Cardioselective Beta Blocker Use in Patients With Asthma

Beta-Adrenergic Blockade

The ß blocker propranolol was introduced in the early 1960s and was shown to be effective in the treatment of angina pectoris, hypertension, cardiac arrhythmias, and thyrotoxicosis.[8,9] Beta blockers were also shown to improve survival for patients after myocardial infarction, even for those with decreased left ventricular function. When the beneficial effects of ß-blocker therapy in patients with congestive heart failure were demonstrated more than two decades ago, such an approach was deemed counterintuitive due to the intrinsic negative inotropic effect of these agents.[10] Over the years convincing evidence of a substantial mortality benefit has been demonstrated so that ß-blocker therapy, once considered heretical, is now the standard of care for the treatment of patients with congestive heart failure. Table I summarizes the mortality benefits that have been found with ß blockers.

Currently there are many different ß blockers available with different pharmacologic properties (Table II). Cardioselective ß blockers, or ß-1 blockers, have more than 20 times more affinity for ß-1 receptors than for ß-2 receptors, whereas nonselective ß blockers have equal affinity for both receptors.[1] Intrinsic sympathomimetic activity is present to varying degrees in some ß blockers, which may result in an attenuation of their ß-blocking effects. Other ß blockers are known to have additional properties, such as a-receptor blockade or vasodilatation.

When the nonselective ß blocker propranolol was first introduced, it was used in doses as high as 240-1600 mg/d and was generally well tolerated with acute and chronic use.[8] However, occasional adverse effects were reported, including bronchospasm, heart failure, fatigue, hypoglycemia, intermittent claudication, decreased libido, and depression.[8,11] The standard lists of contraindications to ß blockers we have today are based on these early case reports that were seen with high doses of nonselective ß blockers. Because of the proven mortality benefit of ß blockers, many of the relative or absolute contraindications traditionally listed for ß blockers, including impaired left ventricular function, peripheral vascular disease, diabetes mellitus, depression, impotence, and advanced age, have been questioned and disproved.[10,12-15]

Previous PageSection 3 of 5Cardiovasc Rev Rep 24(11):564-572, 2003. © 2003 Le Jacq Communications, Inc.
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Pulmonary Arterial Hypertension, November 2005

Susan Steinbis, RN, ACNP The Pulmonary Hypertension Journal Scan is the clinician's guide to the latest clinical research findings from JAMA, The New England Journal of Medicine, CHEST, and other journals of interest. Short summaries of feature articles include links to the article abstracts when available. (Access to full-text articles usually requires registration at the specific journal's Web site.)

FromHeart  ( Volume 91, Number 11 )

Effect of the Oral Endothelin Antagonist Bosentan on the Clinical, Exercise, and Haemodynamic Status of Patients With Pulmonary Arterial Hypertension Related to Congenital Heart DiseaseApostolopoulou SC, Manginas A, Cokkinos DV, Rammos S 
Heart.  2005;91(11):1447-1452

Congenital heart disease (CHD) with Eisenmenger's physiology is a condition that can cause pulmonary arterial hypertension (PAH). PAH is a progressive disease that, if left untreated, leads to early mortality. It is characterized by changes in the pulmonary vasculature that eventually lead to strain on the right ventricle, right ventricular failure, and, ultimately, death. Endothelin, a potent vasoconstrictor, is responsible for these changes.[1] Increased endothelin concentrations have been found in the pulmonary vasculature and actually correlate with disease severity.[2]

Bosentan is the only oral nonselective endothelin receptor antagonist (ERA) available for the treatment of PAH. Efficacy of this drug in the treatment of PAH has been shown in clinical trials.[3,4] Studies have shown benefit with regard to exercise tolerance, hemodynamic function, and improved oxygenation.

In this study, Apostolopoulou and colleagues set out to show the effects of bosentan on patients with PAH secondary to CHD. Twenty-one patients, World Health Organization (WHO) functional class II-IV, with PAH secondary to CHD (either repaired or uncorrected defects) and a fixed pulmonary vascular resistance (PVR) participated in this study. No treatment changes were allowed 1 month before entry or during the trial other than the addition of bosentan. Patients were not on therapy with epoprostenol in this study. The clinical trial was an open-label, noncontrolled study. Complete hemodynamic studies were done before enrollment and at 16 weeks of therapy, with baseline mean pulmonary artery pressures (mPAP) of approximately 92 mm Hg and median PVR index of 2048. WHO functional class was also evaluated at that time. Twelve patients were WHO functional class III, 5 (age < 12 years old) were class II, and the rest were functional class IV. Seventy-one percent of the patients had resting saturations of < 95%.

