Friday, October 28th, 2005

Time	Event
5:59a	New oral drugs for erectile dysfunction. New oral drugs for erectile dysfunction. In 1998, we concluded that sildenafil (Viagra--fizer Ltd), a selective phosphodiesterase type 5 inhibitor, appeared to offer advantages over other medical approaches for erectile dysfunction in terms of ease of administration and cost. Oral drug treatment is now widely advocated as first-line therapy for erectile dysfunction, except where the cause is clearly psychological. In the past 4 years, three more oral preparations have been licensed in the UK for the treatment of men with erectile dysfunction. A sublingual preparation of the dopaminergic agonist apomorphine (Uprima--Abbott Laboratories Ltd) is the first centrally acting drug to be licensed. Tadalafil (Cialis--Eli-Lilly) and vardenafil (Levitra--Bayer PLC) are phosphodiesterase type 5 inhibitors. Here we review the place of these preparations for men with erectile dysfunction. Journal ISSN: 0012-6543 Issue: 42-7 (2004) Pages: 49-52 Vardenafil: structural basis for higher potency over sildenafil in inhibiting cGMP-specific phosphodiesterase-5 (PDE5). Vardenafil: structural basis for higher potency over sildenafil in inhibiting cGMP-specific phosphodiesterase-5 (PDE5). Phosphodiesterase-5 (PDE5) inhibitors act by competing with the substrate, cGMP, for the catalytic site of the enzyme. Two commercialized PDE5 inhibitors, sildenafil and vardenafil, are being used to treat erectile dysfunction. These two compounds differ in the heterocyclic ring system used to mimic the purine ring of cGMP. They also differ in the substituent (ethyl/methyl) of a piperazine side chain. Although these are the only two structural differences, vardenafil has more than 20-fold greater potency than sildenafil for inhibiting purified PDE5. The molecular structural basis for the difference in potency of the two compounds was investigated by synthesizing an analog of sildenafil ("methyl-sildenafil") that contained the sildenafil ring system but with the appended ethyl group found in vardenafil, and an analog of vardenafil ("demethyl-vardenafil") that contained the vardenafil ring system but with the appended methyl group found in sildenafil. The IC50 of methyl-sildenafil for inhibiting PDE5 indicated that it was 64 times less potent than demethyl-vardenafil, which was similar to the finding that, based on IC50, sildenafil was 40 times less potent than vardenafil. Similarly, the EC50 of methyl-sildenafil for inhibiting [3H]vardenafil binding to PDE5 indicated that it was 84 times less potent than demethyl-vardenafil, while the EC50 for sildenafil indicated that it was 31 times less potent than vardenafil. It is concluded that the methyl/ethyl appended group on the piperazine moiety plays very little role in the difference in potency between sildenafil and vardenafil for inhibiting PDE5, whereas the differences in the ring systems play a critical role in higher potency of vardenafil over sildenafil. Journal ISSN: 0197-0186 Issue: 45-6 (2004) Pages: 859-63 Urological manifestations of vascular disease. Urological manifestations of vascular disease. We have detailed several of the urological manifestations of vascular disease. With the aging of the North American population, urologists will encounter the urological complications of vascular disease with ever-increasing frequency. Journal ISSN: 0094-0143 Issue: 30-1 (2003) Pages: 13-26 A new synthesis of carboxyterfenadine (fexofenadine) and its bioisosteric tetrazole analogs. A new synthesis of carboxyterfenadine (fexofenadine) and its bioisosteric tetrazole analogs. A new synthesis of carboxyterfenadine (4), based on the conversion of a alpha-halo-alkylarylketone into the corresponding substituted 2-arylalkanoic ester, is described. The enantioselective synthesis of its two bioisosteric tetrazole analogs together with preliminary biological results are reported. Journal ISSN: 0014-827X Issue: 54-9 (1999) Pages: 600-10 Desloratadine has no clinically relevant electrocardiographic or pharmacodynamic interactions with ketoconazole. Desloratadine has no clinically relevant electrocardiographic or pharmacodynamic interactions with ketoconazole. OBJECTIVE: This study was performed to assess the electrocardiographic safety and pharmacokinetics of desloratadine in combination with the CYP3A4 inhibitor ketoconazole. DESIGN: A randomised, placebo-controlled, third-party-blind, 2-way crossover study. PARTICIPANTS: 24 healthy volunteers (12 men, 12 women; age 19 to 50 years). INTERVENTIONS: 7.5mg of desloratadine orally per day in combination with placebo or with 200mg of ketoconazole every 12 hours for 10 days. After a minimum 7-day washout period, participants received the alternative treatment. MAIN OUTCOME MEASURES: ECG parameters. RESULTS: Comparable maximum