Occurrence of fruiting structures allows determination of Purpureocillium lilacinum as an inciting agent of pleuritis and pneumonia in a loggerhead sea turtle (Caretta caretta) by histopathologic correlation to culture.

Purpureocillium lilacinum and Beauveria bassiana were isolated from lung sampled at necropsy of a 12 year-old female loggerhead sea turtle (Caretta caretta) that had displayed abnormal buoyancy. Histopathologic evaluation revealed pleuritis and pneumonia with non-melanized, septate hyphae and fruiting structures identical to those of P. lilacinum. This case emphasizes the importance of a histological correlate to fungal culture when environmental fungi are isolated and demonstrates the infrequent phenomenon of fruiting or conidial production in tissue.

[Self-collection of test material. Supplement to cervical cancer screening]. / Selbstentnahme von Untersuchungsmaterial. Ergänzung beim Zervixkarzinomscreening.

BACKGROUND: Recent studies have reported high sensitivity of human papillomavirus (HPV) testing from self-collected vaginal specimens. These results suggest the possibility of introducing self-collection of samples for cervical cancer screening to increase overall participation. The current study compared test results from self-collected and physician-collected specimens. PATIENTS AND METHODS: Vaginal samples from patients (n = 102) of a colposcopy clinic were taken by both a physician and themselves. All cell samples were tested using cytological diagnostics with a PAP test and for carcinogenic HPV genotypes (Cervista®). Additionally, all patients had a colposcopy (86% with cervical biopsy) and in 40% of patients was carried out a conisation. RESULTS: Of the patients tested 50 had the histological diagnosis of a cervical intraepithelial neoplasia grade 2 (CIN 2+ or 3). Sensitivity of HPV self-collected samples was much lower than that of physician-collected samples (72 % compared to 92 %). The sensitivity of self-collected PAP tests was only 52 % but the positive predictive value of self-collected PAP tests was very high. The cytological diagnosis of high-grade intraepithelial lesion (HSIL) correlated much better with the histological results of conisation (96 %) than with cervical biopsies (76 %). CONCLUSION: The results of this study indicate that self-collection may not provide an adequate collection method for improving efficiency in cervical cancer screening in Germany.

A thorough QT/QTc study of multiple doses of tapentadol immediate release in healthy subjects.

OBJECTIVE: This randomized, double-blind, placebo- and positive-controlled 4-way crossover study evaluated the effects of tapentadol immediate release (IR) on the QT/QTc interval. MATERIALS AND METHODS: Healthy subjects received tapentadol IR 100 mg or 150 mg, or placebo, every 6 h on Days 1 and 2, with a >= 7-day washout between treatments. Moxifloxacin 400 mg was the positive control. Serial triplicate 12-lead electrocardiograms (ECGs) were performed; the Fridericia correction (QTcF) was the primary correction method. Serial blood sampling was performed for pharmacokinetic analyses. RESULTS: Of the 75 subjects who were randomized, 68 received at least 1 dose of study medication, and 59 completed the study. Upper limits of the 90% confidence intervals (CIs) for the difference in mean DeltaQTcF between tapentadol IR 100 or 150 mg and placebo were < 10 ms (non-inferiority criterion) for all time points. The lower limit of the 90% CI for mean DeltaQTcF between moxifloxacin and placebo exceeded 5 ms from 1 to 6 h after dosing, establishing assay sensitivity. No subject had a postdose QTc interval > 480 ms, change from baseline > 60 ms, or clinically relevant change in heart rate or other ECG variables. Steady-state concentrations were reached within 18 to 24 h. Common adverse events were vertigo (central nervous system (CNS) origin), headache, somnolence, nausea, vomiting, and feeling drunk. CONCLUSION: Therapeutic and supratherapeutic doses of tapentadol do not affect the QT/QTc interval.

Development and evaluation of serotype- and group-specific fluorogenic reverse transcriptase PCR (TaqMan) assays for dengue virus.

