Efficacy and Safety of Nilutamide in Patients with Metastatic Prostate Cancer who Underwent Orchiectomy: A Systematic Review and Metaanalysis.

BACKGROUND: Prostate cancer is the sixth leading cause of death, among all cancer deaths By 2030, this burden is expected to increase with 1.7 million new cases and 499,000 new deaths. We aimed to evaluate the efficacy and safety of Nilutamide in metastatic prostate cancer (mPCa) patients who underwent orchiectomy. METHODS: A comprehensive search was conducted in the Medline/PubMed and Cochrane Library. References from included studies and studies from clinicaltrials.gov were explored without language and date restrictions. We included only randomized controlled trials, comparing the safety and efficacy of Nilutamide in Metastatic Prostate Cancer (mPCa) patients who underwent orchiectomy with placebo. The outcomes of concerns were survival and the response of drug and safety.. Quality of the included studies was assessed using the Cochrane Risk of Bias Tool. Two authors were independently involved in the study selection, data extraction and quality assessment. Disagreements between the two reviewers were resolved by consulting a third reviewer. RESULTS: A total of five out of 244 studies were included in meta-analysis involving1637 participants. Nilutamide group showed improved response rate (RR=1.77, 95%CI 1.46-2.14, p<0.00001), disease progression (RR=0.59, 95%CI 0.47-0.73, p<0.00001), complete response (RR=2.13, 95%CI 1.40-3.23, p=0.003) and clinical benefit (RR=1.23, 95%CI 1.13-1.34, p<0.00001) when compared to placebo; however, stable disease favored the control group (RR=0.80, 95%CI 0.68-0.94, p=0.007). In addition, patients on Nilutamide showed prolonged progression-free survival and overall survival. Nausea and vomiting were the most common adverse events reported in Nilutamide group. CONCLUSION: Evidence suggests that patients with mPCa who underwent orchiectomy receiving Nilutamide showed significant improvement in progression-free survival and overall survival response rate and clinical benefits in comparison with the placebo group.

Population Pharmacokinetic Modeling of JNJ-53718678, a Novel Fusion Inhibitor for the Treatment of Respiratory Syncytial Virus: Results from a Phase I, Double-Blind, Randomized, Placebo-Controlled First-in-Human Study in Healthy Adult Subjects.

BACKGROUND: JNJ-53718678 is a potent small-molecule inhibitor of the F-glycoprotein-mediated complex membrane fusion process of the respiratory syncytial virus. Here, we report the pharmacokinetics, the population pharmacokinetic modeling, and the safety and tolerability of JNJ-53718678 from the first-in-human, double-blind, randomized, placebo-controlled phase I study. METHODS: Healthy subjects were randomized (6:3) into five single-dose groups (25-1000 mg) or three multiple-dose groups [250 mg every 24 h (q24h), 500 mg q24h, 250 mg every 12 h; fed conditions for 8 days] to receive JNJ-53718678 or placebo. Blood and urine samples were collected at several timepoints up to 72 h after intake of JNJ-53718678 and analyzed using validated liquid chromatography-mass spectrometry methods. A population pharmacokinetic model was developed and validated. RESULTS: Peak plasma concentrations of JNJ-53718678 increased with increasing single (159 ± 54.9 to 6702 ± 1733 ng/mL) and multiple (on day 8, 1528 ± 256 to 2655 ± 591 ng/mL) doses. Steady-state conditions were reached on day 2 of the 8-day dosing regimen. Less than 4% of JNJ-53718678 was excreted in urine across all dose groups. Mean exposure of JNJ-53718678 was 7% lower in the fed state compared with the fasted state at the same dose. A two-compartment model with first-order absorption with parallel linear and non-linear elimination best described the pharmacokinetics of JNJ-53718678. No covariate effects were observed. CONCLUSIONS: A population pharmacokinetic model that describes the concentration data well with good precision of all parameter estimates was developed and validated. JNJ-53718678 was well tolerated at all single and multiple doses studied.

[A Case of Life-Threatening Angioedema Occurred During Prolonged Angiotensin-Converting Enzyme Inhibitor Treatment].

