Acute intravascular hemolysis indicating thrombosis of Bjork-Shiley aortic prosthesis.

A patient with a Bjork-Shiley aortic prosthesis inserted two years and four months prior to receiving adequate anticoagulant therapy suddenly had severe intravascular hemolysis develop as a result of thrombosis of her aortic prosthesis. There was no notable hemodynamic compromise. The mechanism of the intravascular hemolysis is discussed.

The first documented outbreak of trichinellosis in Hong Kong Chinese.

An outbreak of trichinellosis occurred in a Chinese family after the ingestion of inadequately cooked pork. Diagnosis was established by the demonstration of antibodies against Trichinella spiralis larval antigen by crossed immunoelectrophoresis and enzyme-linked immunosorbent assays, and living larvae in muscle biopsy. The main presenting symptom of these patients was pyrexia. Typical clinical features of Trichinella infection such as periorbital edema and severe myalgia were either minimal or absent. A history of having eaten insufficiently cooked meat is thus extremely important for correct diagnosis. We believe that this is the first documented report of a Trichinella outbreak in Chinese living in Hong Kong.

Simvastatin does not affect CYP3A activity, quantified by the erythromycin breath test and oral midazolam pharmacokinetics, in healthy male subjects.

Potential for inhibition of CYP3A activity by simvastatin, an HMG-CoA reductase inhibitor, was evaluated in 12 healthy male subjects who received placebo or 80 mg of simvastatin, the maximal recommended dose, once daily for 7 consecutive days. On day 7, an intravenous injection of 3 microCi [14C N-methyl]erythromycin for the erythromycin breath test (EBT) was coadministered with a 2 mg oral solution of midazolam. The values for percent 14C exhaled during the first hour (for EBT) and the pharmacokinetic parameters of midazolam (AUC, Cmax, t1/2) were not affected following multiple once-daily oral doses of simvastatin 80 mg. The 95% confidence interval was 0.97 to 1.18 for EBT and 0.99 to 1.23 for midazolam AUC. In addition, the total urinary recoveries of midazolam and its 1'-hydroxy metabolites (free plus conjugate) obtained from both treatments were not statistically different (p > 0.200). These data demonstrate that multiple dosing of simvastatin, at the highest recommended clinical dose, does not significantly alter the in vivo hepatic or intestinal CYP3A4/5 activity as measured by the commonly used EBT and oral midazolam probes.

Effect of montelukast on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers.

Montelukast, a cysteinyl leukotriene receptor antagonist, is being developed for the treatment of asthma and related diseases. This study was designed to evaluate whether montelukast at clinically used dosage levels would interfere with the anticoagulant effect of warfarin. In a two-period, double-blind, randomized crossover study, 12 healthy male subjects received a single oral dose of 30 mg warfarin on the 7th day of a 12-day treatment with montelukast, 10 mg daily by mouth, or a placebo. Montelukast had no significant effect on the area under the plasma concentration-time curves and peak plasma concentrations of either R- or S-warfarin. However, slight but statistically significant decreases in time to peak concentration of both warfarin enantiomers and in elimination half-life of the less potent R-warfarin were observed in the presence of montelukast. These changes were not considered as clinically relevant. Montelukast had no significant effect on the anticoagulant effect of warfarin, as assessed by the international normalized ratio (INR) for prothrombin time (AUC0-144 and INR maximum). The results of this study suggest that a clinically important interaction between these drugs is unlikely to occur in patients requiring concomitant administration of both drugs.

Lack of pharmacokinetic interaction between rofecoxib and methotrexate in rheumatoid arthritis patients.