Five fluorogenic probe hydrolysis (TaqMan) reverse transcriptase PCR (RT-PCR) assays were developed for serotypes 1 to 4 and group-specific detection of dengue virus. Serotype- and group-specific oligonucleotide primers and fluorogenic probes were designed against conserved regions of the dengue virus genome. The RT-PCR assay is a rapid single-tube method consisting of a 30-min RT step linked to a 45-cycle PCR at 95 and 60 degrees C that generates a fluorogenic signal in positive samples. Assays were initially evaluated against cell culture-derived dengue stock viruses and then with 67 dengue viremic human sera received from Peru, Indonesia, and Taiwan. The TaqMan assays were compared to virus isolation using C6/36 cells followed by an immunofluorescence assay using serotype-specific monoclonal antibodies. Viral titers in sera were determined by plaque assay in Vero cells. The serotype-specific TaqMan RT-PCR assay detected 62 of 67 confirmed dengue virus-positive samples, for a sensitivity of 92.5%, while the group-specific assay detected 66 of 67 confirmed dengue virus-positive samples, for a sensitivity of 98.5%. The TaqMan RT-PCR assays have a specificity of 100% based on the serotype concordance of all assays compared to cell culture isolation and negative results obtained when 21 normal human sera and plasma samples were tested. Our results demonstrate that the dengue virus TaqMan RT-PCR assays may be utilized as rapid, sensitive, and specific screening and serotyping tools for epidemiological studies of dengue virus infections.

Omapatrilat in patients with hepatic cirrhosis. Pharmacodynamics and pharmacokinetics.

OBJECTIVE: The pharmacodynamics and pharmacokinetics of omapatrilat, a member of a new class of cardiovascular compounds, the vasopeptidase inhibitors, were evaluated in subjects with hepatic cirrhosis (n = 10) and in healthy subjects (n = 10) matched for age, weight, gender and smoking history. METHODS: All subjects received omapatrilat 25 mg orally once daily for 14 days. Plasma renin and urinary atrial natriuretic peptide (ANP) levels were measured to assess the effect of omapatrilat on cirrhotic subjects. The effect of omapatrilat on blood pressure as well as changes in ANP and plasma renin levels were not altered by hepatic impairment. Pharmacokinetic parameters were determined from plasma omapatrilat concentrations. RESULTS: There were no significant differences between the two subject groups with regard to log-transformed area under the curve or maximum observed plasma concentration. Systemic accumulation was similar in the two groups. CONCLUSION: These results suggest, based on findings in otherwise healthy cirrhotic subjects, that no adjustment of standard dosing regimens is indicated for hypertensive patients with mild to moderate cirrhosis.

Efecto del hidróxido de aluminio y magnesio en la farmacocinética de irbesartán / Effect of aluminum magnesium hydroxide in pharmacokinetics of irbesartan

Objetivo. Determinar si la farmacocinética de irbesartán en dosis única se altera significativamente tras la administración de hidróxido de aluminio y magnesio (Unimaalox®). Métodos. Estudio abierto, randomizado, de 3 vías de tratamiento, en el que se incluyeron 18 voluntarios sanos. Los días 1, 8 y 15 de tratamiento los voluntarios recibieron por vía oral y en ayunas uno de los siguientes tratamientos: irbesartán 300 mg, irbesartán 300 mg + 10 ml de Unimaalox® suspensión concomitantemente, o irbesartán 300 mg + 10 ml de Unimaalox® suspensión 2 horas antes de la administración de irbesartán. Las muestras sanguíneas se recogieron en los tiempos especificados en el protocolo y hasta 48 horas, tomando como tiempo 0 la administración de irbesartán. Las concentraciones plasmáticas de irbesartán se determinaron mediante HPLC utilizando una técnica validada con extracción en fase sólida. Resultados. No se hallaron diferencias estadísticamente significativas en cuanto a la concentración plasmática máxima (Cmáx) o área bajo la curva de las concentraciones plasmáticas hasta las 48 horas (AUC0-48) postadministración entre los distintos tratamientos administrados. En el caso del AUC extrapolada al infinito (AUC0- ), las diferencias halladas entre los distintos grupos de tratamientos fueron estadísticamente significativas (p = 0,038) cuando se comparó la administración de irbesartán sólo frente a irbesartán más Unimaalox® administrado en las 2 horas previas (p = 0,021). Sin embargo, el intervalo de confianza al 90 por ciento para AUC0- se situó entre 0,67 y 1,5. La mediana para el tiempo en alcanzar la Cmax (tmax) fue de 2,5 horas en todos los grupos de tratamiento. Conclusiones. Estos resultados sugieren que no hay interacción entre el hidróxido de aluminio y magnesio e irbesartán. Por tanto, no es necesario realizar un ajuste de la dosificación cuando se administran concomitantemente (AU)

A Schistosoma mansoni 62-kDa band is identified as an irradiated vaccine T-cell antigen and characterized as calreticulin.

