Nicardipine and hydrochlorothiazide in essential hypertension

Nicardipine is an investigational dihydropyridine calcium channel blocking agent. One hundred fifty-one patients with hypertension received either 30 mg nicardipine t.i.d. or 25 mg hydrochlorothiazide b.i.d. in a double-blind, randomized, multicenter trial. After 4 weeks of therapy and at the end of the dosing interval, nicardipine reduced arterial pressure by 10/6 mm Hg and 12/6 mm Hg in the supine and standing positions, respectively (all p less than 0.01). In the hydrochlorothiazide group, the reductions were 12/6 mm Hg and 14/6 mm Hg, respectively (all p less than 0.01). The maximum reduction in blood pressure of 16/14 mm Hg supine and 20/15 mm Hg standing occurred within 1 hour after administration of nicardipine. The mean reduction in the hydrochlorothiazide group after 1 hour was 14/11 mm Hg supine and 16/12 mm Hg standing. Neither drug affected autonomic reflexes associated with maximum exercise. Nicardipine increased urinary sodium excretion during the 4-hour period after the first dose. Adverse effects of nicardipine were primarily extensions of its vasodilator effect and included flushing, headache, and edema.     

Comparison of ciprofloxacin and rifampicin in experimental Legionella pneumophila pneumonia

We evaluated intraperitoneal ciprofloxacin and rifampicin alone and as combination therapy in experimentally induced Legionella pneumophila pneumonia in guinea pigs. Intraperitoneal treatment began 48 h after intratracheal inoculation of 3 X 10(6) L. pneumophila and consisted of sterile saline (0.3 ml bid), ciprofloxacin (30 mg/kg bid), rifampicin (10 mg/kg/bid), or ciprofloxacin plus rifampicin (same doses). Animals were treated for five days and survivors killed after 11 days. Quantitative lung cultures were done post mortem. Respective mean and median days of animal survival were increased by treatment with ciprofloxacin plus rifampicin (8.4 and 9.5 days), ciprofloxacin (8.2 and 7.5 days), or rifampicin (8.3 and 7.5 days), compared with controls (5.5 and 5.0 days). Compared with control animals (log rank test) survival was improved by treatment with ciprofloxacin plus rifampicin (P less than or equal to 0.047) ciprofloxacin (P less than or equal to 0.047) or rifampicin (P less than or equal to 0.047). Quantitative lung cultures (cfu/g) were also decreased by treatment with ciprofloxacin plus rifampicin (2.0 X 10(4)), ciprofloxacin (5.4 X 10(4)), or rifampicin (1.7 X 10(4)) compared with controls (3.2 X 10(8)). No differences in survival, quantitative lung cultures, or animal weights were noted between treatment groups. This study demonstrates that ciprofloxacin is as effective as rifampicin in the treatment of experimentally induced L. pneumophila pneumonia and that the combination of ciprofloxacin plus rifampicin has no advantages over single agent therapy in this model.     

Tolerability and Pharmacokinetic Properties of Ciprofloxacin Dry Powder for Inhalation in Patients With Cystic Fibrosis: A Phase I,Randomized, Dose-Escalation Study

Background

Inhaled antibacterial agents are used to manage chronic pulmonary infections in cystic fibrosis (CF) and non-CF bronchiectasis. However, established nebulized preparations impose a substantial time burden on patients. A dry powder formulation of ciprofloxacin for inhalation (ciprofloxacin DPI) has been developed using PulmoSphere™ (Novartis, Pharma AG, Basel, Switzerland) technology (administered using a T-326 inhaler) to maximize antibacterial activity and convenience.

Objective

This study investigated the tolerability and pharmacokinetic properties of multiple-dose once-daily and twice-daily ciprofloxacin DPI in adults with CF.