After 16 weeks of therapy, 13 of the 21 patients had shown improvement by 1 functional class. Also demonstrated was an increase in peak oxygen consumption and exercise capacity with a 42-m increase in distance on 6-minute walk test. Increased saturations before completion of exercise were also noted in the cyanotic group, from 64% to 69%. Improvement in hemodynamics such as PVR index, mean right atrial pressure, and pulmonary to systemic blood flow ratio was noted. Two patients died during the study from suspected arrhythmias but had noted improvement in 6-minute walk distance before death as well as improvement in WHO functional class. At 1.3 years post study, the remaining patients were still on therapy and stable.ReferencesWort SJ, Woods M, Warner TD, et al. Endogenously released endothelin-1 from human pulmonary artery smooth muscle promotes cellular proliferation: relevance to pathogenesis of pulmonary hypertension and vascular remodeling. Am J Respir Cell Mol Biol. 2001;25:104-110.Allen SW, Chatfield BA, Koppenhafer SA, et al. Circulating immunoreactive endothelin-1 in children with pulmonary hypertension: association with acute hypoxic pulmonary vasoreactivity. Am Rev Respir Dis. 1993;148:519-522.Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomized placebo-controlled study. Lancet. 2001;358:1119-1123.Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896-903.

Abstract

Supported by an independent educational grant from Actelion.

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FDA Safety Changes: Aptivus

FDA Safety Changes: Aptivus  CME

News Author: Yael Waknine
CME Author: Yael Waknine
DisclosuresRelease Date: February 13, 2008; Valid for credit through February 13, 2009 Credits AvailablePhysicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™ for physicians;
Family Physicians - up to 0.25 AAFP Prescribed credit(s) for physicians

To participate in this internet activity: (1) review the target audience, learning objectives, and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation; (4) view/print certificate View details.
Learning Objectives

Upon completion of this activity, participants will be able to:Describe the appropriate management of ritonavir-boosted tipranavir therapy in patients with asymptomatic elevations in aspartate aminotransferase or alanine aminotransferase levels.Identify agents that are contraindicated in patients receiving ritonavir-boosted tipranavir therapy.Explain the risks associated with concomitant use of certain medications and ritonavir-boosted tipranavir.Authors and Disclosures

Yael Waknine
Disclosure: Yael Waknine has disclosed no relevant financial relationships.

Laurie Barclay, MD
Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

Brande Nicole Martin
Disclosure: Brande Nicole Martin has disclosed no relevant financial information.

This activity is part of an ongoing CME/CE initiative to provide information on labeling changes reported by the FDA. Activities of this nature will be posted on Medscape on a weekly basis.

February 13, 2008 — On October 4, 2007, the US Food and Drug Administration (FDA) granted full approval for tipranavir (TPV) capsules (Aptivus; Boehringer Ingelheim Pharmaceuticals, Inc) based on 48-week data from ongoing phase 3 clinical trials (Randomized Evaluation of Strategic Intervention in Multi-Drug ReSistant Patients with Tipranavir-1 and -2; n = 1483).

Previously, the FDA had granted accelerated approval for tipranavir based on 24-week study data, allowing its use with ritonavir (TPV/r) as antiretroviral therapy for treatment-experienced adults infected with HIV-1 strains resistant to 1 or more protease inhibitors.

The approval was accompanied by safety labeling changes that reflect updated information regarding adverse events and drug interactions.

Ritonavir-Boosted Tipranavir (Aptivus) Linked to Risks for Hepatotoxicity and Rash

Previously, the FDA warned healthcare professionals regarding cases of hepatitis and hepatic decompensation, some with fatal outcomes, in patients receiving TPV/r therapy. Although a causal role for TPV/r could not be established, all patients should be closely observed with clinical and laboratory monitoring; liver function tests should be performed at baseline and frequently during treatment.

According to the new guidelines, TPV/r should be discontinued in patients who develop asymptomatic elevations in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels of more than 10 times the upper limit of normal (ULN) or asymptomatic elevations between 5 and 10 times the ULN in conjunction with increases in total bilirubin of more than 2.5 times the ULN.

Treatment-experienced patients with chronic hepatitis B or hepatitis C coinfection or elevated transaminases are at approximately 2-fold risk of developing severe (grade 3/4) transaminase elevations or hepatic decompensation.