Although angiotensin-converting enzyme (ACE) inhibitors are widely used as the first choice drug for treating hypertension, we have only a superficial understanding of their relationship to angioedema. We report a case of life-threatening angioedema. The case was a 60-year-old man who had been taking an ACE inhibitor for hypertension for 11 years. He visited his home doctor for dyspnea, and tongue and neck swelling. He was transported to our hospital because of the possibility of airway obstruction. On admission, his tongue and neck swelling became more severe. We performed an intubation using an endoscope and started airway management. We also stopped his ACE inhibitor. The severe tongue and neck swelling improved gradually and he was extubated on day 3. On the fifth day he was discharged. We diagnosed angioedema caused by an ACE inhibitor. Although the risk of airway obstruction with ACE inhibitors is acknowledged, we have only a superficial understanding of how prolonged ACE inhibitor treatment induces angioedema. So we should consider angioedema in cases of taking ACE inhibitors, especially in cases of prolonged treatment.

Is there any association between imidapril hydrochloride stability profile under dry air conditions and cancer initiation?

Stability study for imidapril hydrochloride (IMD) was performed under stress conditions of increased temperature (T=373 K) and decreased relative air humidity (RH=0%) in order to obtain and identify its degradation product. The degradation sample stored for 15 days under the above environmental conditions was analyzed by LC-MS technique and it was found that the only degradation impurity formed in the course of the investigated drug degradation was IMD diketopiperazine derivative (DKP) which was produced by dehydration and intramolecular cyclization. The kinetics of its formation was analyzed by a revalidated RP-HPLC method and the kinetic model of this reaction was established. It was concluded that the DKP formation follows Prout-Tompkins kinetics with the rate constant k±Δk=2.034±0.157×10(-6) [s(-1)]. The obtained degradation impurity was further assessed with respect to its mutagenic potential using commercial Ames MPF 98/100 microplate format mutagenicity assay kit equipped with Salmonella typhimurium strains TA 98 and TA 100. Both strains were exposed to six concentrations (in a range of 0.16-5.0mg/mL) of DKP in the presence and absence of metabolic activation system. No mutagenic effect was observed confirming that the presence of DKP in IMD final dosage form has no impact on cancer initiation.

Anti-inflammatory and antinociceptive activities of indole-imidazolidine derivatives.

Non-steroidal anti-inflammatory drugs (NSAIDs) represent a group of approximately 50 different medicines that are widely prescribed for the management of inflammation and that exhibit variable anti-inflammatory, anti-pyretic and analgesic activities. Most NSAIDs also exhibit a shared set of adverse effects, particularly related to gastrointestinal complications; thus, the development of new drugs for the treatment of chronic inflammation and pain continues to be an issue of high interest. Hydantoin and indole derivatives are reported to possess various pharmacological effects, including anti-inflammatory and analgesic activities. Therefore, the aim of this study was to evaluate the potential anti-inflammatory and antinociceptive activities of hybrid molecules containing imidazole and indole nuclei. The anti-inflammatory activities of 5-(1H-Indol-3-yl-methylene)-2-thioxo-imidazolidin-4-one (LPSF/NN-56) and 3-(4-Bromo-benzyl)-5-(1H-indol-3-yl-methylene)-2thioxo-imidazolidin-4-one (LPSF/NN-52) were evaluated using air pouch and carrageenan-induced peritonitis models as well as an acetic acid-induced vascular permeability model followed by IL-1ß and TNF-α quantification. To evaluate the antinociceptive activities of the compounds, acetic acid-induced nociception, formalin and hot plate tests were also performed. The anti-inflammatory activities of the compounds were evidenced by a reduction in both leukocyte migration and the release of TNF-α and IL-1ß in air pouch and peritonitis models. Upon acetic acid-induced nociception, a decrease in the level of abdominal writhing in the groups treated with LPSF/NN-52 (52.1%) or LPSF/NN-56 (63.1%) was observed. However, in the hot plate test, none of the derivatives tested exhibited an inhibition of nociception. These results indicate that the compounds tested exhibited promising anti-inflammatory and antinociceptive activities that likely involved the modulation of the immune system.

Permanent press allergy in an active duty U.S. Army soldier.

Ethylene urea/melamine formaldehyde resin (permanent press) is a common fabric finishing agent added to Army Combat Uniforms for a wrinkle-free appearance and to strengthen the fabric. We describe the case of an active duty U.S. Army soldier with a diffuse eczematous dermatitis in whom patch testing was used to identify an allergy to permanent press, a ubiquitous fabric finishing agent in the Army combat uniform. To our knowledge, this is the first case report of a soldier with an allergic contact dermatitis to ethylene urea/melamine formaldehyde resin. This case highlights the importance of considering the diagnosis of allergic contact dermatitis in patients with a recurrent eczematous dermatitis that does not respond appropriately to therapy and the unique occupational impact of diagnosing an Army soldier with permanent press allergy.

