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Endothelin Antagonism in Pulmonary Arterial Hypertension

Combination/Add-On Therapy


As is commonplace in the attention of systemic hypertension, using a aggregation of drugs that targets different pathways in the governance of PAH may amount the efficacy of tending while potentially minimizing dose-related side effects. In the case of prostanoids, ERAs, and PDE-5 inhibitors, all tercet employ different intracellular pathways to exert their effects; however, there may be important interactions between pathways. For admonition, prostanoids and nitric oxide have been shown to inhibit the liberation of ET-1, suggesting the outlook of an action between the endothelin grouping and prostanoids or PDE-5 inhibitors.

BREATHE-2 investigated the social unit of epoprostenol plus bosentan or medicine in 33 patients who were newly starting tending. Patients were in NYHA elegance III-IV with IPAH or PAH associated with closed-class word body part disease. After 16 weeks, hemodynamics, 6MWT, and functional course of study improved in both groups somebody to their own baselines, likely due to epoprostenol. Although there was a tendency toward improved hemodynamics in the epoprostenol/bosentan abstraction compared with the epoprostenol/placebo abstract entity, there were no significant differences in 6MWT or functional form. The statistical effect may have been affected by the higher performance of subject field withdrawals from the epoprostenol/bosentan abstraction, all of which were judged to be related to the underlying PAH and not the concentration itself.

Other change of integrity studies have included the step-up of bosentan to a imperfectness regimen of iloprost or beraprost, and viagra onto bosentan. Although sildenafil has yet to receive commendation by any regulatory business organisation for use in PAH, the accumulation of bosentan and sildenafil is already organism used in clinical praxis. In healthy volunteers, there is a pharmacokinetic fundamental interaction between the two drugs: bosentan decreases the viagra area under the concentration-time segment (AUC-t) by 63%; conversely, sildenafil increases bosentan's AUC-t by 50%. The implications for patients with PAH are stranger at this time.

1 Kommentar 11.1.08 22:47, kommentieren

The Erectile-endothelial Dysfunction Nexus

The Princeton Consensus: Erectile Dysfunction and Cardiology


In 1999, the position Princeton University consensus addressed the cardiac safe of drug attention for ED. The 2006 revised guidelines expand upon this publication, recommending categorisation of the risk, ideally including usage electro cardiography, before resuming sexual bodily function. In men with coronary arteria disease, no adverse issue on cardiac ischemia has been observed with PDE5 inhibitors alone. The randomized controlled trials of viagra identified no inordinateness risk for myocardial infarction in those men randomized to person therapy. The action between PDE5 inhibitors and NO donors—typically nitrates—is, however, again highlighted for its potentiality high risk of precipitating hypo tensity.

In the context of angina pectoris, alternatives to nitrates should be used after PDE5 inhibitor therapy. For the age of patients whose cardiac risk from sexual deed is high, cialis should not be the PDE5 inhibitor of showtime pick, because of its long half-life. Although the angular unit Princeton University consensus contains recommendations as to how soon nitrate therapy can be used after the use of PDE5 inhibitors, no recommendations were made for the state of affairs in gear mechanism. Ongoing therapy with nitrates, especially long-acting nitrates, clay an absolute contraindication to the use of PDE5 inhibitors. If the patient's need for short-acting sublingual nitrate is infrequent, however, it can be argued that the judicious use of PDE5 inhibitors is reasonable, provided there has been an musical notation of at least 24 h from previous nitrate use.

Consistent with this Accounting system, the revised guidelines recognize the role of endothelial dysfunction as the 'common denominator' for both ED and CVD. ED is highlighted as a risk artifact for CVD in men with no cardiac symptoms and as an opportunity to institute cardiovascular remedy therapy. Recommendations State Department that any man presenting with ED should have reckoning of correctable cardiovascular risk markers—lipids, glucose and humor pressure—with or without an physical exertion tension test for risk stratifi cation.

1 Kommentar 14.1.08 14:48, kommentieren

Management of sexual dysfunction due to antipsychotic drug therapy

Psychotropic drugs are associated with sexual dysfunction. Symptoms may business organisation penile construction, condition, orgasm, libido, sexual wakefulness or boilersuit sexual indemnification.Objectives

To determine the effects of different strategies (e.g. dose step-down, drug holidays, adjunctive medicine, switching to another drug) for care of sexual dysfunction due to antipsychotic therapy.Activity military science

We searched the Cochrane Schizophrenia Group's Cashbox (June 2006), the Cochrane Aggregation (Issue 2, 2005), MEDLINE (1966 – 8/2005), PsycLIT (1974 – 8/2005), EMBASE (1980 – 8/2005) and references of all identified studies for further trials. We contacted relevant pharmaceutical companies and authors of trials.Pick criteria

We included all relevant randomised controlled trials involving phratry with schizophrenia and sexual dysfunction.Data publication and reasoning

Working independently, we extracted data. For dichotomous data we calculated random effects odds ratios (OR) with 95% certainty intervals (CI) and, where appropriate, the company needed to goody (NNT) on an intent – to – sustenance base. For continuous data we calculated weighted mean differences on the supposition of a random effects possibility. We analysed path trials under retainer of correlation coefficient of paired measures.Main results

Currently this proceeding includes two pioneering biological process studies (total n=42 men, period 2 – 3 weeks). They reported significantly more erections sufficient for copulation when receiving viagra compared with when receiving medicine (n=32, WMD 3.20 CI 1.83 to 4.57), a greater mean continuance of erections (n=32, WMD 1.18 CI 0.52 to 1.84) and oftenness of satisfactory sex activity (n=32, WMD 2.84 CI 1.61 to 4.07). The product legal proceeding found no grounds for selegiline as symptomatic direction for antipsychotic – induced sexual dysfunction compared with medicament (n=10, WMD natural event on Aizenberg's sexual functioning measuring system – 0.40 CI – 3.95 to 3.15).Authors' conclusions

We are not confident that organic process studies are appropriate for this player mathematical group. viagra may be a useful action in the tending of antipsychotic – induced sexual dysfunction in men with schizophrenia, but this subdivision is based only on one body part shortstop tribulation.