The Schistosoma mansoni soluble adult worm antigen (SAWA) bands of 62/60 kDa were found to contain immunodominant T-cell immunogen(s) in irradiated cercariae-immunized Swiss and C57BL/6 mice. In the present study, spleen T cells of BALB/c mice immunized twice with ultraviolet light-irradiated cercariae proliferated and produced interleukin 4 in response to the 62/60-kDa SAWA bands in T-cell western assays. To characterize the 62/60-kDa bands, an adult S. mansoni worm cDNA expression library constructed in lambdagt11 was immunoscreened with serum of mice immunized with the 62/60-kDa antigens, and the immunoreactive cDNA inserts were sequenced. Purified 62- and 60-kDa proteins were used for amino acid microsequencing and for immunization studies in Swiss, C57BL/6, and BALB/c mice and rabbits. Taken together, the data indicated that the 60-kDa molecules are poorly immunogenic in mice and rabbits, whereas the 62-kDa species identified as S. mansoni calreticulin, is a good T- and B-cell antigen and represents a potential vaccine candidate.

Pharmacokinetics of single-dose oral stavudine in subjects with renal impairment and in subjects requiring hemodialysis.

Two open-label studies assessed the pharmacokinetics of single orally administered doses of 40 mg of stavudine in subjects with renal impairment. In one study (study I), 15 subjects with selected degrees of renal impairment, but not requiring hemodialysis, were stratified into three groups of five subjects each according to creatinine clearance (CL(CR)) normalized by body surface area (ml/min/1.73 m(2)): mild (CL(CR), 60 to 80), moderate (30 to 50), and severe (/= 90) were also enrolled. The stavudine area under the curve from 0 h to infinity (AUC(0-infinity)) increased nonlinearly with declining renal function: 1,864, 2,215, 3,609, and 5,928 ng. h/ml for normal renal function and for mild, moderate, and severe renal impairment, respectively (P = 0.0001 between renal impairment groups). The following stavudine dosage recommendations for renal impairment were proposed for subjects weighing >/=60 kg: CL(CR) of >50 ml/min/1.73 m(2), 40 mg every 12 h; CL(CR) of 21 to 50 ml/min/1. 73 m(2), 20 mg every 12 h; and CL(CR) of 10 to 20 ml/min/1.73 m(2), 20 mg every 24 h. For subjects weighing <60 kg, the proposed doses were 30, 15, and 15 mg, respectively, with the same dosing intervals specified above. In a second study (study II), 12 subjects with end-stage renal disease requiring hemodialysis three times a week were enrolled in a randomized, open-label crossover study (dialysis 2 h after dosing and lasting 4 h or dosing without dialysis). There were no statistically significant differences for AUC(0-infinity), AUC(2-6), time to maximum concentration of drug in serum, half-life, or apparent oral clearance when the two treatment dosage regimens were compared. As a result of study II, the recommended dosing rate for subjects requiring hemodialysis was the same as that proposed for those with severe renal impairment not requiring hemodialysis; however, dosing was recommended to follow hemodialysis and to occur at the same time each day.

[SIDS prevention program in Tyrol]. / Das SIDS-Vorsorgeprogramm Tirol.

In April 1994, an intervention campaign to reduce the incidence of sudden infant death syndrome (SIDS) was established in the Tyrol. The campaign was intended to increase knowledge concerning risk factors for SIDS in the general community and to improve individual care for infants at risk. In contrast to interventional programmes in other federal states of Austria (i.e. Vorarlberg, Styria), this programme did not utilise polysomnography for identifying infants at risk. A part of the intervention programme was the "Styrian risk questionnaire", a standardised questionnaire concerning risk factors for SIDS. Individual instructions for health care of children at risk (risk score > or = 7) were provided and, if necessary, subscription of home monitoring was performed at the out-patient department (SIDS out-patient service) of the Department of Paediatrics in Innsbruck and other paediatric departments throughout the Tyrol. The educational programme also included information concerning basic life support. Psychological support was offered to parents of SIDS infants. Risk factors for SIDS in the Tyrol before the campaign were assessed in a retrospective case-control study (time period 1984-1994; 99 SIDS infants, 136 controls). The risk of SIDS was markedly reduced when parents had detailed knowledge of the risk factors of SIDS (odds ratio (OR) 0.03; p < 0.001), which emphasises the importance of information and educational programmes. The incidence of SIDS declined after the beginning of the intervention campaign from 1.83/1000 live births (average incidence from 1984-1994) to 0.4/1000 live births and remained at this level thereafter. Post-neonatal mortality also declined from 3.9 to 1.3/1000 live births. The prevalence of the prone sleeping position declined immediately after the campaign (53.7% vs. 5.4%, p < 0.001), as did the frequency of maternal smoking during pregnancy (22.9% vs. 14.5%, p < 0.01). Breast feeding became more popular. In all, the low-cost intervention programme in the Tyrol proved to be highly efficient in reducing the risk of SIDS and in maintaining this effect for several years.

