The mitochondrial NADH shuttle system is a targetable vulnerability for Group 3 medulloblastoma in a hypoxic microenvironment.

Medulloblastoma is a cancerous brain tumor that affects mostly children. Among the four groups defined by molecular characteristics, Group 3, the least well characterized, is also the least favorable, with a survival rate of 50%. Current treatments, based on surgery, radiotherapy, and chemotherapy, are not adequate and the lack of understanding of the different molecular features of Group 3 tumor cells makes the development of effective therapies challenging. In this study, the problem of medulloblastoma is approached from a metabolic standpoint in a low oxygen microenvironment. We establish that Group 3 cells use both the mitochondrial glycerol-3 phosphate (G3PS) and malate-aspartate shuttles (MAS) to produce NADH. Small molecules that target G3PS and MAS show a greater ability to decrease cell proliferation and induce apoptosis specifically of Group 3 cells. In addition, as Group 3 cells show improved respiration in hypoxia, the use of Phenformin, a mitochondrial complex 1 inhibitor, alone or in combination, induced significant cell death. Furthermore, inhibition of the cytosolic NAD+ recycling enzyme lactate dehydrogenase A (LDHA), enhanced the effects of the NADH shuttle inhibitors. In a 3D model using Group 3 human cerebellar organoids, tumor cells also underwent apoptosis upon treatment with NADH shuttle inhibitors. Our study demonstrates metabolic heterogeneity depending on oxygen concentrations and provides potential therapeutic solutions for patients in Group 3 whose tumors are the most aggressive.

HIF-1 inactivation empowers HIF-2 to drive hypoxia adaptation in aggressive forms of medulloblastoma.

Medulloblastoma (MB) is the most prevalent brain cancer in children. Four subgroups of MB have been identified; of these, Group 3 is the most metastatic. Its genetics and biology remain less clear than the other groups, and it has a poor prognosis and few effective treatments available. Tumor hypoxia and the resulting metabolism are known to be important in the growth and survival of tumors but, to date, have been only minimally explored in MB. Here we show that Group 3 MB tumors do not depend on the canonical transcription factor hypoxia-inducible factor-1α (HIF-1α) to mount an adaptive response to hypoxia. We discovered that HIF-1α is rendered inactive either through post-translational methylation, preventing its nuclear localization specifically in Group 3 MB, or by a low expression that prevents modulation of HIF-target genes. Strikingly, we found that HIF-2 takes over the role of HIF-1 in the nucleus and promotes the activation of hypoxia-dependent anabolic pathways. The exclusion of HIF-1 from the nucleus in Group 3 MB cells enhances the reliance on HIF-2's transcriptional role, making it a viable target for potential anticancer strategies. By combining pharmacological inhibition of HIF-2α with the use of metformin, a mitochondrial complex I inhibitor to block respiration, we effectively induced Group 3 MB cell death, surpassing the effectiveness observed in Non-Group 3 MB cells. Overall, the unique dependence of MB cells, but not normal cells, on HIF-2-mediated anabolic metabolism presents an appealing therapeutic opportunity for treating Group 3 MB patients with minimal toxicity.

Influence of gender on the pharmacokinetics, safety, and tolerability of cerivastatin in healthy adults.

The pharmacokinetics, safety, and tolerability of cerivastatin, a synthetic HMG-CoA reductase inhibitor were studied in 49 healthy volunteers. In this double-blind, parallel group, multiple-dose study, volunteers were randomized as age-matched, male-female pairs and stratified into younger (18-65 years, premenopausal females) or older (65-85 years, postmenopausal females) groups. Thirty-two (16 female, 16 male) subjects received 0.2 mg cerivastatin daily for 7 days; 17 received placebo. Between all males and females, no differences in cerivastatin pharmacokinetics were observed. The AUCnorm in older females was 21% higher than in older males, while the AUCnorm in younger females was 26% lower than in younger males. The Cmax in older females was 30% higher than in age-matched males or younger males and females. All other pharmacokinetic parameters, including half-life, tmax, accumulation ratios, and steady state plasma levels were similar in all treatment groups. The most common adverse events, including headache (4), dyspepsia (4), and rash (4), were equally distributed between groups. Treatment-emergent elevations (< 2 x ULN) in creatine kinase occurred in one subject. Transaminase elevations occurred in nine subjects, most were less than 3 x ULN, and were equally distributed between groups. In conclusion, cerivastatin was well tolerated. The minor differences in the pharmacokinetics of cerivastatin 0.2 mg between genders does not require modification of dosage.