Methods

A Phase I, randomized, single-blind, placebo-controlled, dose-escalation study in patients with CF (median age 29.0 years [19–40]), stable pulmonary status, and chronic Pseudomonas aeruginosa colonization. Sequential cohorts received ciprofloxacin DPI 32.5 mg qd (1 capsule for inhalation; n = 6), 65 mg qd (2 capsules for inhalation; n = 6), or 32.5 mg (n = 6) bid for 7 days. Each group was placebo controlled.

Results

Twenty-five patients were enrolled (12 men; median age, 29.0 years [range, 19–40 years]; 6, 6, 6, and 7 patients in the ciprofloxacin DPI 32.5 mg qd, 65 mg qd, and 32.5 mg bid and placebo groups, respectively). No serious treatment-emergent adverse events or clinically relevant changes in tolerability parameters, including lung function measurements, were reported. Twenty-one patients (ciprofloxacin, n = 17; placebo, n = 4) experienced 29 mild drug-related treatment-emergent adverse events, including bitter taste (ciprofloxacin, 17 patients; placebo, 2) and bronchospasm (ciprofloxacin, 3; placebo, 2). Ciprofloxacin DPI was absorbed rapidly after inhalation. Systemic exposure to ciprofloxacin was low and comparable between single and multiple dosing in all 3 dose groups, suggesting an absence of substantial drug accumulation. The geometric mean AUCs after the last dose were 0.383, 1.472, and 0.781 mg · h/L with ciprofloxacin DPI 32.5 mg qd, 65 mg qd, and 32.5 mg bid, respectively. The range of geometric mean t_½ in plasma was 3.4 to 9.5 hours. Sputum concentrations of ciprofloxacin were high, with substantial variability. Geometric mean ciprofloxacin concentrations (%CV) in induced sputum were 57.7 (118.2), 177.5 (53.4), and 149.7 (249.7) mg/L 0.75 hours after the last dose of ciprofloxacin DPI 32.5 mg qd, 65 mg qd, and 32.5 mg bid, respectively.

Conclusions

Ciprofloxacin DPI was well tolerated, especially with respect to lung function, with minimal systemic exposure compared with data from previous studies of oral and intravenous administration, and with no apparent accumulation at steady state. Sputum ciprofloxacin concentrations above 100-times the minimum inhibitory concentration for P aeruginosa were detected. Ciprofloxacin DPI may be effectively delivered to the lungs at microbiologically active concentrations while minimizing the risk for systemic intolerabilities. Eudra clinical trial identifier: 2006-003690-26.     

Effect of X‐ray irradiation on pharmacokinetics of irinotecan hydrochloride and expression of CES1 and CYP3A1 in rats

Concurrent chemoradiation with irinotecan hydrochloride (CPT‐11) is accepted for cancer treatment. However, the effects of X‐ray irradiation on chemotherapeutics in the plasma remain unclear. We evaluated the pharmacokinetics of CPT‐11 in rats after exposure to X‐ray irradiation and examined the changes of protein and mRNA expression of CES1 and CYP3A1. The X‐ray irradiation with 1 Gy and 5 Gy was delivered to the whole body of rats. CPT‐11 at 30 and 60 mg/kg, respectively, was intravenously infused 24 h after irradiation. CPT‐11 was determined by RP‐HPLC in plasma. ELISA and PCR were used to analyze the protein and mRNA expression of CES1 and CYP3A1, respectively. Compared with control rats, the X‐ray irradiation decreased the AUC of CPT‐11 (30 mg/kg) by 15.6% at 1 Gy and 39.0% at 5 Gy and increased the CL by 60.0% at 5 Gy. The X‐ray irradiation could also decrease the AUC of CPT‐11 (60 mg/kg) and increase the CL. In addition, the protein and mRNA expression of CES1 and CYP3A1 were increased significantly in rats after irradiation. This study found significant changes in the pharmacokinetics of CPT‐11 in rats after exposure to X‐ray irradiation, and they might be due to significant increases in the expressions of CYP3A1 and CES1. The pharmacokinetics of CPT‐11 should be rechecked, and the optimal CPT‐11 dose should be reevaluated during concurrent chemoradiation therapy.     