Comparison of the pharmacokinetics of fosinoprilat with enalaprilat and lisinopril in patients with congestive heart failure and chronic renal insufficiency.

AIMS: To compare the serum pharmacokinetics of fosinoprilat with enalaprilat and lisinopril after 1 and 10 days of dosing with fosinopril, enalapril and lisinopril. METHODS: Patients with congestive heart failure (CHF, NYHA Class II-IV) and chronic renal insufficiency (creatinine clearance

Irbesartan does not affect the steady-state pharmacodynamics and pharmacokinetics of warfarin.

OBJECTIVES: To determine whether the initiation or titration of irbesartan alters the pharmacodynamics and/or pharmacokinetics of warfarin in a clinically significant manner, thereby requiring additional monitoring of the anticoagulant effect of warfarin. METHODS: Daily doses of warfarin were administered to 16 healthy males for 21 days (10 mg on day 1 and 2.5-10 mg on days 2-21). Irbesartan (300 mg/day) or placebo was concomitantly administered on days 15-21. The pharmacodynamic parameters prothrombin time (PT) and prothrombin time ratio (PTR) were evaluated throughout the study. Plasma and urine samples were collected before and up to 24 h after administration on days 14, 15 and 21 for the determination of the maximum concentration (C(max)), time to reach C(max)(t(max)), the area under the concentration-time curve (AUC) of S-warfarin and the cumulative urinary excretion of warfarin and its metabolites. Pre-dose plasma samples were also collected to determine the C(min) of S-warfarin (days 12, 13, 14 and 21) and irbesartan (days 19, 20 and 21). RESULTS: Analysis of PTR data revealed no significant difference between the group mean PTR values at day 22 and those at day 15 (P=0.699). S-warfarin concentrations in plasma and urine, as well as the urinary concentrations of the metabolites of warfarin, were not affected by concomitant single- or multiple-dose administration of irbesartan. Plasma C(min) concentrations of S-warfarin and irbesartan were also not affected. CONCLUSIONS: No clinically important effect of irbesartan on the pharmacodynamics and pharmacokinetics of warfarin are likely to occur during concomitant administration; therefore, neither a dosage adjustment of irbesartan or warfarin nor any additional monitoring of the anticoagulant effect of warfarin is necessary.

Fosinopril/hydrochlorothiazide: single dose and steady-state pharmacokinetics and pharmacodynamics.