The CHORUS (Cerivastatin in Heart Outcomes in Renal Disease: Understanding Survival) protocol: a double-blind, placebo-controlled trial in patients with esrd.

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin)-mediated lowering of serum cholesterol has been associated with a significant reduction in cardiovascular morbidity and mortality. Recent studies suggest that additional non-lipid lowering effects (eg, endothelial stabilization, anti-inflammatory, antithrombogenic) may be important in modulating their effectiveness. Dyslipidemia is common in end-stage renal disease (ESRD), and hemodialysis patients have increased cardiovascular morbidity and mortality. Cerivastatin, a new statin with powerful low-density lipoprotein-cholesterol (LDL-C) lowering capabilities, possesses some unique non-LDL-C-mediated properties that may contribute to a reduction of coronary events in the patient with ESRD. The primary objective of this multicenter multinational study of 1,054 hemodialysis patients is to compare 2 years of treatment with cerivastatin (0.4 mg/d) versus placebo on the composite clinical event rate of myocardial infarction, sudden cardiac death, ischemic stroke, and the need for coronary arterial bypass graft (CABG) or percutaneous transluminal coronary angioplasty (PTCA) procedures in these patients. Changes in lipids, inflammatory proteins including heat stable C-reactive protein (hsCRP), interleukin-6 (IL-6), oncostatin-M, intracellular adhesion molecule-1 (ICAM-1) and monocyte-chemoattractant protein-1 (MCP-1), as well as markers of cardiac muscle pathology, such as troponin I and troponin T, will be assessed in a subset of patients. This study is the first of its kind to assess the effect of a statin on the reduction of cardiovascular morbidity and mortality in an incident hemodialysis population. It will determine whether treatment with cerivastatin can effectively reduce the significant cardiovascular morbidity and mortality.

Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either cerivastatin or pravastatin.

BACKGROUND: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are metabolized by distinct pathways that may alter the extent of drug-drug interactions. Cerivastatin is metabolized by cytochrome P450 (CYP)3A4 and CYP2C8. Atorvastatin is metabolized solely by CYP3A4, and pravastatin metabolism is not well defined. Coadministration of higher doses of these statins with CYP3A4 inhibitors has the potential for eliciting adverse drug-drug interactions. OBJECTIVE: To determine the comparative effect of itraconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of cerivastatin, atorvastatin, and pravastatin. METHODS: In this single-site, randomized, three-way crossover, open-labeled study, healthy subjects (n = 18) received single doses of cerivastatin 0.8 mg, atorvastatin 20 mg, or pravastatin 40 mg without and with itraconazole 200 mg. Pharmacokinetic parameters [AUC(0-infinity), AUC(0-tn), peak concentration (Cmax), time to reach Cmax (tmax), and half-life (t1/2)] were determined for parent statins and major metabolites. RESULTS: Concomitant cerivastatin/itraconazole treatment produced small elevations in the cerivastatin AUC(0-infinity), Cmax, and t1/2 (27%, 25%, and 19%, respectively; P < .05 versus cerivastatin alone). Itraconazole coadministration produced similar changes in pravastatin pharmacokinetics [AUC elevated 51% (P < .05 versus pravastatin alone), 24% (Cmax), and 23% (t1/2), respectively]. However, itraconazole dramatically increased atorvastatin AUC (150%), Cmax (38%), and t1/2 (30%) (P < .05). The elevation in atorvastatin AUC was significantly greater than that of cerivastatin (P < .005) or pravastatin (P < .005). CONCLUSION: Itraconazole markedly elevated atorvastatin plasma levels (2.5-fold) after 20 mg dosing, suggesting that concomitant itraconazole/atorvastatin therapy be carefully considered. Itraconazole produced modest elevations in the plasma levels of cerivastatin 0.8 mg or pravastatin 40 mg (1.3-fold and 1.5-fold, respectively), indicating that combination treatment with itraconazole with cerivastatin or pravastatin may be preferable.