The comparative efficacy of nicardipine and nifedipine in stenocardia patients

Altogether 12 patients with stable angina pectoris of effort were examined for the efficacy of nicardipine as compared to nifedipine and placebo by means of pharmacodynamic studies using treadmill. Nicardipine exerted a significant antianginal and anti-ischemic action 1, 2 and 3 hours after the intake of single dose (40 or 60 mg). The efficacy of nifedipine in a single dose of 20 or 30 mg was more remarkable in spite of the fact that differences in the drug efficacy were not statistically significant. The side effects such as headache, heat sensation and face hyperemia were more frequently recorded after the intake of nicardipine than after the intake of nifedipine. Therefore nicardipine, a new calcium antagonist of the dihydropyridine series, can be applied to the treatment of patients with stable angina pectoris of effort. However, as compared to nifedipine, it has no advantages over it.     

Calcium channel blocker drugs and diabetic control

Calcium channel blockers are now widely used and there have been case reports of hyperglycemia with nifedipine. In a double-blind, randomized, crossover study of the effects of 4 weeks of therapy, each with two dihydropyridine calcium channel blocker drugs, nifedipine and nicardipine, glucose tolerance, plasma insulin levels, and hemoglobin A1 were assessed in 20 patients with non-insulin-dependent diabetes (mean age 59 years). There was no significant difference in glucose tolerance on active therapy (AUC: control, 548.3 +/- 24.8; nifedipine, 559.3 +/- 41.0; and nicardipine, 589.3 +/- 40.3). Similarly, despite producing significant hemodynamic effects, these drugs produced no significant effect on plasma insulin and hemoglobin A1 levels. Calcium channel blocker drugs may be useful alternatives to thiazide diuretics and beta-blockers in the treatment of ischemic heart disease and hypertension, especially in patients with diabetes.     

A case of isoniazid-induced liver injury diagnosed by use of the DLST,and successful reintroduction of isoniazid for pleural tuberculosis

A 54-year-old woman was admitted for pleural tuberculosis diagnosed by right chest pain and cough. She received combination antituberculosis therapy consisting of isoniazid, rifampicin, ethambutol, and pyrazinamide. However, liver damage was observed 15 days after initiation of therapy (aspartate aminotransferase (AST) 248 IU/l, alanine transaminase (ALT), 132 IU/l). The patient was given glycyrrhizinate intravenously, but liver damage gradually increased (AST 628 IU/l, ALT 467 IU/l) and all tuberculosis drugs were ceased. We diagnosed drug-induced liver damage due to isoniazid according to results of the drug lymphocyte stimulation test. We successfully reintroduced rifampicin and streptomycin, and carried out desensitization therapy for isoniazid without liver injury recurrence. Reintroduction of a drug suspected to cause drug-induced liver injury is generally not recommended; however, our experience suggests that isoniazid, a first-line antituberculosis drug, may be reintroduced after desensitization.     

E‐selectin gene in essential hypertension: a case‐control study

Background

Hypertension is associated with endothelial cell dysfunction. E‐selectin, an endothelial cell adhesion molecule, is specific for endothelial cell activation. Polymorphism in E‐selectin gene has recently been identified among which Leu554Phe E‐selectin gene polymorphism is least investigated in essential hypertension. This study reports the association of E‐selectin gene Leu554Phe polymorphism and the expression of E‐selectin gene in patients with essential hypertension.

Materials and methods

We analysed the Leu554Phe polymorphism and expression of E‐selectin gene in 250 patients with essential hypertension and 250 normal healthy controls. Genotyping of Leu554Phe polymorphism was performed by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP), and the expression of E‐selectin gene at mRNA and protein levels were carried out by real‐time PCR and Western blot, respectively.

Results

A significant association of E‐selectin genotypes (CT + TT) with essential hypertension (P < .0001, Odds ratio = 2.2 [1.58‐3.24] at 95% CI) was observed. The expression of mRNA for E‐selectin gene in patients with essential hypertension was ~12‐fold higher as compared to control. We observed an elevated level of E‐selectin protein expression (up to 1.9 times) in patients as compared to controls.