corrected QT (QT(c)) intervals were observed after coadministration of desloratadine and placebo or ketoconazole (431 and 435 msec, respectively). The desloratadine/ketoconazole combination did not induce any statistically significant or clinically relevant changes in QT(c), QT, PR or QRS intervals compared with desloratadine alone; ventricular rate was slightly slower when desloratadine was given with ketoconazole. At steady state, coadministration of ketoconazole resulted in no significant change in area under the desloratadine concentration-time curve (AUC) from 0 to 24 hours compared with desloratadine/placebo. Coadministration of desloratadine and ketoconazole resulted in a 1.3-fold increase in desloratadine maximum concentration (C(max)) that was not clinically relevant. The most common adverse event was headache, reported in 42 and 38% of individuals, respectively, after coadministration of desloratadine/placebo and desloratadine/ketoconazole. There were no reports of dizziness or syncope. CONCLUSION: Coadministration of desloratadine and ketoconazole was well tolerated and was associated with minimal increase in AUC and C(max). The combination did not induce any clinically relevant electrocardiographic changes. Journal ISSN: 0312-5963 Issue: 41 Suppl 1- (2002) Pages: 37-44
11:59a	IC351 (tadalafil, Cialis): update on clinical experience. IC351 (tadalafil, Cialis): update on clinical experience. IC351 (tadalafil, trade name Cialis) is a new representative compound of the second generation of selective phosphodiesterase 5 (PDE-5) inhibitors. The selectivity ratio vs PDE-5 is more than 10 000 for PDE-1 through PDE-4 and PDE-7 through PDE-10 and 780 for PDE-6. In the European daily-dosing trial, the efficacy rates were up to 93% for successful intercourses with completion in the 50-mg dose in patients with mild to moderate erectile dysfunction (ED). In two different dose-ranging studies with 2-25 mg taken as needed, efficacy rates of up to 88% improvement in erections and up to 73% successful intercourses with completion were achieved. In a placebo-controlled, fixed-dose (10- and 20-mg) trial in diabetic patients, improved erections of 56% and 64% were reported compared with 25% after placebo. Drug-related adverse effects, with headache in up to 23% of patients (placebo, up to 17%), dyspepsia in up to 11% (placebo, up to 7%), back pain in up to 4.7% (placebo, 0%), and myalgia in up to 4.1% (placebo, up to 2.4%), were mostly mild to moderate. Neither drug-related serious cardiovascular adverse events nor color vision disturbances were encountered. The long half-life (>17 h), with a comfortably long window of opportunity, releases couples from the need to plan sexual activities and therefore provides the highest amount of spontaneity for sexual activities. Journal ISSN: 0955-9930 Issue: 14 Suppl 1- (2002) Pages: S57-64 Safety and efficacy of vardenafil in patients with erectile dysfunction: result of a bridging study in Japan. Safety and efficacy of vardenafil in patients with erectile dysfunction: result of a bridging study in Japan. AIM: Vardenafil is a selective and highly potent phosphodiesterase type 5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED), with improved selectivity for PDE5 and demonstrated efficacy for improving sexual function in men with ED. The current study investigated the safety and efficacy of this new PDE5 inhibitor in Japanese men with ED. METHODS: This was a prospective, double blind, randomized clinical trial designed to evaluate the efficacy and safety of vardenafil. Following a 4-week treatment-free observation period, 283 eligible patients were randomized to 12 weeks treatment with vardenafil 5 mg, 10 mg, 20 mg, or placebo. Primary efficacy responses were assessed using the scores of Q3 and Q4 of the international index of erectile function (IIEF). RESULTS: All three vardenafil doses showed significantly better improvement than the placebo group in Q3 and Q4 scores of the IIEF questionnaire, either at 12 weeks or at the @apos;last observation carried forward@apos; (LOCF, P < 0.0001). Q3 scores were improved to 4.06 with vardenafil 5 mg, 4.53 with vardenafil 10 mg, and 4.64 with vardenafil 20 mg, versus 3.17 with placebo. Comparable scores for Q4 were 3.47, 4.15 and 4.31 versus 2.31 for placebo. Up to 86% of patients achieved improved erections as assessed by the global assessment question (GAQ). Reported adverse event rates were 35.3%, 45.3% and 54.5% with vardenafil 5 mg, 10 mg and 20 mg, respectively, versus 21.1% in the placebo group. No serious adverse drug reactions were reported. The most common treatment-emergent adverse events were transient headache, flushing and rhinitis, which were mostly mild. CONCLUSION: Vardenafil is an effective and well-tolerated treatment for ED and provides improvement in key indices