Candesartan versus imidapril in hypertension: a randomised study to assess effects of anti-AT1 receptor autoantibodies.

BACKGROUND: Anti-angiotensin II receptor subtype 1 (AT1 receptor) autoantibodies have previously been shown in sera of hypertensive patients. This study assessed whether anti-AT1-receptor autoantibody in serum is correlated with the efficacy of an AT1-receptor blocker (ARB; candesartan)-based regimen in hypertensive patients after 8 weeks of treatment. DESIGN: The Study of Optimal Treatment in Hypertensive Patients with Anti-AT1-Receptor Autoantibodies is a multicentre, randomised, blinded endpoint, open-label, parallel-group comparison clinical trial conducted in five centres in Wuhan, China. Treatment is designed as stepwise added-on therapy to reduce blood pressure (BP) < 140/90 mm Hg. 512 patients with moderate to severe primary hypertension were randomly assigned to an 8-week treatment with either ARB (candesartan)-based regimen (n=257) or ACE inhibitor (imidapril)-based regimen (n=255). RESULTS: Systolic and diastolic BP was reduced significantly in both treatment groups. The candesartan-based regimen achieved a significantly greater systolic BP reduction than imdapril (30.8 ± 10.3 vs 28.8 ± 10.3 mm Hg, p = 0.023). In those anti-AT1 receptor autoantibody-positive hypertensive patients, the mean systolic BP at baseline was higher than in the anti-AT1 receptor autoantibody-negative group (160.5 ± 16.5 vs 156.2 ± 17.7 mm Hg; p = 0.006). The mean BP reduction was greater in the candesartan-based regimen than the imidapril-based regimen (-35.4 ± 9.8/16.9 ± 6.9 vs -29.4 ± 9.8/14.2 ± 6.9 mm Hg; p = 0.000 and 0.002, respectively), and more patients on imidapril required add-on medications to achieve BP control (94% vs 86%; p=0.03). No correlation was observed between the titre of anti-AT1 receptor autoantibody and the efficacy of candesartan-based therapy. In those anti-AT1 receptor autoantibody-negative patients similar BP lowering was reached in the candesartan and the imidapril-based regimens. CONCLUSIONS: An ARB-based regimen is more effective in BP lowering than an ACE inhibitor-based regimen in the presence of anti-AT1 receptor autoantibodies. Trial registration number This trial has been registered at http://www.register.clinicaltrials.gov/ (identifier: NCT00360763).

Aldose reductase inhibitors in the treatment of diabetic peripheral neuropathy: a review.

PURPOSE: The purpose of this article was to examine how aldose reductase (AR) inhibitors are used in the prevention and treatment of peripheral neuropathy in diabetes, specifically focusing on efficacy. METHODS: Medline searches were used to identify clinical trials investigating AR inhibitors and their proposed mechanism of action, efficacy, and adverse effects. Additionally, the references of the articles returned by the Medline search were examined for pertinent publications. RESULTS: Three AR inhibitors were selected for review. Modest improvements in the preservation and restoration of nerve conduction velocities were reported in the studies. Additionally, patients reported improvements in the subjective symptoms associated with diabetic peripheral neuropathy. Adverse effects for the studied agents were minimal or not reported. CONCLUSIONS: Given the mechanism by which diabetic peripheral neuropathy can result, targeting the polyol pathway as a method of treatment appears promising, yet the efficacy of newer AR inhibitors is still to be proven. Currently, these agents are not marketed in the United States. As newer studies emerge, diabetes educators will learn more about their efficacy and safety in preventing and treating diabetic peripheral neuropathy.

[Hospital pharmacists prevented advance of lithium intoxication through pharmaceutical interventions].