Conclusions

A significant association of E‐selectin (Leu554Phe) gene and increased expression of E‐selectin gene at mRNA and protein levels in patients might be related to the genetic predisposition to develop essential hypertension.     

Initial experience with isradipine for the treatment of hypertension in children

BACKGROUND: Isradipine is a calcium channel blocker of the dihydropyridine class. It has limited effects on myocardial contractility; is available in a powder-filled capsule and has a half-life of 6 to 8 hours. METHODS: Pharmacy records were reviewed to identify pediatric patients who had received isradipine. The following demographic data were obtained: age, weight, sex, underlying medical problems, and initial blood pressure values. Information concerning isradipine included the initial dose and its interval, subsequent dose escalations, blood pressure response to the medication, and duration of therapy. RESULTS: The study population comprised 12 patients, ranging in age from 10 days to 11 years. The etiology of the hypertension was renal in 9 cases and nonrenal in 3. Initial dosing with isradipine was 0.1 mg/kg/dose. Six patients had emergent hypertension, and their blood pressure had been controlled with intravenous nicardipine before oral isradipine. Six patients received initial therapy with oral isradipine. Isradipine was monotherapy in 7 patients and in combination with other agents in 5 patients. The dose of isradipine required for blood pressure control was 0.6 +/- 0.3 mg/kg/day (range, 0.3 to 1.2 mg/kg/day). Isradipine failed to provide effective blood pressure control in 2 patients. In 1 of these patients, isradipine was effective after peritoneal dialysis. CONCLUSIONS: Isradipine is an effective, orally administered agent for control of hypertension in children.     

Massive overdose with controlled‐release carbamazepine resulting in delayed peak serum concentrations and life‐threatening toxicity

Introduction: Peak serum levels following overdose with immediate‐release formulations of carbamazepine have been reported to occur up to 2 days postingestion. We report a case of poisoning with carbamazepine controlled‐release resulting in peak levels 96 h postingestion. Case Reports: A 31‐year‐old female presented following a suspected polypharmacy overdose. She was haemodynamically stable with a Glasgow Coma Scale score of 3 and was endotracheally intubated in the emergency department. A single‐dose of activated charcoal was administered on admission and her neurological status improved gradually. Results of qualitative urine drug screen available 24 h postadmission to the intensive care department revealed benzodiazepines and carbamazepine. The serum carbamazepine concentration at this time was 66 µmol/L (therapeutic 17–42 µmol/L). A history of therapy with controlled‐release carbamazepine was discovered. Repeat‐dose activated charcoal and whole‐bowel irrigation were commenced, but poorly tolerated. Serum carbamazepine levels continued to rise and gastrointestinal tract decontamination was ceased due to the presence of an ileus. By day 4, the serum carbamazepine concentration peaked at 196 µmol/L. This was associated with coma, generalized intermittent seizure activity and hypotension. Charcoal haemoperfusion was commenced due the presence of end‐organ toxicity and failed gastrointestinal tract decontamination. Serum carbamazepine concentrations fell from 176 to 106 µmol/L after 1 h of haemoperfusion and the patient was rousable to voice and could obey commands at this time. She confirmed ingestion of 300 Tegretol‐CR® (200 mg) on extubation and was discharged without long‐term sequelae. Conclusion: Unrecognized poisoning with controlled‐release carbamazepine has the potential to produce significant delayed carbamazepine toxicity and delayed peak serum carbamazepine concentrations. This may occur much later than previously reported with immediate‐release carbamazepine preparations.     

Effect of calcium channel antagonists nifedipine and nicardipine on rat cytochrome P-450 2B and 3A forms.

