for the prevention of vascular accidents. In clinical practice in Korea, ginkgo extract may be administered along with ticlopidine to enhance the inhibition of platelet aggregation.Objective: To meet the requirements for marketing a combined fixed-dose formulation in Korea, the investigators compared the pharmacokinetic characteristics of ticlopidine in a combined fixed-dose tablet of ticlopidine/ginkgo extract with the concomitant administration of ticlopidine and ginkgo extract tablets.Methods: An open-label, 2-period, 2-treatment, single-dose, randomized-sequence crossover study was conducted in healthy Korean male volunteers. Subjects were randomly allocated to 2 sequence groups. In one period, a combined ticlopidine 250 mg/ ginkgo extract 80-mg fixed-dose tablet was administered and, in the other period, ticlopidine 250-mg and ginkgo extract 80-mg tablets were concomitantly administered. A 7-day washout separated the 2 periods. For analysis of pharmacokinetic properties, including Cmax, Tmax, t½, AUC0−∞, and AUC0−last, serial blood sampling was performed up to 48 hours after study drug administration during each period. Ticlopidine concentrations in plasma were determined by a validated method using LC-MS/MS. In order for the 2 treatments to be considered bioequivalent, the 90% CI of the geometric means ratios for Cmax and AUC needed to be between 80% and 125%. Bleeding time was determined before dosing (0 hour) and at 5 and 24 hours after dosing. Adverse events (AEs) were identified through patient interview, recording of blood pressure, heart rate, and body temperature, physical examination, 12-lead ECG, and laboratory assessments.Results: Twenty-four healthy Korean male subjects (mean [range] age, 23.9 [22–38] years; height, 174.0 [162–184] cm; weight, 67.4 [56–80] kg) completed the study. Median (range) Tmax of ticlopidine was 1.5 (0.5–2.0) hours in both groups. The mean (SD) t½ of ticlopidine in the combined fixed-dose formulation and the concomitant administration groups was 19.5 (3.4) and 19.0 (3.3) hours after study drug administration, respectively. The geometric means ratios of ticlopidine AUC0−last, AUC0–∞, and Cmax between the combined fixed-dose formulation and concomitant administration were 1.04 (90% CI, 0.96–1.13), 1.04 (90% CI, 0.96–1.13), and 1.09 (90% CI, 0.96–1.23), respectively. The mean (SD) bleeding time at predose (0), and 5 and 24 hours after dose administration was 4.5 (1.6) to 5.4 (1.7) minutes in the combined fixed-dose formulation group and 4.4 (1.6) to 5.1 (1.1) minutes in the concomitant administration group. Five subjects (3 in the combined fixed-dose formulation group and 2 in the concomitant administration group) had bleeding times >8 minutes, but this was not considered to be clinically significant. A total of 24 AEs were reported in 13 of 24 subjects: nausea (3 cases), diarrhea (3), dizziness (3), epigastric discomfort (2), headache (2), rhinorrhea (2), purulent sputum (2), dyspepsia (1), upper abdominal pain (1), cough (1), pharyngolaryngeal pain (1), oropharyngeal swelling (1), dysphonia (1), and dysphagia (1). All were considered mild or moderate in nature. There was no statistically significant difference between the 2 treatments in the number of AEs or in the number of subjects who reported an AE.Conclusion: Administration of a single dose of a combined fixed-dose formulation of ticlopidine 250 mg/ ginkgo extract 80-mg tablets and concomitant administration of ticlopidine and ginkgo extract tablets did not result in statistically significant differences in the pharmacokinetics of ticlopidine in these healthy Korean male volunteers

Assessment of Sirolimus-Eluting Coronary Stent Implantation With Aspirin Plus Low Dose Ticlopidine Administration One Year Results From CYPHER Stent Japan Post-Marketing Surveillance Registry (J-PMS)

Clinical data of sirolimus-eluting stent (SES) implantation are under investigation in Japan. The CYPHER stent Japan Post-Marketing Surveillance Registry (J-PMS) was conducted at 50 medical centers to assess the results of SES in daily clinical practice exclusively under aspirin plus low dose ticlopidine (200 mg/day). A total of 2,459 lesions in 2,054 patients were treated with 3,285 SES. The mean age was 67.1 +/-10.1 years, 75.6% were men and 43.3% were diabetics. Intravascular ultrasound was used in 77.2%. The 8-month angiographic and 1-year clinical follow-up data were available in 85.4% and 96.8%, respectively. Quantitative coronary angiography showed the reference vessel diameter and percentage diameter stenosis at baseline were 2.47 +/-0.58 mm and 72.0 +/-16.1%. The 8-month late loss was 0.20 +/-0.50 mm. The major adverse cardiovascular events at 1 year was 7.3%; cardiac death: 1.1%, myocardial infarction (MI): 1.2%, and target lesion revascularization (TLR): 4.2%. The rates of definite and probable stent thrombosis at 1 year were 0.30% and 0.10%, respectively. Hemodialysis was the strongest predictor of death/MI or TLR. J-PMS showed the effectiveness of SES implantation under aspirin plus low dose ticlopidine administration at 1 year, although further studies are necessary to demonstrate the safety.