Influence of renal function on the pharmacokinetics of cerivastatin in normocholesterolemic adults.

OBJECTIVE: The influence of impaired renal function on the pharmacokinetics of single and multiple doses of cerivastatin was evaluated in this nonrandomized, non-blinded, 7-day, multiple-dose study. METHODS: Thirty-five adults between the ages of 21 years and 75 years with normal renal function (CL(CR) >90 ml/min/1.73 m2, n = 9), or patients with either mild (CL(CR) 61 ml/min/1.73 m2 to < or =90 ml/min/1.73 m2, n = 9), moderate (CL(CR) 30 ml/min/1.73 m2 to < or =60 ml/ min/1.73 m2, n = 8), or severe (CL(CR) <30 ml/min/ 1.73 m2, but not on dialysis, n = 9) renal impairment were given cerivastatin 0.3 mg daily each evening for 7 days. The steady-state pharmacokinetics of cerivastatin, including the area under the concentration-time curve (AUC)0-24, peak plasma concentration (Cmax), time to reach Cmax (tmax) and elimination half-life (t1/2), were determined on day 1 and day 7. The logarithm of the pharmacokinetic variables was analyzed using analysis of variance (ANOVA). Safety assessments included physical examination, fundoscopy, vital signs, electrocardiogram (ECG), adverse events, and laboratory safety indices. RESULTS: The day-1 AUC in patients with mild renal impairment was similar to that of patients with normal function (19.6 microg/h/l vs 19.2 microg/h/l, respectively). However, the AUC for cerivastatin patients with moderate or severe renal impairment was 40-60% higher (30.8 microg/h/l and 29.0 microg/h/l, respectively). Cmax values for patients with normal, mild, moderate, and severe renal impairment were 3.3, 3.4, 4.6, and 5.2 microg/l, respectively. This modest increase in plasma cerivastatin levels is nearly equivalent to a 0.4-mg daily dose, which has been recently approved in the United States. The mean t1/2 of cerivastatin was less than 4.5 h in all patients, indicating that renal dysfunction did not promote cerivastatin accumulation. This observation was confirmed by the finding that the cerivastatin plasma levels on day 1 and day 7 were similar in all patient groups. Furthermore, the mean AUC and Cmax values for both demethylated and hydroxylated cerivastatin were similar in the patients with the most severe renal dysfunction to the corresponding values in healthy subjects. Cerivastatin was well tolerated in all patients irrespective of renal function. Adverse events were observed in 37% of the subjects; nearly all were mild and generally of short duration, and most resolved without intervention. Incidence of adverse events was similar across all three renal groups and the control group. There were no clinically significant laboratory changes other than those consistent with renal disease. CONCLUSION: This study demonstrates that dosage adjustment of the daily 0.3-mg cerivastatin dose in patients with significant renal impairment is likely unnecessary.

Lack of mutual pharmacokinetic interaction between cerivastatin, a new HMG-CoA reductase inhibitor, and digoxin in healthy normocholesterolemic volunteers.