Rofecoxib is a highly selective and potent inhibitor of cyclooxgenase-2 (COX-2). Methotrexate is a disease-modifying agent with a narrow therapeutic index frequently prescribed for the management of rheumatoid arthritis. The objective of this study was to investigate the influence of clinical doses of rofecoxib on the pharmacokinetics of methotrexate in patients with rheumatoid arthritis. This was a randomized, double-blind, placebo-controlled study in 25 rheumatoid arthritis patients on stable doses of methotrexate. Patients received oral methotrexate (7.5 to 20 mg) on days -1, 7, 14, and 21. Nineteen patients received rofecoxib 12.5, 25, and 50 mg once daily on days 1 to 7, 8 to 14, and 15 to 21, respectively. Six patients received placebo on days 1 to 21 only to maintain a double-blinded design for assessment of adverse experiences. Plasma and urine samples were analyzed for methotrexate and its major although inactive metabolite, 7-hydroxymethotrexate. The AUC(0-infinity) geometric mean ratios (GMR) and their 90% confidence intervals (90% CI) (rofecoxib + methotrexate/methotrexate alone) for day 7/day -1, day 14/day -1, and day 21/day -1, for rofecoxib 12.5, 25, and 50 mg, were 1.03 (0.93, 1.14), 1.02 (0.92, 1.12), and 1.06 (0.96, 1.17), respectively (p > 0.2 for all comparisons to day -1). All AUC(0-infinity), GMR and Cmax GMR 90% CIs fell within the predefined comparability limits of (0.80, 1.25). Similar results were observed for renal clearance of methotrexate and 7-hydroxymethotrexate at the highest dose of rofecoxib tested (50 mg). It was concluded that rofecoxib at doses of 12.5, 25, and 50 mg once daily has no effect on the plasma concentrations or renal clearance (tested at the highest dose of rofecoxib) of methotrexate in rheumatoid arthritis patients.

Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers.

Steady-state inhibitory activity of rofecoxib (Vioxx) on COX-2 versus COX-1 was compared with that of commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) in 76 healthy volunteers randomized to placebo, rofecoxib 12.5 mg qd, rofecoxib 25 mg qd, diclofenac 50 mg tid, ibuprofen 800 mg tid, sodium naproxen 550 mg bid, or meloxicam 15 mg qd. All of these doses include the high end of the approved clinical dose range. Ex vivo whole-blood assays were used to determine the effect on COX-2 and COX-1 activity, respectively. Urinary prostanoids were also measured. Mean inhibition of COX-2 (measured as the weighted average inhibition [WAI] of lipopolysaccharide [LPS]-induced PGE2 generation over 8 hours on day 6 vs. baseline) was -2.4%, 66.7%, 69.2%, 77.5%, 93.9%, 71.4%, and 71.5% for placebo, rofecoxib 12.5 mg, rofecoxib 25 mg, meloxicam, diclofenac, ibuprofen, and naproxen, respectively. Corresponding values for mean inhibition of COX-1 (measured as TXB2 generation in clotting whole blood) were -5.15%, 7.98%, 6.65%, 53.3%, 49.5%, 88.7%, and 94.9%. Rofecoxib had no significant effect on urinary excretion of 11-dehydro TXB2, a COX-1-derived product. These data support the contention that rofecoxib is the only drug of the regimens tested that uniquely inhibits COX-2 without affecting COX-1.

Two years experience with the Palmaz-Schatz coronary stent in a heterogeneous patient population.

Between January 1991 and December 1992, 136 Palmaz-Schatz coronary stents were implanted in 113 native coronary arteries in 106 patients. Forty-seven patients presented with stable angina, 50 with unstable angina, 7 with congestive cardiac failure and unstable angina and 2 were asymptomatic. Stenting was carried out in 15 patients for restenosis after coronary angioplasty (PTCA), 32 for significant dissection during PTCA (with 19 acute and 13 threatened closure), 10 for suboptimal PTCA results and 56 for de novo lesions, 52 (92.9%) of which were either ACC/AHA type B or C. Successful delivery was achieved in 97.2% (103/106) of patients or 97.3% (110/113) of vessels. Percent diameter stenosis was reduced from 78 +/- 13% to 4 +/- 11%. There were two subacute stent thromboses (1.9%), resulting in Q-Wave myocardial infarction. Three deaths (2.9%) occurred, all from the group with congestive cardiac failure and unstable angina. Major bleeding/vascular complications occurred in 4 patients (3.9%). All patients were followed up for a mean of 18 months (6 months to 30 months). Eighty-five patients were asymptomatic. Three patients were angina-free but continued to have, albeit improved, congestive cardiac failure. Ten patients had recurrence of angina, all within 6 months of the stenting procedure. Four were treated medically and 4 had PTCA of whom one eventually had coronary bypass surgery. Two patients had new lesions, successfully treated by PTCA or stenting. In conclusion, a high rate of successful delivery of the Palmaz-Schatz coronary stent can be achieved in a wide spectrum of patients with few complications which are mostly related to anticoagulation. It offers very effective bailout for acute closure during PTCA. Despite the presence of unfavorable pre-procedure patient and lesion characteristics, the acute and long term clinical results are encouraging.