AIMS: Fosinoprilat, the active product of fosinopril, is eliminated by an hepatic pathway in addition to the renal pathway shared by other angiotensin converting enzyme inhibitors (ACEIs). This study aimed to determine whether impaired renal function affects the pharmacokinetics and pharmacodynamics of a combination of fosinopril and hydrochlorothiazide (HCTZ). METHODS: The study had a parallel-group design comparing patients with renal impairment and body-mass-index-matched normal controls. The study was done in a University clinic in 13 patients with renal impairment (mean creatinine clearance 55.7+/-15.6 ml min-1 1.73 m-2 ) and 13 age-, sex-, and body-mass-index-matched normal controls (mean creatinine clearance 102.4+/-8.9 ml min-1 1.73 m-2 ). All patients and normal controls received fosinopril sodium 20 mg and HCTZ 12.5 mg as a daily oral administration on days 1-5. Non-compartmental pharmacokinetic parameters of fosinoprilat and HCTZ were determined from blood and urine samples obtained over 48 h starting on Day 1 (single dose) and Day 5 (steady state): maximum serum concentration (Cmax ), time to maximum serum concentration (tmax ), area under the serum concentration-time curve during the dosing interval (AUC), cumulative urinary excretion (CUE) and the accumulation index (AI; ratio of AUC-day 5/AUC-day 1). Pharmacodynamic parameters were also measured over 24 h on day 1 and over 48 h on day 5: serum ACE activity and arterial blood pressure. RESULTS: Fosinoprilat pharmacokinetic parameters on day 1 in renally impaired vs normal patients: Cmax=387+/-0.19 vs 324+/-0.25 ng ml-1 (P=0.07); tmax=3.5 vs 3.0 h (P=0.58); AUC=3510+/-0.29 vs 2701+/-0.35 ng ml-1 h (P=0. 072); CUE=5.08+/-2.70 vs 7.40+/-2.56% (P=0.009). Fosinoprilat parameters on day 5: Cmax=517+/-0.40 vs 357+/-0.19 ng ml-1 (P=0. 007); tmax=3.0 vs 3.0 h (P >0.99); AUC=4098+/-0.43 vs 2872+/-0.30 ng ml-1 h (P=0.027); CUE=6.81+/-3.53 vs 8.10+/-2.80% (P=0.068). AI=1. 17+/-0.33 vs 1.06+/-0.23 (P=0.29). In both groups ACE inhibition and blood pressure response were similar over 24 h and slightly greater 48 h after last dosing. CONCLUSIONS: In renally impaired subjects fosinopril and HCTZ can be coadministered without undue increases in fosinoprilat concentrations or any clinically significant pharmacodynamic effects. This is probably due to the dual excretory pathways for fosinoprilat.

Pharmacodynamic effects of dual neutral endopeptidase-angiotensin-converting enzyme inhibition versus angiotensin-converting enzyme inhibition in humans.

BACKGROUND: There is currently no clear evidence that dual neutral endopeptidase-angiotensin-converting enzyme inhibitors have effects on angiotensin-converting enzyme, renin, or blood pressure that are different from specific angiotensin-converting enzyme inhibitors in humans. METHODS AND RESULTS: In a double-blind, placebo-controlled crossover study, single oral doses of the dual neutral endopeptidase-angiotensin-converting enzyme inhibitor, 10 mg BMS-186716 and the angiotensin-converting enzyme inhibitor fosinopril (20 mg) were administered to 9 normotensive subjects with induced mild sodium depletion. Values for area under the time curve from 0 to 24 hours [AUC(0-24)] for the plasma angiotensin II/angiotensin I ratio and for angiotensin II were similar for 10 mg BMS-186716 and 20 mg fosinopril. Plasma atrial natriuretic peptide decreased significantly after 20 mg fosinopril (9+/-3 pg/mL; P < .05 versus 10 mg BMS-186716 and placebo) compared with 10 mg BMS-186716 (16+/-5 pg/mL) and placebo (16+/-5 pg/mL). BMS-186716, 10 mg, significantly increased urinary atrial natriuretic peptide from baseline by 2+/-1.3-fold (P < .05 versus placebo and 20 mg fosinopril). AUC(0-24) of plasma active renin did not differ significantly between 10 mg BMS-186716 (3898+/-333 pg x h x mL(-1)) and 20 mg fosinopril (4383+/-302 pg x h x mL(-1); difference not significant). Both drugs decreased blood pressure, but the AUC(0-24) of the changes in mean blood pressure differed significantly from placebo (79+/-84 mm Hg x h) only for 20 mg fosinopril (181+/-6 mm Hg x h; P < .05) but not for 10 mg BMS-186716 (118+/-7 mmHg x h). CONCLUSIONS: In this model, single oral doses of 10 mg BMS-186716 and 20 mg fosinopril induced similar 24-hour in vivo angiotensin-converting enzyme inhibition. BMS-186716, 10 mg, increased urinary atrial natriuretic peptide and blunted the expected decrease in plasma atrial natriuretic peptide caused by angiotensin-converting enzyme inhibition. BMS-186716, 10 mg, did not inhibit plasma active renin rise compared with 20 mg fosinopril. A single oral dose of 10 mg BMS-186716 had a shorter blood pressure-lowering effect than 20 mg fosinopril.

Detection of elevated levels of circulating antigen 85 by dot immunobinding assay in captive wild animals with tuberculosis.