The potential mutual interaction between cerivastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, and digoxin was assessed in this nonmasked, nonrandomized, multiple-dose study. The effect of cerivastatin 0.2 mg on mean plasma digoxin levels and the effect of digoxin on the single-dose pharmacokinetics of cerivastatin were assessed in 20 healthy normocholesterolemic men between 18 and 45 years of age weighing 140 to 200 lbs (63.3 to 90.0 kg). Subjects were given a single dose of cerivastatin 0.2 mg. After a 2-day washout period, subjects were given a loading dose of digoxin 0.5 mg for 3 days followed by 0.25 mg daily for 5 additional days (period 1-digoxin alone). Concurrent dosing with cerivastatin 0.2 mg continued for 14 days (period 2-digoxin and cerivastatin), followed by an 8-day course of digoxin-only administration and an optional 6-day extension of digoxin-only treatment for a total of 14 days (period 3). Safety was assessed through physical examination, electrocardiography, laboratory tests, and ophthalmologic examination. Ratio analyses of mean digoxin plasma trough levels, 24-hour urinary digoxin levels, and digoxin clearance with and without concurrent cerivastatin dosing also were carried out. In addition, single-dose pharmacokinetic variables for cerivastatin, including area under the curve (AUC(0-24)), peak concentration (C(max)), time to peak concentration (T(max)), and elimination half-life (t1/2), were examined with and without concurrent digoxin dosing. Eleven of the 20 subjects completed the entire study. Seven subjects discontinued the study because of treatment-emergent adverse events or laboratory abnormalities that were mostly unrelated to cerivastatin, and 2 subjects were discontinued because of protocol violations. Treatment-emergent adverse events developed in 12 subjects receiving cerivastatin; 11 of these subjects were receiving digoxin concurrently. Six adverse events that led to discontinuation of treatment were unrelated to cerivastatin but were related to digoxin or to a preexisting condition. The most commonly reported event was headache, which occurred with equal frequency compared with placebo groups in large cerivastatin clinical trials. Other events were mild or moderate and resolved without intervention. Mild and transient elevations in hepatic transaminase and creatine kinase values (all <2 times the upper limit of normal) were observed in 7 subjects. After 14 days of concurrent dosing of cerivastatin and digoxin, steady-state digoxin plasma levels, urinary digoxin levels, and urinary digoxin clearance were unchanged compared with steady-state digoxin levels when digoxin was given alone. Compared with dosing with digoxin alone, the AUC(0-24), Cmax, and t1/2 for cerivastatin increased 3%, 20%, and 7%, respectively, while the T(max) was reduced by 18% during concurrent treatment with digoxin. These changes are minimal and would not be expected to be clinically relevant. These results demonstrate that when cerivastatin is administered concurrently with digoxin, neither digoxin nor cerivastatin plasma levels are altered. The combination therapy was generally well tolerated.

Biopharmaceutical profile of cerivastatin: a novel HMG-CoA reductase inhibitor.

The biopharmaceutical properties of cerivastatin were evaluated in a series of worldwide clinico-pharmacological studies. Young healthy males aged 18-45 years were randomized to receive 0.05-0.8 mg cerivastatin orally, given either as single or multiple once-daily doses under fed or fasting conditions in the morning, with evening meal or at bedtime. Following administration, cerivastatin was rapidly and almost completely absorbed into the gastrointestinal tract (> 98%), with maximum plasma concentrations (Cmax) reached at 2-3 h post dose. The plasma concentration/time profile of the tablet is similar to an aqueous oral solution (relative bioavailability is 100%). The dose-proportionality of cerivastatin (0.05-0.8 mg) in area under the curve and Cmax showed low intra- and interindividual variability. The effect of food (single-dose studies testing administration of cerivastatin with a high-fat meal and clinical investigations in patients) or time of administration (single- and multiple-dose once-daily/twice-daily studies) had no clinically relevant effects on the pharmacokinetics of cerivastatin. Marketed tablet strengths and drug formulations from different sources were found to be bioequivalent. Cerivastatin is a noncomplicated drug with respect to its biopharmaceutical profile and bioavailability.

Pharmacodynamics, safety, tolerability, and pharmacokinetics of the 0.8-mg dose of cerivastatin in patients with primary hypercholesterolemia.