of erectile function among Japanese men with ED. The results of our trial show that up to nearly 90% of patients achieve improved erections with the administration of vardenafil. Journal ISSN: 0919-8172 Issue: 11-7 (2004) Pages: 515-24 New therapies for erectile dysfunction. New therapies for erectile dysfunction. The quest for improving and maintaining sexual function has been going on since time immemorial. The advent of an effective oral drug, sildenafil, has brought about unprecedented open discussion on male erectile dysfunction, and gas accelerated the pace of development of new therapies for erectile dysfunction. New knowledge in the physiology of sexual function has enabled researchers to target drug treatment at the whole network of the central nervous system and the numerous cascadic enzymatic reactions leading to relaxation of the corporal smooth muscle. One of the brightest potential applications of future molecular technology in the study of erectile dysfuction is in the utilization of gene therapy. Journal ISSN: 0105-6263 Issue: 23 Suppl 2- (2000) Pages: 87-8 Evaluation of first-pass cytochrome P4503A (CYP3A) and P-glycoprotein activities using alfentanil and fexofenadine in combination. Evaluation of first-pass cytochrome P4503A (CYP3A) and P-glycoprotein activities using alfentanil and fexofenadine in combination. Cytochrome P4503A (CYP3A) and P-glycoprotein (P-gp) are major determinants of oral bioavailability. Development of in vivo probe(s), for both CYP3A and P-gp, which could be administered in combination, is a current goal. Nevertheless, there is considerable overlap in CYP3A and P-gp substrate selectivities; there are few discrete probes. Alfentanil is a selective CYP3A probe but not a P-gp substrate. Fexofenadine is a P-gp probe but not a CYP3A substrate. This investigation tested the hypothesis that alfentanil and fexofenadine could be administered in combination to probe first-pass CYP3A and P-gp activities in humans. Two 3-way crossover studies were conducted in healthy volunteers. In the first protocol, subjects received oral alfentanil alone, fexofenadine alone, or fexofenadine 1 hour after alfentanil. In the second protocol, subjects abstained from citrus and apple products for 5 days and received fexofenadine alone, fexofenadine 1 hour after alfentanil, or alfentanil 4 hours after fexofenadine. An assay using solid-phase extraction and electrospray liquid chromatography/mass spectrometry was developed for the simultaneous quantification of plasma alfentanil and fexofenadine. In both protocols, alfentanil plasma concentrations and area under the concentration versus time curve (AUC) were unaffected by fexofenadine or meal composition. Fexofenadine given 1 hour after alfentanil and followed 1 hour later by a meal containing orange or apple juice had a somewhat lower AUC compared with fexofenadine alone (geometric mean ratio with and without the interacting drug = 0.73, 90% confidence interval [CI] = 0.59-1.04). Fexofenadine given 1 hour after alfentanil and followed 2 hours later by a meal not containing citrus or apple products had an AUC that was unchanged compared with fexofenadine alone (ratio = 0.91, 90% CI = 0.70-1.35). These results show that alfentanil disposition was not affected by fexofenadine. A dosing regimen was identified in which fexofenadine disposition was not affected by alfentanil. The timing and content of meals after fexofenadine had a significant effect on fexofenadine disposition. Alfentanil and fexofenadine in combination appear to be a useful probe for evaluating both first-pass CYP3A and P-gp activities in humans. Journal ISSN: 0091-2700 Issue: 45-1 (2005) Pages: 79-88 Decongestant efficacy of desloratadine in patients with seasonal allergic rhinitis. Decongestant efficacy of desloratadine in patients with seasonal allergic rhinitis. Recent advances in experimental immunologic approaches to seasonal allergic rhinitis (SAR) have led to a shift in the concepts of its pathogenesis. The conventional view of SAR as a local response to inhaled allergens has largely given way to a new view of this disorder as a systemic condition with local tissue manifestations. This concept, together with an increasing recognition of specific mediators' distinct roles in driving the early- and late-phase allergic responses, has opened multiple lines of therapeutic attack within the allergic cascade. Potent inhibition of inflammatory mediator release at distinct points in this cascade is conferred by desloratadine. In addition to the familiar range of SAR symptoms amenable to antihistamine therapy, desloratadine uniquely attenuates patient ratings of nasal congestion. This novel, nonsedating histamine H1-receptor antagonist is the only once-daily antiallergic product with a consistent decongestant effect that begins within