Calcium channel antagonists are widely prescribed for treatment of hypertension. In this study, we examined whether treatment with the calcium channel antagonists, nicardipine, nifedipine or diltiazem, alters cytochrome P-450 2B or 3A (CYP2B or CYP3A, respectively) expression in rat liver. Western blot analyses were undertaken using antibodies specific for one or several members of these cytochrome P-450 subfamilies. Nicardipine was found to be an effective inducer of CYP3A; in particular, CYP3A23 was increased approximately 36-fold following treatment with 100 mg of nicardipine/kg/day. Nicardipine induced CYP2B forms up to approximately 3.1-fold. Nifedipine did not alter CYP3A expression but did increase CYP2B expression such that total CYP2B, CYP2B1, and CYP2B2v (a splice variant of CYP2B2) were increased approximately 5- to 15-fold after treatment with 100 mg of nifedipine/kg/day, with increases in benzyloxyresorufin O-dealkylase and erythromycin N-demethylase activities, respectively. The distinct differences in cytochrome P-450 induction profile induced by nicardipine and nifedipine suggest that they may enhance cytochrome P-450 expression by different mechanisms unrelated to their effects on calcium channels.     

5‐HT3 receptors antagonists reduce serotonin‐induced scratching in mice

Serotonin (5‐hydroxytryptamine, 5‐HT) acts as a pruritogen in humans and animals, but the mechanisms of action through that serotonin induces itch response have not been extensively discovered. In our study, we attempted to investigate the role of 5‐HT3 receptors in scratching behavior due to intradermal serotonin injection. Intradermal injection of serotonin (14.1–235 nmol/site) into the nape of the neck of mice was performed to elicit itch. Scratching behavior was evaluated by measuring the number of bouts during 60 min after injection. We evaluated the effect of intraperitoneal pretreatment with ondansetron and tropisetron (0.1, 0.3, and 1 mg/kg) on itch induced by serotonin. Also, intradermal ondansetron and tropisetron at doses 50, 100, and 200 nmol/site were concurrently administrated with serotonin. Serotonin produced a significant enhancement in scratching at dose 141 nmol/site. Concurrent administration of ondansetron (50, 100, and 200 nmol/site) and tropisetron (100 and 200 nmol/site) with serotonin reduced scratching activity compared to the animals that only received serotonin. Also, pretreatment with intraperitoneal ondansetron and tropisetron (0.3 and 1 mg/kg) 30 min before serotonin attenuated the itch response. We showed that the scratching induced by intradermal serotonin is mediated by 5‐HT3 receptors subtype. It can be concluded that 5‐HT3 may play a role in mediating serotonin‐associated itch responses, and we introduce 5‐HT3 receptors as possible targets for antipruritic agents.     

Systematic review with network meta-analysis on the treatments for latent tuberculosis infection in children and adolescents

BackgroundWe aimed to synthesize the evidence on the efficacy and safety of different treatment regimens for latent tuberculosis infection (LTBI) in children and adolescents.MethodsA systematic review with network meta-analysis was performed (CRD142933). Searches were conducted in Pubmed and Scopus (Nov-2021). Randomized controlled trials comparing treatments for LTBI (patients up to 15 years), and reporting data on the incidence of the disease, death or adverse events were included. Networks using the Bayesian framework were built for each outcome of interest. Results were reported as odds ratio (OR) with 95% credibility intervals (CrI). Rank probabilities were calculated via the surface under the cumulative ranking analysis (SUCRA) (Addis-v.1.16.8). GRADE approach was used to rate evidence's certainty.ResultsSeven trials (n = 8696 patients) were included. Placebo was significantly associated with a higher incidence of tuberculosis compared to all active therapies. Combinations of isoniazid (15–25 mg/kg/week) plus rifapentine (300–900 mg/week), followed by isoniazid plus rifampicin (10 mg/kg/day) were ranked as best approaches with lower probabilities of disease incidence (10% and 19.5%, respectively in SUCRA) and death (20%). Higher doses of isoniazid monotherapy were significantly associated to more deaths (OR 18.28, 95% ICr [1.02, 48.60] of 4–6 mg/kg/day vs. 10 mg/kg/3x per week).ConclusionsCombined therapies of isoniazid plus rifapentine or rifampicin for short-term periods should be used as the first-line approach for treating LTBI in children and adolescents. The use of long-term isoniazid as monotherapy and at higher doses should be avoided for this population.     