Lithium carbonate is used to treat depressive episodes in patients with manic depressive disorder. Lithium toxicity is closely related to serum levels of lithium, and can occur with doses of lithium carbonate close to those used in therapy. Herein we report a case in which pharmaceutical intervention led to a patient's early recovery. The patient was hospitalized with a complaint of dyspnea, and clinical findings revealed signs of bradyarrhythmia. We investigated the medications the patient brought with him and the record of his prescribed medications in his drug notebook. From this we found that he had been taking imidapril (an angiotensin-converting enzyme inhibitor) in addition to lithium carbonate, and surmised that lithium toxicity may have occurred from the drug interactions between the lithium carbonate and imidapril in this patient. To prevent the level of toxicity from advancing, we proposed to the physician in charge that the patient's serum lithium levels be measured immediately and that all drugs be discontinued. By receiving care centered on detoxification, the patient avoided measures such as placement of a permanent pacemaker and thereby made a quick recovery from a dangerous state. This is a good example of a case in which pharmaceutical intervention improved the patient's quality of life (QOL) and contributed to conserving limited medical resources. As shown by this case, regular checks of patients' current medications and drug notebooks at the time of hospitalization are an effective means of implementing pharmaceutical interventions that can contribute to medical care.

Recurrent severe angioedema associated with imidapril and diclofenac.

BACKGROUND: Angioedema due to angiotensin-converting enzyme inhibitors (ACEIs) therapy occurs not infrequently and is sometimes associated with life-threatening conditions. CASE SUMMARY: A 59-year-old woman presented with recurrent angioedema of the tongue complicated by upper airway obstruction which required endotracheal intubation. Laboratory tests including complement levels were normal. ACEI-associated angioedema precipitated by NSAIDs was suspected. Her condition improved after discontinuation of imidapril and diclofenac without other specific treatment. DISCUSSION: ACEIs, and in particular concomitant use with NSAIDs, should be avoided in patients with a history of angioedema because continuing administration tends to lead to more severe attacks.

Azimilide reduces emergency department visits and hospitalizations in patients with an implantable cardioverter-defibrillator in a placebo-controlled clinical trial.

OBJECTIVES: The goal of this study was to determine whether azimilide, as compared with placebo, will reduce the number of emergency department (ED) visits and hospitalizations caused by arrhythmias or cardiac events in patients with an implantable cardioverter-defibrillator (ICD). BACKGROUND: Patients with an ICD may require ED visits and hospitalizations because of arrhythmias, which trigger ICD therapies. The effect of adjunctive antiarrhythmic therapy on these outcomes is not known. METHODS: A total of 633 patients with an ICD were randomized in the SHIELD (SHock Inhibition Evaluation with AzimiLiDe) trial, a blinded, placebo-controlled randomized trial of the investigational class III antiarrhythmic azimilide (75 and 125 mg/day), and, prospectively, cardiac and arrhythmic ED visits and hospitalization data were collected over 1 year. RESULTS: All patients had symptomatic sustained ventricular tachycardia (72%) or ventricular fibrillation (28%) before study entry. Overall, 44% (n = 276) experienced at least 1 cardiac ED visit or hospitalization. Among 214 patients assigned to placebo, 38.3% had at least 1 arrhythmic-related ED visit or hospitalization compared with 21.8% of 220 patients assigned to 75-mg azimilide (p < 0.001) and 27.6% of 199 patients assigned to 125 mg azimilide (p < 0.05). Symptomatic ventricular tachycardia treated by antitachycardia pacing, shocks, and shocks plus symptomatic arrhythmias were significant predictors of cardiac-related ED visits or hospitalizations (relative risk: 2.0, 3.0, and 3.1, respectively). In a stepwise logistic regression model, the presence of congestive heart failure (New York Heart Association functional class II/III) was the only additional independent predictor of cardiac ED visits or hospitalizations. CONCLUSIONS: Azimilide significantly reduces the number of ED visits and hospitalizations in patients with an ICD at high risk of arrhythmias.

Drug-induced interstitial pneumonia.

(1) Interstitial pneumonia usually develops gradually. The signs and symptoms are non-specific, and generally include dyspnea, cough, fatigue, and weight loss. In other cases onset is acute, sometimes beginning with a flu-like syndrome. Interstitial pneumonia can lead to acute respiratory failure, sometimes gradual deterioration of respiratory function, and pulmonary fibrosis progressing to respiratory failure. The fibrosis does not regress when the causal factor is withdrawn. (2) There are numerous causes of interstitial pneumonia, including medicinal drugs. (3) Amiodarone generally induces slow and insidious lung disease. (4) Methotrexate induces lung disease. Most cytotoxic drugs cause chronic dose-dependent lung disease and fibrosis, in some cases long after treatment cessation. (5) The many other implicated drugs include nitrofurantoin, Nonsteroidal antiandrogens, drugs that induce connective tissue diseases, laxatives based on mineral oil, and many other drugs, some of which are known to cause hypersensitivity reactions. (6) In practice, a drug-related cause should be kept in mind in cases of interstitial pneumonia, as symptoms generally improve after drug withdrawal, unless fibrosis has already started to develop.