Platelet release proteins in plasma in peripheral arterial obliterative disease during ticlopidine administration

Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study

Rezidivierende Thromboembolien infolge gesteigerter, gegen Acetylsalicylsäure resistenter Thrombozytenaggregation

A 49-year-old man had for 30 years suffered from severe recurrent thromboembolism with leg-vein thrombosis, pulmonary emboli, mesenteric infarction, cerebrovascular accident, cerebral vein thrombosis, portal vein thrombosis and femoral artery occlusion requiring leg amputation. In addition to moderately increased clotting activation with single-fold positive demonstration of fibrin monomers and a D-dimer concentration of 1 mg/l platelet aggregation was increased and could not be influenced by aspirin, 300 mg daily. Despite aspirin there were recurrent transitory attacks of cerebral ischaemia. Fibrin monomers were threefold positive and D-dimer concentration was increased to 4 mg/l (elevated clotting activation). Ticlopidine administration (250 mg daily) reduced adenosine diphosphate-induced platelet aggregation by 30% without effect on collagen-induced platelet aggregation. In parallel to these changes the patient's general condition clearly improved: fibrin monomers were no longer demonstrated and the D-dimer level fell to 0.5 mg/l.

MANAGEMENT OF ANTIPLATELET THERAPY FOR ENDOSCOPIC PROCEDURES: OPTIMAL CESSATION PERIOD OF ANTIPLATELET THERAPY FOR JAPANESE

Although antiplatelet agents are widely used for the treatment and prevention of thrombotic diseases, only a few studies have reported the validity of the cessation period prior to endoscopic procedures. In 2002, the American Society for Gastrointestinal Endoscopy (ASGE) published a reference on the management of anticoagulation and antiplatelet therapy for endoscopic procedures, but it should be confirmed as appropriate for use in Asian patients. To evaluate the optimal cessation period of antiplatelet agents prior to endoscopic procedures for Japanese, we have studied: (i) the current clinically adopted cessation period of antiplatelet agents prior to invasive endoscopic procedures in Japan; (ii) the relationship between the cessation period of antiplatelet agents and complications around the invasive endoscopic procedures; (iii) colonic mucosal bleeding time after aspirin ingestion; and (iv) the time course of primary hemostasis after cessation of antiplatelet agents. We conclude that 3 days cessation period for aspirin, 5 days cessation for ticlopidine and 7 days cessation for aspirin + ticlopidine administration should be sufficient for Japanese.

Poor Responsiveness to Clopidogrel: Drug-Specific or Class-Effect Mechanism?: Evidence From a Clopidogrel-to-Ticlopidine Crossover Study

This study was designed to investigate whether poor responders to thienopyridines after clopidogrel remain so even after ticlopidine administration (class effect) or whether a drug-specific effect exists between currently available thienopyridines. Whether clopidogrel poor responders also display inadequate platelet inhibition after ticlopidine administration remains undefined. Platelet aggregation (PA) was measured in 143 patients, while they were taking aspirin, with light transmission aggregometry using adenosine diphosphate as an agonist at baseline (T0) and at clopidogrel steady state (T1). After T1) clopidogrel was stopped and substituted with ticlopidine. Then PA was assessed at ticlopidine steady state (T2). Resistance was defined as an absolute difference between T0 and after-treatment (T1 or T2) PA < or =10%. Clopidogrel and ticlopidine responsiveness was normally distributed; PA at T1 did not differ compared with T2. Thirty (21%) and 28 (19%) patients were clopidogrel and ticlopidine nonresponders, respectively. Only 5 patients (3.5%) were nonresponders to both clopidogrel and ticlopidine (class effect), whereas 25 patients (83%) who were clopidogrel nonresponders at T1 were responsive to ticlopidine, reaching a higher level of platelet inhibition at T2 (PA 69 +/- 15 vs. 44 +/- 18, p < 0.01) (drug-specific response). On the other hand, 23 patients who were responsive to clopidogrel showed resistance to ticlopidine at T2 (PA 46 +/- 15 vs. 70 +/- 15, p < 0.01) (drug-specific response). Poor responsiveness to either clopidogrel or ticlopidine at steady state was common, whereas nonresponders to both drugs were relatively infrequent (3.5%, 95% confidence interval 1.5% to 7.9%), suggesting that poor response to thienopyridines may frequently be a drug-specific mechanism.