Antihypertensive effects of parenteral nicardipine alone and in combination with captopril

We studied the safety and efficacy of intravenous nicardipine alone and in combination with oral captopril. Sixteen patients with essential hypertension received a single oral dose of captopril, 50 mg, to be certain that excessive hypotension would not occur. Nicardipine was given intravenously as a 2 mg bolus, followed by an infusion at a rate designed to lower the supine diastolic blood pressure at least 10 mm Hg; then oral captopril, 50 mg, or placebo was given. The next week, nicardipine was again infused, but the alternate oral treatment was given. Intravenous nicardipine reduced blood pressure from 156 +/- 15/101 +/- 5 mm Hg (mean arterial blood pressure 120 +/- 6 mm Hg) to 140 +/- 11/88 +/- 4 mm Hg (mean arterial blood pressure 105 +/- 5 mm Hg). When captopril was added to nicardipine, the mean arterial blood pressure fell an additional 8 mm Hg but the heart rate did not increase. The combination of angiotensin-converting enzyme inhibition and calcium channel blockage produces additive antihypertensive effects without additional reflex tachycardia.     

Resistance to low‐dose aspirin therapy among patients with acute coronary syndrome in relation to associated risk factors

Background:  A substantial proportion of patients have recurrence of vascular events despite daily intake of low‐dose aspirin therapy. Therefore, different patients may require different aspirin dosages to achieve complete inhibition of platelet function. Objective:  The aim of this work was to measure the response to low‐dose aspirin therapy (150 mg/day) among patients with unstable angina or non‐ST‐segment elevation myocardial infarction and to find out whether titrating aspirin dosage to 300 mg/day, would provide a better therapeutic response in the resistant cases. Moreover, we also aimed to study any association between aspirin non‐responsiveness and atherothrombotic risk factors. Methods:  The antiplatelet effect of 150 mg/day aspirin was studied prospectively in 50 consecutive patients with unstable angina or non‐ST‐segment elevation myocardial infarction. Platelet aggregation was measured using optical platelet aggregometry and serum thromboxane B₂ level. Aspirin resistance was defined as collagen (1 μg/mL) and adenosine diphosphate (ADP) (5 μmol/L)‐induced platelet aggregation of ≥40% when compared with control values. Twenty healthy age‐ and sex‐matched individuals were taken as a control group. All patients were subjected to complete medical history (risk factors, medications), thorough clinical examination, ECG, coronary angiography and laboratory investigations including: complete haemogram, coagulation, kidney, liver and lipid profiles, fasting blood glucose and glycated haemoglobin (HbA_1C). Results:  Eleven of 50 patients (22%) were found to be aspirin resistant. A highly significant difference was found between the mean values of ADP, collagen‐induced platelet aggregation percentage and thromboxane B₂ level after aspirin 150 mg/day when compared with the corresponding mean values after aspirin 300 mg/day among the resistant patients (66 ± 7·01%, 62 ± 4·34% and 620 ± 64·58 pg/mL, respectively, vs. 26·87 ± 2·85%, 16·5 ± 3·8% and 77 ± 11·3 pg/mL) indicating enhanced response to aspirin after escalating the dose. The presence of atherothrombotic risk factors (hypertension, smoking, family history of ischaemic heart disease and previous MI) were not statistically different between aspirin‐resistant and aspirin‐sensitive patients. However, there was a highly significant difference between the aspirin sensitive and the resistant patients regarding the other risk factors (diabetes mellitus and dyslipidaemia) (P < 0·01). Conclusion:  There is inter‐individual variability in response to the antiplatelet effect of standard doses of aspirin (150, 300 mg/day). The response to aspirin 300 mg/day is enhanced in resistant patients when compared to 150 mg/day. There was a significant association between aspirin resistance and atherothrombotic risk factors (diabetes, hyperlipidaemia and obesity).     