Cerivastatin is a third generation hydroxy-methyl-glutaryl-Co-enzyme A (HMG-CoA) reductase inhibitor proven to lower low-density lipoprotein (LDL) cholesterol 28% to 31% in patients with primary hypercholesterolemia when given at 0.3 mg/day. This study evaluates the safety, tolerability, pharmacodynamics, and pharmacokinetics of cerivastatin 0.8 mg once daily for 4 weeks. In this randomized, double-blind, placebo-controlled parallel group trial conducted at 2 study centers, 41 patients (63% women) with primary hypercholesterolemia were placed on an American Heart Association Step 1 diet for 4 weeks. Single-blind placebo was administered for the final 2 weeks, before randomization. Patients received cerivastatin 0.8 mg (n = 28) or placebo (n = 13) once each evening for 28 days. Cerivastatin at 0.8 mg daily was well tolerated. No discontinuations occurred during the study. Adverse events were mild and transient. One cerivastatin-treated patient experienced asymptomatic creatinine kinase, 8x the upper limit of normal (ULN) elevation on the last day of the study, which resolved 6 days after the completion of the study. Cerivastatin 0.8 mg daily significantly reduced LDL cholesterol compared with placebo (-44.0 +/- 2.0% vs 2.2 +/- 2.8%, p <0.0001); total cholesterol (-30.8 +/- 1.4% vs 2.6 +/- 2.1%, p <0.0001), triglycerides (-11.2 +/- 5.9% vs 15.9 +/- 8.6%, p <0.02), but did not significantly alter high-density lipoprotein (HDL) cholesterol (3.2 +/- 2.1% vs -1.2 +/- 3.1%, p = NS). The pharmacokinetics of the 0.8-mg dose revealed dose proportional elevations in the 24-hour area under the curve and maximum plasma concentration relative to 0.3- and 0.4-mg doses with no change in time to maximum concentration or the elimination half-life in plasma. The increased efficacy and lack of clinically significant laboratory abnormalities or adverse events demonstrates a need for a large long-term study to confirm the safety and efficacy of this dose of cerivastatin.

Influence of age on the safety, tolerability, and pharmacokinetics of the novel HMG-CoA reductase inhibitor cerivastatin in healthy male volunteers.

The safety, tolerability, and pharmacokinetics of cerivastatin, a novel, synthetic, potent, and highly selective HMG-CoA reductase inhibitor, were studied in 48 young and elderly male volunteers in a randomized, double-blind, placebo-controlled study. Eight men ranging from 18 to 38 years of age (young) and 15 men ranging from 65 to 78 years of age (elderly) received 0.1-mg cerivastatin tablets daily for 7 days. The remaining subjects (8 young and 17 elderly) received matching placebo tablets. Cerivastatin was well tolerated in elderly and young subjects. Adverse events were mild and occurred less frequently in the participants receiving cerivastatin than in those receiving placebo. In those participants given cerivastatin, the incidence of adverse events was similar for both age groups (4 of 8 young subjects and 8 of 15 elderly subjects). Transient and mild elevations in creatine kinase and transaminase levels were evenly distributed across the cerivastatin and placebo groups. Pharmacokinetic parameters, including area under the concentration curve (AUC), peak plasma concentration (Cmax), time to Cmax (tmax), and elimination half-life (t1/2), were similar between the two age groups. The mean elimination t1/2 for both groups was approximately 4 hours. These results indicate that cerivastatin is well tolerated in elderly male volunteers at a dosage of 0.1 mg/day. Further, the pharmacokinetics of cerivastatin are not altered as a consequence of age. Dose adjustment is therefore not required in elderly men.

Thrombolytic therapy with urokinase reduces increased circulating endothelial adhesion molecules in acute myocardial infarction.