Antemortem diagnosis of tuberculosis in captive wild animals is often difficult. In addition to the variability of host cellular immune response, which does not always indicate current active infection, reactivity to saprophytic or other mycobacteria is common and may interfere with the interpretation of the intradermal tuberculin skin test. Furthermore, the immobilization required for administering the test and evaluating skin reactions in these animals may result in unacceptable levels of morbidity and mortality, of particular concern in individuals of rare or endangered species. Proteins of the antigen 85 (Ag85) complex are major secretory products of actively metabolizing mycobacteria in vitro. Production of these proteins by mycobacteria during growth in vivo could result in increases in circulating levels of Ag85 in hosts with active tuberculosis. A dot blot immunoassay has been used to detect and quantify circulating Ag85 in captive wild animals with tuberculosis. Elevated levels of Ag85 were observed in animals with active tuberculosis as compared with uninfected animals. Study populations included a herd of nyala (Tragelaphus angasi) (n = 9) with no history of exposure to Mycobacterium bovis. Serum Ag85 levels ranged from <5 to 15 microU/ ml (median, 5 microU/ml). The other group included 11 animals from a mixed collection with a documented history of an M. bovis outbreak. Animals with pulmonary granulomatous lesions (n = 3) had serum Ag85 levels ranging from 320 to 1,280 microU/ml (median, 320 microU/ml). Animals with only chronic mediastinal or mesenteric lymphadenitis (n = 4) had serum Ag85 levels ranging from <5 to 320 microU/ml (median, 52.5 microU/ml). Animals with no lesions present on necropsy (n = 4) had serum Ag85 levels ranging from <5 to 80 microU/ml (median, <5 microU/ml). This assay could provide an important adjunct to intradermal skin testing for antemortem diagnosis of tuberculosis in nondomestic species.

Effectiveness of low dose urokinase on dialysis catheter thrombolysis.

Thrombosis, a major cause of hemodialysis catheter dysfunction, can be treated with urokinase. We compared protocols using full strength urokinase to the volume of the catheter with low dose therapy. Clotting episodes and successful declottings (blood flow > 200 ml/min) were tracked for 6 months. One hundred four clotting episodes were treated with 5,000 U/ml urokinase to the volume of the catheter lumen for a 1 hr dwell. If unsuccessful, a second dose of 5,000 U/ml was administered and, if needed, a third dose of 125,000 U/lumen. Post treatment, catheters were locked with 5,000 U/ml heparin to the volume of the lumen. Using new protocols, clotting episodes were treated with 2,500 U/lumen urokinase, followed by saline to the volume of the lumen for a 1 hr dwell. A mid dwell injection of 0.2 ml/lumen saline was added to advance the front of active urokinase. If unsuccessful, a second 2,500 U/lumen dose was administered. Heparin lock was 10,000 U/ml heparin to the volume of the lumen. Revised protocols decreased clotting episodes 60% and urokinase charges 81%, while maintaining successful declottings at 74%. Low dose urokinase was as effective as full strength when the active front was advanced mid dwell.

Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporine-treated kidney graft patients after multiple doses.

OBJECTIVES: To study pravastatin and lovastatin pharmacokinetic and pharmacodynamic effects and their interactions with cydosporine (INN, ciclosporin) in kidney transplant patients after single and multiple doses. SUBJECTS AND METHODS: The pharmacokinetic and pharmacodynamic effects of administration of 20 mg/day oral pravastatin and lovastatin for 28 days and their interactions with cyclosporine (2 to 6 mg/kg/day) were studied in a double-blind, double-dummy, randomized, parallel-group multicenter trial in 44 stable kidney graft recipients. RESULTS: The median area under the curve [AUC(0-24)] of pravastatin was 249 microg x hr/L (range, 104 to 1026 microg x hr/L) after a single dose (day 1) and 241 microg x hr/L (114 to 969 microg x hr/L) after multiple doses (day 28) and was fivefold higher than values reported in the absence of cyclosporine. The median AUC(0-24) of lovastatin was 243 microg x hr/L (105 to 858 microg x hr/L) on day 1 and 459 microg x hr/L (140 to 1508 microg x hr/L) on day 28. Besides a significant accumulation during the study period (p < 0.001), the lovastatin AUC(0-24) values were twentyfold higher than values reported without cyclosporine. Coadministration of pravastatin or lovastatin did not alter cyclosporine pharmacokinetics. In this study, 20 mg/day doses of both drugs resulted in a significant improvement of the lipid profile and were well tolerated. CONCLUSIONS: In contrast to lovastatin, pravastatin did not accumulate over the study period, which is probably one of the reasons rhabdomyolysis has been reported in lovastatin-treated but not pravastatin-treated transplant patients receiving cyclosporine immunosuppression.