Study on the health hazards of scrap metal cutters.

Scrap metal cutters seemed to be left out in most preventive programmes as the workers were mainly contract workers. The health hazards of scrap metal cutting in 54 workers from a foundry and a ship breaking plant were evaluated. Environmental sampling showed lead levels ranging from 0.02 to 0.57 mg/m3 (threshold limit values is 0.15 mg/m3). Exposure to lead came mainly from the paint coat of the metals cut. Metal fume fever was not reported although their main complaints were cough and rhinitis. Skin burns at all stages of healing and residual scars were seen over hands, forearms and thighs. 96% of the cutters had blood lead levels exceeding 40 micrograms/100 ml with 10 workers exceeding 70 micrograms/100 ml. None had clinical evidence of lead poisoning. The study showed that scrap metal cutting is a hazardous industry associated with significant lead exposure. With proper medical supervision, the blood lead levels of this group of workers decreased illustrating the importance of identifying the hazard and implementing appropriate medical surveillance programmes.

UGT2B17 genetic polymorphisms dramatically affect the pharmacokinetics of MK-7246 in healthy subjects in a first-in-human study.

MK-7246, an antagonist of the chemoattractant receptor on T helper type 2 (Th2) cells, is being developed for the treatment of respiratory diseases. In a first-in-human study, we investigated whether genetic polymorphisms contributed to the marked intersubject variability in the pharmacokinetics of MK-7246 and its glucuronide metabolite M3. Results from in vitro enzyme kinetic studies suggested that UGT2B17 is probably the major enzyme responsible for MK-7246 metabolism in both the liver and the intestine. As compared with those with the UGT2B17*1/*1 wild-type genotype, UGT2B17*2/*2 carriers, who possess no UGT2B17 protein, had 25- and 82-fold greater mean dose-normalized values of area under the plasma concentration-time curve (AUC) and peak concentration of MK-7246, respectively, and a 24-fold lower M3-to-MK-7246 AUC ratio. The apparent half-life of MK-7246 was not as variable between these two genotypes. Therefore, the highly variable pharmacokinetics of MK-7246 is attributable primarily to the impact of UGT2B17 genetic polymorphisms and extensive first-pass metabolism of MK-7246.

Examination of the effect of increasing doses of etoricoxib on oral methotrexate pharmacokinetics in patients with rheumatoid arthritis.

The authors designed 2 randomized controlled studies to examine the effects of etoricoxib 60 to 120 mg daily on methotrexate pharmacokinetics in 50 rheumatoid arthritis (RA) patients on stable doses of methotrexate (7.5-20 mg). Patients received oral methotrexate at baseline and on days 7 and 14. In study 1, patients received etoricoxib 60 mg (days 1-7) and then 120 mg (days 8-14); in study 2, patients received etoricoxib 90 mg (days 1-7) and then 120 mg (days 8-14). For study 1, the AUC(0-infinity) geometric mean ratio (GMR) (90% confidence interval [CI]) for day 7 versus baseline was 1.01 (0.91, 1.12) for etoricoxib 60 mg; the area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)) GMR (90% CI) for day 14 was 1.28 (1.15, 1.42) for etoricoxib 120 mg. For study 2, the AUC(0-infinity) GMR (90% CI) for day 7 versus baseline was 1.07 (1.01, 1.13) for etoricoxib 90 mg; the AUC(0-infinity) GMR (90% CI) for day 14 was 1.05 (0.99, 1.11) for etoricoxib 120 mg. In summary, etoricoxib 60 and 90 mg had no effect on methotrexate plasma concentrations. Although no effect on methotrexate pharmacokinetics was observed with etoricoxib 120 mg in study 2, GMR AUC(0-infinity) fell outside the prespecified bounds in study 1. Standard monitoring of methotrexate-related toxicity should be continued when etoricoxib and methotrexate are administered concurrently, especially with doses >90 mg etoricoxib.

Molecular characterization of the Cryptosporidium cervine genotype.