Low serum fetuin‐A concentration predicts poor outcome only in the presence of inflammation in prevalent haemodialysis patients

Background Fetuin‐A, a negative acute phase protein that inhibits vascular calcification, has a controversial association with mortality in chronic kidney disease (CKD) patients. Chronic inflammation, which is common in CKD, may promote vascular calcification. Materials and methods We investigated the impact of inflammation on the relationship between serum fetuin‐A and mortality (42 months) in 222 prevalent haemodialysis (HD) patients. Results Serum fetuin correlated negatively with comorbidity score (assessed by Davies score) and circulating inflammatory markers. Patients with low fetuin‐A levels (< median) had higher mortality (Hazard ratio ‘HR’ 2·2; CI 1·4–3·5, P < 0·001), but this association was lost after adjustment for age, gender, comorbidities score, dialysis vintage and inflammation (CRP > median). In inflamed patients with low fetuin a significantly independent association with mortality (HR 2·3; CI 1·2–4·5, P = 0·01) was observed compared to non‐inflamed patients with high fetuin‐A, after adjusting for the same variables. Non‐inflamed patients with low fetuin‐A and inflamed patients with high fetuin‐A did not have increased mortality compared to non‐inflamed patients with high fetuin‐A. Conclusions The results show that low levels of serum fetuin‐A are associated with increased mortality in HD patients only in the presence of inflammation. This suggests that coexistence of a low serum fetuin‐A level and low‐grade inflammation exerts an additive effect on the risk of death in HD patients.     

Intravenous nicardipine: cardiovascular effects and clinical relevance

Nicardipine hydrochloride is the first intravenous dihydropyridine calcium antagonist to become available in the United States. Its chemical structure makes it unique among its drug class and confers clinically useful properties for the treatment of acute cardiovascular conditions, such as ischemia, hypertension, congestive heart failure, cerebrovascular disease, and related disorders. For patients with coronary artery disease, IV nicardipine reduces myocardial oxygen demand by reducing afterload and increases myocardial oxygen supply through coronary vasodilatation. Preliminary data suggest that nicardipine also has cardioprotective and vascular antispastic effects. Nicardipine has been shown to be effective in the treatment of mild to moderate hypertension both as monotherapy and in combination with other antihypertensive agents. In congestive heart failure, nicardipine enhances left ventricular pumping activity and augments coronary blood flow beyond that required by increased myocardial oxygen consumption. Its lack of major effects on sinoatrial and atrioventricular conduction makes it safe for use in patients with certain types of conduction disturbances. Nicardipine's rapid onset and short duration of action are additional advantages for use in the management of acute cardiovascular disorders.     

Cytochrome P450 induction by rifampicin in healthy subjects: determination using the Karolinska cocktail and the endogenous CYP3A4 marker 4beta-hydroxycholesterol

The Karolinska cocktail, comprising caffeine, losartan, omeprazole, and quinine, was given before and after administration of rifampicin (20, 100, or 500 mg daily) to measure induction of cytochrome P450 (P450) enzymes. Rifampicin was given for 14 days to eight healthy subjects (all of whom possessed at least one wild-type CYP2C9 and one wild-type CYP2C19 gene) in each dose group. 4beta-hydroxycholesterol was assessed as an endogenous marker of CYP3A4 induction. A fourfold induction of CYP3A4 was seen at the highest dose by both quinine:3'-hydroxyquinine and 4beta-hydroxycholesterol measurements (P < 0.001). CYP3A4 was also induced at the two lower doses of rifampicin when measured by these two markers (P < 0.01 or P < 0.001). CYP1A2, CYP2C9, and CYP2C19 were induced after 500 mg rifampicin daily (1.2-fold, P < 0.05; 1.4-fold, P < 0.05; and 4.2-fold, P < 0.01, respectively). In conclusion, we have shown that the Karolinska cocktail and 4beta-hydroxycholesterol can be used for an initial screening of the induction properties of a drug candidate.     