The aim was to investigate circulating E-selectin and Intercellular Adhesion Molecule-1 (ICAM-1) in acute myocardial infarction. Our study was carried out in 80 patients, 40 hospitalized for acute myocardial infarction (AMI), 20 suffering from chronic stable angina and 20 healthy control subjects. Samples of venous blood were taken from all patients at the moment of hospitalization and after 2, 4, 6, 8, 10, 12 and 24 hours from the thrombolytic treatment (AMI + urokinase) or conventional therapy (AMI + nitroglycerin), for the dosage of creatinine kinase (CK) and adhesion molecules. The CK was determined by means of a Hitachi 901 automatic analyser using an enzymatic method (reagents Boheringer-Biochemia, Germany). Soluble E-selectin (sE-selectin) and soluble ICAM-1 (sICAM-1) were measured in the serum using a specific immunoassay (British Biotechnology Products). The serum levels of Tumor Necrosis Factor (TNF-alpha) were evaluated using an immunoenzymatic assay to quantitate the serum levels of the cytokine (British Biotechnology Products). Patients with acute myocardial infarction (AMI) had increased serum levels of soluble E-selectin (sE-selectin; AMI + urokinase = 312 +/- 20 ng/ml; AMI + nitroglycerin = 334 +/- 15 ng/ml) and soluble ICAM-1 (sICAM-1; AMI + urokinase = 629 +/- 30 ng/ml; AMI + nitroglycerin = 655 +/- 25 ng/ml) compared to both patients with chronic angina (sE-selectin = 67 +/- 10 ng/ml; sICAM-1 = 230 +/- 20 ng/ml) and healthy control subjects (sE-selectin = 53 +/- 15 ng/ml; sICAM-1 200 +/- 16 ng/ml). Furthermore patients with acute myocardial infarction also had increased serum levels of Tumor Necrosis Factor (TNF-alpha = 309 +/- 10 pg/ml; control subjects = 13 +/- 5 pg/ml). Thrombolytic therapy with urokinase (1,000,000 IU as an intravenous bolus for 5 minutes, followed by an infusion of an additional 1,000,000 IU for the following two hours) succeeded in producing reperfusion and reduced the serum levels of sE-selectin (52 +/- 13 ng/ml) and sICAM-1 (202 +/- 31 ng/ml). In contrast patients not eligible for thrombolytic therapy and therefore treated with conventional therapy (a continuous i.v. infusion of nitroglycerin at the dose of 50 mg/die) did not show any significant reduction in both sE-selectin and sICAM-1 throughout the study. Our results confirm previous experimental data and indicate that adhesion mechanisms supporting leukocyte-endothelium interaction may also be operative in human acute myocardial infarction.

Early reactivation of ischaemia after abrupt discontinuation of heparin in acute myocardial infarction.

Intravenous heparin after thrombolytic therapy for acute myocardial infarction is an effective, widely used treatment. Six cases of acute myocardial infarction are reported with early disease reactivation following the abrupt discontinuation of heparin infusion three days after alteplase thrombolysis and concomitant aspirin therapy. Immediate reinfusion of heparin resulted in regression of symptomatic ischaemia in all six patients. The activated partial thromboplastin time values, determined four hours before the discontinuation of heparin therapy, were within the therapeutic range in five of the six patients, and no difference was found in the values obtained one hour after the reinfusion of heparin (P = 0.065).

Myocardial bridging involving more than one site of the left anterior descending coronary artery: an uncommon cause of acute ischemic syndrome.

An infrequent angiographic finding is reported of myocardial bridging involving more than one site of the left anterior descending coronary artery in a symptomatic patient with ischemia exacerbated by nitroglycerin administration. Beta-blocker therapy alone was followed by a favorable long-term outcome.

Comparative effects of nitrendipine and hydrochlorothiazide on calciotropic hormones and bone density in hypertensive patients.