In this study, the 27 kDa immunodominant antigen (CP23), 70 kDa heat shock protein (HSP70), actin and beta-tubulin genes were amplified and sequenced for the first time from human isolates of Cryptosporidium cervine genotype. New primers were designed from reported sequences of other Cryptosporidium species and genotypes as well as the whole genome sequences of C. parvum and C. hominis, which enabled novel gene sequences and regions extending beyond those deposited in GenBank to be determined. In comparison with other species in the Cryptosporidium genus, multiple sequence alignment and phylogenetic analysis revealed that the Cryptosporidium cervine genotype isolates from humans clustered most closely with Cryptosporidium deer mouse genotype and C. suis (n. sp. formerly pig genotype I). The complete coding sequence of CP23 was determined to reveal low (72.4% and 68.0-69.8% respectively) identity to C. parvum and C. hominis sequences and the presence of a unique multiple proline-alanine-proline-valine (PAPV) repeat region.

Retrieval of undeployed intracoronary Palmaz-Schatz stents.

Two patients undergoing stent placement with the Palmaz-Schatz coronary stent delivery system experienced intracoronary stent embolization. Using a two-wire technique, the stents were successfully removed from the coronary circulation, and this allowed completion of the percutaneous revascularization procedure without any clinical sequelae. These two cases represent the first report of successful percutaneous retrieval of undeployed, retained intracoronary Palmaz-Schatz stents.

Intracoronary stenting in acute myocardial infarction.

Stent implantation into an infarct-related artery during acute myocardial infarction is generally contraindicated because of the risk of stent thrombosis. We report on 3 patients who had successful stenting for an acute occlusive dissection that developed during direct infarct coronary angioplasty and was refractory to conventional prolonged balloon dilatation, with good long-term clinical and angiographic results. The prerequisites for success include proper premedication, presence of only a minimal amount of thrombus in the infarct-related artery, liberal use of intracoronary thrombolytic therapy, as perfect an angiographic result as possible, as well as careful and aggressive post-stenting anticoagulation.

Recurrent meningitis of 5 years duration due to Cryptococcus neoformans.

A patient with recurrent meningitis over five and a half years due to Cryptococcus neoformans is reported. The relapsing course and the unusual diagnostic features are emphasized.

Echocardiographic assessment of the Hall Kaster mitral prosthesis.

To study the effect of the Hall Kaster prosthesis on left ventricular filling characteristics after mitral valve replacement, postoperative M-mode echocardiograms of the left ventricle from sixteen patients were digitized to determine the peak rate of dimension (D) increase of the left ventricle during diastole (peak dD/dt) and the rapid filling period (RFP). These were compared with fourteen normal controls, thirty patients with Starr Edwards and thirty patients with Bjork Shiley mitral prosthesis. Results suggest that the Hall Kaster mitral prosthesis is less obstructive than either the Starr Edwards or the Bjork Shiley prosthesis, and tends to approximate the normal mitral valve.

Chlorhexidine feeding and its effect on growth and intestinal microflora in rats.

Chlorhexidine digluconate was administered to rats by incorporating the drug in drinking water and by regular gastric intubation. Incorporating the drug in the drinking water resulted in feed and water rejection. Relatively high doses (30 mg/day) could be administered over a period of 30 to 45 days without apparent effect on feed and water intake and growth. The total number of bacteria as well as the number of colony-forming units from cecal samples were determined. Chlorhexidine intake did not reduce the cultivable or total intestinal flora.

Clinical application of a new Palmaz-Schatz coronary stent delivery system with a short (8 mm) nonarticulated stent.

The standard Palmaz-Schatz coronary stent delivery system (SDS), with a 15 mm articulated stent and a 5F protective sheath, is relatively rigid and high in profile. Its use is contraindicated in vessels where there is severe tortuosity proximal to or in the lesion itself. Recently a new SDS, with a short (8 mm) nonarticulated stent, has become available. We present three patients with complex coronary anatomy solved with this new SDS. The first patient had a distal stenosis in an extremely tortuous and diffusely diseased right coronary artery (RCA). The second patient had a severe proximal RCA stenosis occurring at a bend of more than 90 degrees. The third patient had a very long stenosis of the left anterior descending coronary artery involving the ostium, requiring multiple tandem stenting. The availability of this short stent will greatly expand the clinical application of intracoronary stenting to patients with complex coronary anatomy.