In vitro metabolism of N-(5-chloro-2-methylphenyl)-N'-(2-methylpropyl)thiourea: species comparison and identification of a novel thiocarbamide-glutathione adduct.

The in vitro metabolism of SDZ HDL 376, a thiocarbamide developed for the treatment of atherosclerosis, was investigated in rat, dog, monkey, and human liver microsomes, as well as in rat and human liver slices. [14C]SDZ HDL 376 was extensively metabolized in all the species except human. In rat liver microsomes an S-oxide was the major metabolite. In human and monkey microsomes, carbon hydroxylation was favored. The NADPH-dependent oxidation of SDZ HDL 376 resulted in covalent binding to microsomal protein. Addition of GSH to the incubations decreased protein binding in a concentration-dependent manner and resulted in a novel SDZ HDL 376-GSH adduct. Adduct formation required NADPH and was mediated predominantly by cytochrome P450. Inhibition of cytochrome P450 by 1-aminobenzotriazole resulted in a 95% decrease in adduct formation, while heat inactivation of flavin-containing monooxygenases resulted in a 10% decrease. Unlike other thiocarbamides which form disulfide adducts with GSH, the SDZ HDL 376 adduct contained a thioether linkage as characterized by LC/MS/MS and reference to a synthetic standard. Reactions performed with [35S]GSH resulted in a [35S]SDZ HDL 376-GSH adduct, demonstrating the sulfur was derived from GSH. Adduct formation was faster in rat microsomal reactions compared to human microsomes. Other structurally unrelated thiocarbamides (phenylthiourea, methimazole, 2-mercaptobenzimidazole, 2-mercaptoquinazoline, and 2-propyl-6-thiouracil) did not form similar adducts in rat liver microsomes supplemented with GSH. Therefore, the GSH adduct of SDZ HDL 376 is unique for this type of thiocarbamide. These results suggest that the bioactivation and detoxification of SDZ HDL 376 differ significantly from other thiocarbamides. Furthermore, the in vitro formation of S-oxides and GSH adducts in rat hepatic tissue, and ring hydroxylation and glucuronidation in human hepatic tissue, suggests rats may be more susceptible to the toxicity of SDZ HDL 376 compared to humans.

Homologous and heterologous protective immunity to Egyptian strains of Schistosoma mansoni and S. haematobium induced by ultraviolet-irradiated cercariae.

C57BL/6 and Balb/c mice were immunized with ultraviolet-irradiated cercariae of Egyptian strains of Schistosoma mansoni and S. haematobium, challenged with nonirradiated cercariae of the homologous or heterologous species, and assayed for protection against challenge infection by comparing the adult worm burdens of immunized and non-immunized mice. Homologous protection (per cent reduction in worm recovery) ranged from 56% to 69% for S. mansoni and 88% to 99% for S. haematobium. Significant heterologous protection was consistently induced against S. haematobium by immunization with S. mansoni, but not against S. mansoni by immunization with S. haematobium. These results are discussed in relation to those of previous studies and in terms of implications for vaccine development.

Induction of the adipose differentiation-related protein in liver of etomoxir-treated rats.

The effects of etomoxir, an irreversible carnitine palmitoyltransferase I inhibitor, on the liver protein pattern and on liver morphology were examined by two-dimensional gel electrophoresis in female Sprague-Dawley rats treated with 125 mg/kg/day etomoxir for 28 days. In livers of treated animals a protein spot was found which was not present in controls. The spot was identified by internal amino acid sequence analysis as the adipose differentiation-related protein (ADRP). The expression of ADRP in liver is a novel finding as the protein has been described previously as adipocyte-specific. Additionally we found histopathologic evidence of lipid accumulation in the livers of etomoxir rats. The data show that for each treated rat there was a good correlation between ADRP levels and degree of lipid droplet formation. This observation may suggest a potential relationship between drug-induced expression of ADRP in liver and lipid accumulation.