The effects of the calcium antagonist nitrendipine and the diuretic hydrochlorothiazide on plasma calciotropic hormone concentrations and lumbar bone density were compared during the treatment of hypertension in a randomized, double-blind, 8 week parallel study, followed by a 52 week open label study. There were 32 subjects with stable essential hypertension (sitting diastolic blood pressure > or = 95 mm Hg and < or = 115 mm Hg without medication) without evidence of renal insufficiency or active heart disease. They were randomly assigned to receive either 10 mg nitrendipine twice daily or 50 mg hydrochlorothiazide daily. In order to reach and maintain target blood pressure (diastolic blood pressure < or = 95 mm Hg) during the open label period, the nitrendipine dose was titrated up to 30 mg twice daily, and additional antihypertensive drugs, of differing classes, were added as necessary. Blood samples were analyzed for concentrations of calcium, parathyroid hormone, and calcitonin, and lumbar bone density was determined by dual photon absorptiometry, at the baseline and at 24 and 52 weeks of antihypertensive drug therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Multiple dose pharmacokinetics of four different doses of nisoldipine in hypertensive patients.

This randomized double-blind parallel group study characterized the pharmacokinetics of the calcium channel antagonist, nisoldipine (core-coat tablets), administered once daily for 7 days in doses of 5 mg (n = 12), 10 mg (n = 13), 20 mg (n = 12), and 30 mg (n = 11) to patients with mild to moderate hypertension. Serial blood samples were obtained from 0 to 24 hours and from 0 to 48 hours after nisoldipine administration on days 1 and 7, respectively. Nisoldipine plasma concentrations were determined by gas chromatography with electron capture detection. No statistically significant difference was found in dose-normalized area under the curve between the four groups. Area under the curve (standardized to body weight) correlated to dose (r = .74, P less than .05). No significant difference existed in oral clearance (L/h/kg) when analyzed for equivalence across the four doses: 8.21 +/- 3.47 (5 mg), 11.84 +/- 13.85 (10 mg), 11.48 +/- 7.49 (20 mg), and 10.36 +/- 5.49 (30 mg). The present investigation characterizes the pharmacokinetics of nisoldipine core-coat tablets in hypertensive patients and demonstrates the dose proportionality or linearity of nisoldipine plasma concentrations and area under the curve, measured over a dose range of 5 to 30 mg.

[Aortic stenosis and coronary pathology. Their implications for the transvalvular gradient]. / Stenosi aortica e coronaropatia. Implicazioni sul gradiente transvalvolare.

To assess the incidence of coronary artery disease in patients with valvular aortic stenosis and its implication on peak systolic valvular gradient, 31 consecutive patients who underwent cardiac catheterization were examined. Associated significant coronary artery disease (> 50% reduction in luminal diameter evaluated in proximal segments and right dominant circulation) was present in 54.8% of patients. There was no difference in the distribution of risk factors among patients with and without significant luminal narrowings. The prevalence of coronary artery disease was found not to be significantly correlated with age (p = 0.276). There was no relationship between typical angina pectoris and the presence of coronary artery disease (p = 0.063). Fourty-seven percent of cases resulted free of chest pain. Ejection fraction was found to be significantly lower in patients with coronary artery disease (45 +/- 14.2%) than in patients without coronary artery disease (65.1 +/- 3.9%; p = 0.03) and a reverse relationship was observed between the presence of coronary artery disease and peak systolic valvular gradient (p = 0.006) which, in turn, correlated significantly with ejection fraction (r = 0.68; p = 0.023). These data demonstrate that the value of peak systolic valvular gradient, as the only index for the evaluation of the severity of aortic stenosis, is greatly limited in patients with associated coronary artery disease. Moreover, confirming the guidelines of the American College of Cardiology and of the American Heart Association task force, these data also stress the necessity of performing coronary angiography regardless angina pectoris is present or not.

[Unusual anatomic coronary variants: parallel left anterior descending artery. Description of 3 cases]. / Insolita variante anatomica coronarica: ramo discendente anteriore parallelo. Descrizione di 3 casi.

Three cases with a variation of the classic anatomic left anterior descending artery pattern, encountered unexpectedly during coronary arteriography, are reported. The importance of this unusual and rare coronary artery pattern is only anatomic, and the possibility to carry out these findings by the coronary arteriography, can increase their occurrence instead of an incidental finding.