hours of the first morning dose and is sustained for the entire treatment period. Journal ISSN: 0105-4538 Issue: 56 Suppl 65- (2001) Pages: 14-20 Dynamics of the skin blood flow response to histamine. Comparison of the effects of cetirizine and loratadine on the skin response to a histamine dry prick test monitored with laser-Doppler flowmetry. Dynamics of the skin blood flow response to histamine. Comparison of the effects of cetirizine and loratadine on the skin response to a histamine dry prick test monitored with laser-Doppler flowmetry. In previous studies, we noticed that intradermal injection of histamine solutions might significantly complicate the interpretation of clinical data and of laser-Doppler flowmetry recordings (LDF). Therefore, we used the histamine dry skin prick test (HPT) for pharmacological studies. In this study, LDF monitoring of the physiological skin response to histamine was made in a randomized, placebo-controlled, double-blind study comparing the in vivo anti-H1 activity of cetirizine (10 mg) or loratadine (10 mg), 6 h after a single oral intake. As compared with responses recorded after intake of placebo, LDF readings performed at HPT sites (increase in LDF signal) and at 1 cm from HPT (reduction of LDF signal) conclusively illustrate the stable and almost complete blockade of H1 receptors by cetirizine. In vivo effects obtained with loratadine were considered weaker because (1) there was no significant influence of loratadine on the blood flow recorded at HPT sites, (2) a significant reduction at 1 cm from HPT sites was observed only after a lag phase (> or = 10 min) and (3) there were significantly higher skin perfusion levels at 1 cm from HPT sites between 6 and 10 min after the test under loratadine as compared with cetirizine. Hence, multipoint probing with LDF over time appears as a sensitive method for discriminating response profiles between two anti-H1 agents. Furthermore, this is the first time that anti-H1-related changes of the dynamics of expansion of the flare response have been demonstrated. Journal ISSN: 1018-8665 Issue: 186-4 (1993) Pages: 281-3
6:03p	Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension: a randomized prospective study. Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension: a randomized prospective study. OBJECTIVES: We sought to compare the short-term impact of three different phosphodiesterase-5 (PDE5) inhibitors on pulmonary and systemic hemodynamics and gas exchange parameters in patients with pulmonary arterial hypertension (PAH). BACKGROUND: The PDE5 inhibitor sildenafil has been reported to cause pulmonary vasodilation in patients with PAH. Vardenafil and tadalafil are new PDE5 inhibitors, recently being approved for the treatment of erectile dysfunction. METHODS: Sixty consecutive PAH patients (New York Heart Association functional class II to IV) who underwent right heart catheterization received short-term nitric oxide (NO) inhalation and were subsequently assigned to oral intake of 50 mg sildenafil (n = 19), 10 mg (n = 7) or 20 mg (n = 9) vardenafil, or 20 mg (n = 9), 40 mg (n = 8), or 60 mg (n = 8) tadalafil. Hemodynamics and changes in oxygenation were assessed over a subsequent 120-min observation period. RESULTS: All three PDE5 inhibitors caused significant pulmonary vasorelaxation, with maximum effects being obtained after 40 to 45 min (vardenafil), 60 min (sildenafil), and 75 to 90 min (tadalafil). Sildenafil and tadalafil, but not vardenafil, caused a significant reduction in the pulmonary to systemic vascular resistance ratio. Significant improvement in arterial oxygenation (equally to NO inhalation) was only noted with sildenafil. CONCLUSIONS: In PAH patients, the three PDE5 inhibitors differ markedly in their kinetics of pulmonary vasorelaxation (most rapid effect by vardenafil), their selectivity for the pulmonary circulation (sildenafil and tadalafil, but not vardenafil), and their impact on arterial oxygenation (improvement with sildenafil only). Careful evaluation of each new PDE5 inhibitor, when being considered for PAH treatment, has to be undertaken, despite common classification as PDE5 inhibitors. Journal ISSN: 0735-1097 Issue: 44-7 (2004) Pages: 1488-96 Drug approval highlights for 2003. Drug approval highlights for 2003. In the past 12 months, the FDA has approved important new pharmaceutical drugs and devices of particular interest to primary health care providers. The drugs include: Oxytrol (for urinary incontinence), Valtrex (for reducing the risk of heterosexual transmission of genital herpes), Femring (for vaginal delivery of hormone therapy), Uroxatral (for benign prostatic hypertrophy), Levitra (for erectile dysfunction), Flumist (for preventing influenza), Xolair (for asthma), Raptiva (for psoriasis), Cubicin (for skin infections), Crestor (for hypercholesterolemia), and Coreg (for severe heart failure). Journal ISSN: 0361-1817 Issue: 29-2 (2004) Pages: 8-15, 19-21; quiz 21-3 Effects of grapefruit juice on the pharmacokinetics of sildenafil. Effects of grapefruit juice on the pharmacokinetics of sildenafil. BACKGROUND AND OBJECTIVES: Because of extensive first-pass metabolism, oral bioavailability of sildenafil reaches only 40%. Formation of the primary metabolite, N -desmethylsildenafil, is mainly mediated by the cytochrome P450 enzyme CYP3A4. In this study we investigated the influence of grapefruit juice, containing inhibitors of intestinal CYP3A4, on the pharmacokinetics of sildenafil and N -desmethylsildenafil. METHODS: In a randomized crossover study, 24 healthy white male volunteers received single 50-mg doses of sildenafil. Two doses each of 250 ml grapefruit juice or water, respectively, were administered 1 hour before and together with the drug. Plasma concentrations of sildenafil and N -desmethylsildenafil were determined up to 24 hours post dose by use of liquid chromatography-tandem mass spectrometry (limit of quantification, 1 ng/ml). RESULTS: Grapefruit juice changed the area under the sildenafil plasma concentration-time curve from time zero to infinity [AUC(0-infinity) from 620 [1.53] ng/ml x h to 761 [1.58] ng/ml x h (geometric mean with geometric standard deviation), corresponding to a 23% increase (90% confidence interval, 13%-33%). N-Desmethyl sildenafil AUC(0-infinity) increased by 24% (90% confidence interval, 17%-32%). Maximum plasma concentrations (C(max)) of sildenafil and N -desmethylsildenafil were essentially unchanged. There was a trend toward a prolonged time to reach C(max) during the grapefruit juice period (from a median of 0.75 hour to a median of 1.13 hours), corresponding to an increase by 0.25 hour (90% confidence interval, 0-0.63 hour). Interindividual variability was pronounced in both periods. CONCLUSIONS: Grapefruit juice increases sildenafil bioavailability and tends to delay sildenafil absorption. Sildenafil pharmacokinetics may become less predictable with grapefruit juice. Although patients usually will not be endangered by concomitant use of grapefruit juice, it seems advisable to avoid this combination. Journal ISSN: 0009-9236 Issue: 71-1 (2002) Pages: 21-9 Multicenter study of the efficacy and safety of fexofenadine 60 mg. twice daily in 108 Thai patients with chronic idiopathic urticaria. Multicenter study of the efficacy and safety of fexofenadine 60 mg. twice daily in 108 Thai patients with chronic idiopathic urticaria. Fexofenadine is a non-sedating antihistamine indicated for relieving symptoms from allergic conditions with a rapid onset of action without cardiotoxic risks. Controlled studies showed that fexofenadine 180 mg daily provides significant relief of symptoms of chronic idiopathic urticaria (CIU). The purpose of this study was to demonstrate the efficacy and safety of fexofenadine 60 mg twice daily in Thai patients with CIU in a multicenter trial. Patients were assigned to receive twice daily doses of fexofenadine 60 mg for 6 weeks. Patients rated symptom severity every night, investigators rated patients' signs and symptoms at recruitment and at 1, 3 and 6 weeks. Ninety eight out of 108 patient (90.7%) completed the study. The patients reported 95 per cent improvement and, of those, 91 per cent had very favorable responses (excellent 15%, very good 42%, good 30%, fair 8%). The objective assessment by their physicians paralleled those responses. Fexofenadine provided a rapid clinical response that was significantly superior to before treatment in relieving symptoms of CIU (p < 0.001). Adverse events occurred in 20 cases (18.5%), mostly mild headache and drowsiness. Fexofenadine 60 mg twice daily provides effective relief of the symptoms of CIU with minimal adverse events. Journal ISSN: 0125-2208 Issue: 84-2 (2001) Pages: 153-9 Impact and modulation of nasal obstruction. Impact and modulation of nasal obstruction. Nasal obstruction, the leading symptom of allergic rhinitis, results from the combined activity of early- and late-phase allergic reactions. Desloratadine inhibits both early- and late-phase inflammatory mediators in vitro. Thus, double-blind, placebo-controlled, randomized, crossover trials were conducted to assess the efficacy of desloratadine against nasal obstruction, measured objectively and subjectively, during controlled exposure of patients with seasonal allergic rhinitis to allergen. Positive results were obtained in three single-dose studies; desloratadine 5 mg resulted in a greater improvement from baseline than did placebo in the total symptom score and the nasal obstruction symptom score (P Journal ISSN: 0105-4538 Issue: 57 Suppl 75- (2002) Pages: 25-8

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