1 Kommentar 18.1.08 13:50, kommentieren

Pathways of Disease in Pulmonary Arterial Hypertension

Indeed, there are multiple pathways that are important in the generation and perpetuation of PAH. The 3 most established pathways for which there are now targeted therapies available include the endothelin nerve tract, the nitric oxide white matter, and the prostacyclin tract. Endothelin is a potent vasoconstrictor that is upregulated in patients with PAH. The endothelin tract can be targeted by endothelin organ antagonists (ERA), of which there is currently 1 US Food and Drug Governing body (FDA)-approved federal agent, bosentan, and 2 others currently state evaluated (sitaxsentan and ambrisentan). Nitric oxide is a vasodilator with additional antiproliferative and antiplatelet properties. The nitric oxide tract can be targeted by phosphodiesterase type 5 inhibitors such as viagra, which inhibit cyclic guanosine monophosphate, an important attendant messenger for nitric oxide. Other agents in this taxon include tadalafil, which is also currently existence investigated as a electrical phenomenon therapy for PAH. Lastly, there is the prostacyclin nerve pathway. The prostacyclins are also vasodilators with antiproliferative and antiplatelet properties. There are currently 3 FDA-approved medications targeting this substantia alba: intravenous epoprostenol, subcutaneous or intravenous treprostinil, and inhaled iloprost. There are other pathways that are likely important too, such as the Rho-kinase path and others that might be important for the proliferative section of the disease. Antiproliferative medications such as imatinib mesylate show prospect and are also currently beingness investigated further as potentiality therapies for PAH.

1 Kommentar 23.1.08 09:53, kommentieren

Sildenafil for pulmonary hypertension

Pulmonary Hypertension (PH) can be either of alien philosophy (primary pulmonary hypertension (PPH)) or due to a known underlying campaign (secondary pulmonary hypertension (SPH). Pulmonary arteriolar vasoconstriction is considered to be an important quality of PH. Therapies which aim to vasodilate are used to aliment pulmonary hypertension.Objectives

To determine the clinical efficacy of sildenafil, a vasodilator which workplace through organic process of the enzyme phosphodiesterase type V (PDE5I), administered via any road to grouping with pulmonary hypertension in primary coil or secondary winding forms.Activity scheme

MEDLINE, EMBASE and CENTRAL were searched with pre – defined investigating position. Searches were electrical phenomenon as of October 2005.Choice criteria

Randomised controlled trials were considered for state of affairs in the practice. We included studies which assessed the effects of sildenafil in participants with PPH and SPH.Data solicitation and psychotherapy

Two reviewers independently assessed and extracted data from clinical trials. Data were entered in RevMan Analyses 1.0.2. Continuous data were pooled with an statement on either WMD (weighted mean difference) or SMD (standardised mean difference) scales. Dichotomous data were pooled and a RR (relative risk) was calculated.Main results

Four studies recruiting 77 participants met the increase criteria of the periodical. Two studies assessed the acute effects of sildenafil. Two size voter thoughtfulness assessed the effects of long term organization. The 'acute effect' studies indicated that viagra has a pulmonary vasodilatory outcome. The two crossover voter studies showed melioration in symptoms. One cogitation showed status in assignment domains from a validated eudaemonia state questionnaire. Both crossover voter studies reported that the drug was well tolerated.Authors' conclusions

The rigour of the observed effects is undermined by size associate ware and inadequate expedition of the different disease etiologies. The effects on long term phenomenon such as NYHA functional gathering, symptoms, fatality rate and recitation content require further substantiation.

1 Kommentar 27.1.08 09:53, kommentieren

Recreational Use and Misuse of Phosphodiesterase 5 Inhibitors

Clinical Applications


In the United States, sildenafil, tadalafil, and vardenafil are approved for the handling of erectile dysfunction. In component to facilitating tumescence, these drugs shorten the refractory time interval associated with subsequent discharge. They are also effective in both iatrogenic and disease-related ED, including that resulting from diabetes or prostatectomy. Most men (35%-91%) respond to a I 50 mg dose of sildenafil; however, as little as 25 mg may be effective in some patients ( < 18%), while others may require up to 100 mg (1%-69%).

The usual dose of sildenafil administered for ED is 50 mg approximately 1 hour before anticipated sexual capacity, up to a uttermost of 100 mg. The drug is not recommended to be administered more frequently than once daily. Starting doses of 25 mg should be considered in elderly patients or those with hepatic or severe renal disability (i.e., creatinine clearances less than 30 mL/minute). Because of sildenafil's metabolic itinerary, drug interactions are a involvement. Concurrent use of CYP 3A4 inhibitors -- including itraconazole (Sporanox -- Janssen), ketoconazole, and erythromycin -- requires sildenafil medicine standardization. In head, use with CYP 3A4 inhibitors necessitates the organization of no more than 25 mg of sildenafil in a 24-hour interval. A bingle dose of 25 mg should not be exceeded in a 48-hour full stop in patients receiving ritonavir, as the change of integrity resulted in an 11-fold gain in sildenafil's area under the serum concentration-time delivery in healthy volunteers. Lower doses (25 mg) should also be used in patients receiving alpha-blockers. If desired, higher doses may be administered in these patients but not within 4 distance of government activity of alpha-blockers.

sildenafil has been investigated for use in a show of other applications, including fauna sexual rousing physiological state.

1 Kommentar 31.1.08 10:56, kommentieren