Ticlopidine prevents the formation but delays the healing of ethanol-induced gastric lesions in the rat

The effects of acute or long-term oral ticlopidine administration in normal rat gastric mucosa or on gastric lesions induced by ethanol 50% (EtOH, 1 ml/rat, os) were examined and compared with those of acetylsalicylic acid (ASA). Ticlopidine does not affect gastric mucosal integrity either after acute (100 and 300 mg kg −1) or 1-week (100 mg kg −1, die) oral administration. Ticlopidine (30–300 mg kg −1, os) administered 1 h before EtOH dose-dependently prevented the development of gastric haemorragic lesions. When ticlopidine was administered 1 h after EtOH, it significantly ( p < 0.05) delays gastric lesions healing. Acute ASA (50 and 100 mg kg −1, os) administration causes a mild irritant activity similar to that observed after 1 week of ASA (50 mg kg −1, os/die) administration. In condition of mucosal damage, ASA does not modify either the induction or the healing of EtOH-induced gastric lesions. To assess the possible involvement of endogenous nitric oxide (NO) or prostaglandins (PG) in the gastric protective activity of ticlopidine, the rats were pretreated with an inhibitor of NO-synthesis, l-NAME (70 mg kg −1, s.c.) or the inhibitor of PG synthesis, indomethacin (Indo, 10 mg kg −1, s.c.). Indo, but not l-NAME, was able to significantly counteract the gastroprotective activity of ticlopidine against EtOH injury. Furthermore, ticlopidine increases (47%) gastric PGE 2 content in normal mucosa compared to the one detected in control rats, thus suggesting that endogenous PGs contribute to enhanced mucosal resistance by ticlopidine. These results indicate that ticlopidine exerts dual effects during the development and healing of gastric lesions induced by EtOH.

Incidence of Side-Effects of Ticlopidine After Sirolimus-Eluting Stent Implantation Retrospective Analysis From Three Hospitals

Because of its side-effects, long-term administration of ticlopidine limits the use of the sirolimus-eluting stent (SES) in Japan. Side-effects of ticlopidine occurred in 41 (9.3%) of 440 patients who underwent SES implantation. The majority were liver dysfunction (4.5%) and rash (3.6%). One patient died from severe liver dysfunction. Neutropenia occurred in 3 patients (0.7%). It is remarkable that 28% of side-effects occurred >8 weeks after the initiation of ticlopidine. Ticlopidine has a relative high rate of side-effects. Clopidogrel should be approved for prevention of stent thrombosis as soon as possible.

The Effects of Ergoloid Mesylates and Ginkgo Biloba on the Pharmacokinetics of Ticlopidine

Ticlopidine is sometimes coadministered with ergoloid mesylates or ginkgo biloba in clinical situations. Our objective was to examine the effect of ergoloid mesylates and ginkgo biloba on ticlopidine pharmacokinetics. Ticlopidine, ergoloid mesylates, and ginkgo biloba significantly inhibited the organic anion transporting polypeptide (OATP-B)-mediated uptake of [(3)H]-estrone-3-sulfate in a concentration-dependent manner. When ergoloid mesylates was coadministered with ticlopidine, the ticlopidine area under the plasma drug concentration-time profile (AUC) from 0 to 12 hours was decreased 30% and the peak plasma drug concentration (C(max)) was decreased 29%, compared with ticlopidine administration alone. There were no significant changes in the pharmacokinetic parameters of ticlopidine when it was coadministered with ginkgo biloba. In summary, ergoloid mesylates is a more potent inhibitor of OATP-B than is ginkgo biloba, and it can reduce the oral bioavailability of drugs transported by OATP-B. Ergoloid mesylates markedly decreased the AUC and C(max) of ticlopidine, probably by inhibiting the OATP-B-mediated uptake of ticlopidine during the intestinal absorption phase. The results support a new model of intestinal drug-drug interaction.