QT Interval prolongation and torsades de pointes due to a coadministration of ciprofloxacin and azimilide in a patient with implantable cardioverter-defibrillator.

The presented case report describes a male patient with an implanted cardioverter-defibrillator (ICD) in whom a coadministration of ciprofloxacin and azimilide caused QT interval prolongation and multiple episodes of torsades de pointes (TdP) followed by ICD shocks (arrhythmic storm). The case highlights a not described drug interaction between azimilide and ciprofloxacin, which is believed to be the safest member of fluoroquinolones class.

Imidapril: a review of its use in essential hypertension, Type 1 diabetic nephropathy and chronic heart failure.

Imidapril (Tanatril), through its active metabolite imidaprilat, acts as an ACE inhibitor to suppress the conversion of angiotensin I to angiotensin II and thereby reduce total peripheral resistance and systemic blood pressure (BP). In clinical trials, oral imidapril was an effective antihypertensive agent in the treatment of mild to moderate essential hypertension. Some evidence suggests that imidapril also improves exercise capacity in patients with chronic heart failure (CHF) and reduces urinary albumin excretion rate in patients with type 1 diabetes mellitus. Imidapril was well tolerated, with a lower incidence of dry cough than enalapril or benazepril, and is a first choice ACE inhibitor for the treatment of mild to moderate essential hypertension.

Dechallenge and rechallenge method showed different incidences of cough among four ACE-Is.

OBJECTIVE: To determine the incidence of cough secondary to (1) Cilazapril, (2) Enalapril, (3) Imidapril, and (4) Perindopril and their efficacy in the control of hypertension. STUDY DESIGN AND SETTING: Randomized double-blind study conducted in selected medical centers in the Philippines from the first quarter of 1999 to March, 2001. RESULTS: A total of 301 patients, aged 28-86 years with stage I or II hypertension were included. Patients were randomized to Cilazapril 2.5-5.0 mg/day (n=70), Enalapril 10-20 mg/day (n=82), Perindoril 4-8 mg/day (n=73), or Imidapril 10-20 mg/day (n=76). Hydrochlorothiazide 12.5 mg/day was added if needed. Using a dechallenge and rechallenge method, a strict criteria to attribute cough to angiotensin converting enzyme inhibitors (ACE-Is) not yet used in previous reports, the cough incidence were as follows: (1) Cilazapril--22.86% (16/70), (2) Enalapril--21.95% (18/82), (3) Perindopril--10.96% (6/73), and (4) Imidapril--13.16% (10/76) (P=0.041). Control of hypertension was significantly better with Enalapril during the first follow-up period. CONCLUSION: Statistically significant differences in the incidence of cough among the studied ACE-Is were noted. Control of hypertension was observed to be better in those with a higher incidence of cough; however, the mean change of both systolic and diastolic blood pressure levels were not significantly different.

A multicentre, 12-week study of imidapril and candesartan cilexetil in patients with mild to moderate hypertension using ambulatory blood pressure monitoring.

BACKGROUND: Twenty-four-hour ambulatory blood pressure monitoring (ABPM) provides the most accurate efficacy assessment of an antihypertensive agent throughout a 24-hour dosing interval. The objective of this prospective, randomised, double-blind, parallel-group, multicentre study was to compare the antihypertensive efficacy of imidapril versus candesartan cilexetil using ABPM. METHODS: After screening and a single-blind, placebo run-in phase, ambulatory adult patients with mild to moderate hypertension (defined as a mean office sitting diastolic BP [DBP] and systolic BP [SBP], respectively, of 90-109 mm Hg and 140-179 mm Hg, and a mean ABPM DBP and SBP, respectively, of >or=80 mm Hg and >or=125 mm Hg) were randomised to once-daily treatment with imidapril or candesartan cilexetil for 12 weeks. ABPM was performed at baseline and at the end of the 12-week treatment period in 112 patients (imidapril group, n=55; candesartan cilexetil group, n=57). To achieve the target BP of