CENTRAL CARDIOVASCULAR EFFECTS OF DIHYDROPYRIDINES IN SPONTANEOUSLY HYPERTENSIVE RATS

Summary— Intracerebroventricular (i.c.v.) injections of dihydropyridine derivatives calcium channel agonist (BAY K8644) and antagonists (nifedipine, nicardipine, PN 200–110) induced opposite long-lasting changes in blood pressure (BP) in pentobarbital anesthetized spontaneously hypertensive rats (SMR). I.c.v. nifedipine (NIF), nicardipine (NIC), and PN 200–110 decreased mean blood pressure dose-dependently and stereoselec-tively, (+) NIC and (+) PN being 8 and 3 times more potent than their (-) isomers, respectively. The decrease in BP was due to a withdrawal of the sympathetic tone, since NIF- and NIC-induced falls in BP were suppressed after either hexamethonium (HXM), 6 OHDA or bilateral adrenalectomy. I.c.v. BAY K8644 increased BP dose-dependently. The i.c.v. BAY K8644-induced hypertensive effect was inhibited: a), by NIF and (+) PN but not by (-) PN, therefore probably occurring at central DHP sites; b), by HXM and reserpine, thus probably mediated by an increase in sympathetic tone; c), by i.c.v. methylatropine (MA) while i.v. MA and i.c.v. HXM had no inhibitory effect, thus probably involving central muscarinic sites. In SHR, NIC did not after the K+-evoked ACh release but suppressed the BAY K8644-induced increase in ACh release. In anesthetized normotensive control rats (WKY), neither i.c.v. NIF, NIC or BAY K8644 changed BP, nor did the latter after ACh release. Moreover, in conscious WKY, i.c.v. nicardipine increased BP and HR while, in conscious SHR it decreased BP without any change in HR. These data suggest that central DHP sites may be involved in the cholinergic transmission and may participate in genetic hypertension via sympathetic tone.     

Two Cases of Thyrotoxicosis due to Redotex Ingestion,a Mexican Weight Loss Drug

BackgroundRedotex? is a Mexican weight-loss supplement that is not U.S. Food and Drug Administration–approved. It consists of the following five ingredients: tri-iodothyronine 75 μg, atropine 0.36 mg, diazepam 8 mg, aloin 16 mg, and d-norpseudoephedrine 50 mg per tablet. There are few case reports with clinically severe ingestions. We report two cases of clinical thyrotoxicosis due to use of Redotex.Case ReportsA 29-year-old woman presented to the emergency department (ED) with anxiety and palpitations. She reported taking Redotex daily for 1 week. Her temperature was 37.1°C, blood pressure (BP) was 166/104 mm Hg, and heart rate (HR) was 140 beats/min. Laboratory analysis was significant for a bicarbonate level of 20 mmol/L (reference 22–29 mmol/L), free T4 0.75 ng/dL (reference 0.93–1.70 ng/dL), and thyroid-stimulating hormone (TSH) 0.05 uIU/mL (reference 0.27–4.20 uIU/mL). She was treated with 2 mg i.v. lorazepam and 20 mg oral propranolol. A 37-year-old woman presented with chest pain, palpitations, and nausea after taking Redotex 1 to 2 tablets daily for 6 weeks. Her HR was 134 beats/min and BP was 130/66 mm Hg. Thyroid function tests on initial presentation showed a TSH of 0.013 uU/mL, free T4 of 0.24 ng/dL, and free T3 of >30 pg/mL. She was treated with propranolol 1 mg i.v. twice per day and 2 doses of lorazepam 1 mg. Both patients had resolution of their symptoms.Why Should an Emergency Physician Be Aware of This?When taken chronically and at recommended doses, Redotex can present with clinically significant T3 thyrotoxicosis. This has not been seen in prior reports.