Rash with Both Clopidogrel and Ticlopidine in Two Patients Following Percutaneous Coronary Intervention with Drug-Eluting Stents

To describe 2 cases of rash that occurred following oral administration of both clopidogrel and ticlopidine and to review previously published case reports. Two patients developed maculopapular pruritic rashes that began on the abdomen and spread to the back, neck, and face following clopidogrel administration after placement of a drug-eluting intracoronary stent. Following recurrence of the rash after ticlopidine was initiated, thienopyridines were discontinued, and the patients were treated for 3-6 months with aspirin, cilostazol, and enoxaparin or warfarin for prevention of stent thrombosis and reinfarction. One patient self-discontinued cilostazol, reinitiated clopidogrel, and redeveloped a rash. While there have been several published cases of thienopyridine-associated rash, there have been only 2 reported cases of cross-sensitivity between orally administered clopidogrel and ticlopidine. Preliminary reports suggest that clopidogrel desensitization may be accomplished in selected patients several months to years following thienopyridine rash using an allergy desensitization protocol, with close monitoring for anaphylaxis. An objective causality assessment using the Naranjo probability scale indicated that both ticlopidine and clopidogrel were probable causes of the rash in the first patient; in the second patient, clopidogrel was judged a definite cause and ticlopidine was a probable cause of the rash. In a patient who develops a rash following clopidogrel treatment after intracoronary stent placement, ticlopidine therapy should be attempted, provided the initial reaction did not include life-threatening symptoms. In a patient who experiences rash with both clopidogrel and ticlopidine and does not have a contraindication to cilostazol or anticoagulation, therapy with aspirin, cilostazol, and either enoxaparin or warfarin may be administered for 2-6 months following placement of a drug-eluting stent.

Bioequivalence of two preparations of ticlopidine evaluated using a pharmacodynamic end point

To evaluate the bio-equivalence of 2 ticlopidine preparations, 250 mg Iclopid tablets (Pabianickie Zaklady Farmaceutyczne, Polfa, Poland; test formulation) and 250 mg Ticlid tablets (Sanofi, France; reference formulation) using a pharmacodynamic end point, i.e the platelet aggregation test ex vivo. The study was open, randomized, multiple-dose, two-period, crossover with a four-week washout interval. Volunteers were screened for sensitivity towards the platelet aggregation (ex vivo) effect of ADP (30 micromol/l) and sensitivity to the antiplatelet activity of ticlopidine (250 mg daily, for 3 consecutive days). Only those responding to 30 micromol/l of ADP with aggregation in the range of 40 - 75% of control (0.9% NaCI), and those responding to ticlopidine within 40 - 75% of inhibition of platelet aggregation to ADP ex vivo were randomized to the study. The dose of ticlopidine in each phase was 250 mg daily for four days. Blood samples were taken on Day 0 and Days 2, 4 (last day of ticlopidine administration), 5, 6, 9, 11 and 16 in order to follow platelet recovery. The pharmacodynamic parameter measured was expressed as the percentage inhibition of ex vivo platelet aggregation calculated from the number of platelets in the sample of whole blood remaining after ADP (30 micromol/l) compared to the control sample. The following values were calculated: area under the inhibition curve of platelet aggregation (AUC(inh 1-16)), maximal inhibition of platelet aggregation (Max(inh)) and time at which maximal inhibition of aggregation occurred (T(max inh)). The ratios (90% confidence intervals) of Iclopid/Ticlid for AUC(inh 1-16), Max(inh), and T(max inh) were: 1.008 (0.973 - 1.044), 1.009 (0.991 - 1.028) and 1.015 (0.988 - 1.043), respectively, satisfying the bioequivalence criteria. The test and the reference products are bioequivalent on the basis of the ex vivo platelet aggregation test. Our study has shown that the bioequivalence of two different preparations can be assessed by measuring a pharmacodynamic end point in a suitably selected group of subjects.

Patient characteristics in ticlopidine hydrochloride-induced liver injury: Case–control study

Ticlopidine hydrochloride-induced liver abnormalities have been reported in the world. In Japan, the five-year (1995-2000) spontaneous serious reports of ticlopidine finds that liver injury accounts for about half of the reports. Clinical characteristics of ticlopidine-induced liver injury were investigated to establish the prevention strategy. We used a medical information system at Hiroshima University Hospital and analyzed statistically. In this study 288 cases were reviewed. Sixty-two cases were identified as the Cases that showed liver function abnormality after ticlopidine administration. And 226 cases were identified as the Controls. There were no significant differences in gender, age or daily dose between the two groups. Fluctuation of liver function was observed within 30 days in the most of Cases and cholestatic type accounted for about 60%. The risk of this abnormality increased significantly in patients with pre-existing abnormal liver or renal function [odds ratio (95% CI): 2.96 (1.43-6.13), p=0.005; 2.47 (1.13-5.39), p=0.037]. The renal protective agent, an oral carbonaceous adsorbent, reduced the risk of ticlopidine-induced liver function abnormalities in patients with renal abnormalities significantly [odds ratio (95% CI): 0.04 (0.002-0.767), p=0.004]. Liver function tests should be checked frequently, especially in cases with pre-existing liver or renal function abnormalities.

Hemangioendotelioma kaposiforme torácico. Cuatro casos con evolución variable

Kaposiform hemangioendothelioma (KHE) is a rare, frequently congenital, neoplasm associated with the Kasabach-Merritt phenomenon (KMP) and predilection for the trunk. Its clinical course is unpredictable. A child with KHE can die as a result of hemorrhage or show early spontaneous regression. In addition various and concurrent therapies can be used to treat this tumor and it is difficult to predict which treatment will be successful. We present four consecutive cases of KHE (larger than 20 cm) of the thorax. All patients developed KMP, without skin involvement in one patient. Patient 1, a neonate with KHE occupying both hemithoraces (nearly 50% of the body surface area), died shortly after birth due to coagulopathy and generalized bleeding. Patient 2, a neonate, was treated with interferon alpha-2a and showed accelerated correction of coagulopathy and complete tumoral regression at 9 months. Patient 3 showed no response to steroids, interferon or vincristine therapy. Thrombocytopenia (platelet count 40,000) persisted for 8 years and was resolved by administration of aspirin plus ticlopidine, without tumoral disappearance. Patient 4 underwent incomplete removal of the tumor on her right chest wall after showing no response to antiangiogenic therapy. The coagulopathy persisted and a second radical surgical procedure resolved KMP. Given the variable response to pharmacological treatment and the scant possibilities of surgical resection, the management of KHE with KMP must include a multidisciplinary approach. As little is known about the pathogenesis of these highly aggressive vascular tumors, further molecular research is needed to understand their long-term behavior.

Comparative effect of antiplatelet therapy in retinal vein occlusion evaluated by the particle-counting method using light scattering

To evaluate platelet aggregation in patients with retinal vein occlusion (RVO) by the light-scattering method and compare the effects of three antiplatelet drugs on aggregate formation. Prospective, nonrandomized, interventional clinical trial. (1) Platelet aggregation was measured in 42 patients with untreated branch RVO (BRVO), 26 patients with central RVO (CRVO), and 30 healthy control subjects using a light-scattering platelet aggregometer. Platelet aggregates were classified as small, medium, and large according to light intensity. Total light intensities of each aggregate size were compared between BRVO, CRVO, and control subjects. (2) In 33 patients with RVO, platelet aggregation before and 2 weeks after the administration of ticlopidine, beraprost, or aspirin were compared. (1) There was a statistically significant difference (P = 0.0073) between the control subjects (8.3 x 10(6) a.u.) and CRVO patients (22.9 x 10(6) a.u.) with respect to small aggregates. There was no statistically significant difference with respect to medium and large aggregate formation between the control subjects and either patient group. (2) Compared with aggregates formed in the absence of antiplatelet drugs, ticlopidine significantly inhibited only the formation of small aggregates and beraprost that of all sizes; aspirin did not significantly inhibit the formation of any aggregate sizes. Increase in small platelet aggregates may be attributable to RVO pathogenesis. Beraprost and ticlopidine appear to inhibit small aggregate formation in RVO patients and may represent effective antiplatelet treatments. The light-scattering method is useful to investigate the pathogenesis of RVO and the effects of antiplatelet drugs.

Probucol and ticlopidine: effect on platelet and monocyte activation markers in hyperlipidemic patients with and without type 2 diabetes

We investigated the effects of probucol and ticlopidine on circulating levels of platelet activation markers, microparticles, soluble selectins, and malondialdehyde-low density lipoprotein (MDA-LDL) in hyperlipidemic patients with or without type 2 diabetes. There were significant differences in the levels of CD62P, PAC-1, annexin V, PDMP, MDMP, sP-selectin, sE-selectin and MDA-LDL between the hyperlipidemic patients and the controls. In particular, these markers were significantly increased in hyperlipidemic patients who had type 2 diabetes. In the hyperlipidemic patients with diabetes, MDA-LDL was decreased by both monotherapy with probucol and combination therapy (probucol and ticlopidine). In these patients, CD62P, PAC-1, annexin V, MDMP, PDMP, sP-selectin, and sE-selectin were also significantly decreased after treatment. The decreases of CD62P, PAC-1, annexin V, PDMP and sP-selectin were greater combination therapy than with monotherapy. These findings suggest that administration of probucol and ticlopidine to hyperlipidemic patients with type 2 diabetes may help to prevent the development of cardiovascular complications caused by modified LDL, selectins, or activated platelets and monocytes.