Rash (including urticarial and maculopapular rash and possible photosensitivity) has also been reported in subjects receiving TPV/r. In some cases, the rash was accompanied by joint pain or stiffness, throat tightness, or generalized pruritus.

New 48-week data have revealed that the incidence of rash (all grades, all causality) was 10% and 8% for women and men, respectively (discontinuation rate, 0.5%); median time to onset was 53 days and median duration, 22 days. In an uncontrolled compassionate–use program, some cases of rash were accompanied by myalgia, fever, erythema, and desquamation, and mucosal erosions were reported. TPV/r should be discontinued and appropriate therapy initiated in patients who develop a severe skin rash.

Rifampin and Other Drugs Contraindicated With Ritonavir-Boosted Tipranavir (Aptivus)

Coadministration of TPV/r with drugs that are highly dependent on cytochrome P450 isoenzyme 3A (CYP3A) for clearance or are potent CYP3A inhibitors is contraindicated.

Rifampin, St. John's wort, and the 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors lovastatin and simvastatin have been added to the list of drugs in the contraindications section of the tipranavir safety label.

Concomitant use of rifampin or St. John's wort with TPV/r may lead to loss of virologic response and possible resistance to TVP or protease inhibitors as a class; rifampin may also cause resistance to other coadministered antiretroviral agents. Use of lovastatin or simvastatin is linked to a risk for myopathy, including rhabdomyolosis.

Other contraindicated drugs previously listed in this section include the antiarrhythmics amiodarone, bepridil, flecainide, propafenone, and quinidine; the ergot derivatives dihydroergotamine, ergonavine, ergotamine, and methylergonavine; the promotility agent cisapride; the neuroleptic pimozide; and the sedative/hypnotics midazolam and triazolam.

Warnings Issued Regarding Concomitant Use of Ritonavir-Boosted Tipranavir (Aptivus) With Other Drugs

The FDA has advised caution when prescribing carbamazepine, phenobarbital, or phenytoin because of decreased TPV plasma concentrations and efficacy.

Caution is likewise advised when using valproic acid with TPV because of decreased valproic acid concentrations and efficacy. Concomitant use of TPV/r may also decrease omeprazole concentrations, requiring increased dosages.

Because TPV/r increases plasma levels of atorvastatin and rosuvastatin and therefore the risk for myopathy, the lowest possible dose should be used with careful monitoring; consideration should be given to use of the other HMG-CoA reductase inhibitors pravastatin or fluvastatin.

The FDA also warned that TPV/r increases plasma concentrations of phosphodiesterase type 5 inhibitors, potentially increasing the risk for adverse events such as hypotension, visual changes, and priapism. Starting doses should not exceed 25 mg within 48 hours for sildenafil citrate, 2.5 mg every 72 hours for vardenafil HCl, and 10 mg every 72 hours for tadalafil.

http://www.fda.gov/medwatch/safety/2007/Oct_PI/Aptivus_PI.pdf

http://www.fda.gov/cder/foi/label/2006/021814s001s002lbl.pdf

Pearls for Practice

TPV/r should be discontinued in patients who develop asymptomatic AST or ALT elevations of more than 10 times the ULN, or between 5 to 10 times the ULN accompanied by increases in total bilirubin of more than 2.5 times the ULN. Patients with chronic hepatitis B or C coinfection have an approximately 2-fold risk of developing severe transaminase elevations or hepatic decompensation.Rifampin, St. John's wort, lovastatin, and simvastatin are contraindicated in patients receiving TPV/r therapy.Caution is advised when prescribing carbamazepine, phenobarbital, phenytoin, valproic acid, atorvastatin, rosuvastatin, sildenafil citrate, vardenafil HCl, and tadalafil with TPV/r therapy.

CME/CE Test

Questions answered incorrectly will be highlighted.

Which of the following statements is not correct regarding the use of TPV/r in treatment-experienced adult patients?Discontinuation of therapy is indicated for asymptomatic ALT elevation of 8 times the ULN without changes in total bilirubinTreatment should be discontinued for asymptomatic AST elevation of 12 times the ULNPatients with hepatitis B or C coinfection are at increased risk for hepatotoxicityTreatment should be stopped if AST is 6 times the ULN and total bilirubin level is more than 2.5 times the ULN

Which of the following statements is correct regarding concomitant medication use in patients receiving TPV/r therapy?Concomitant use of herbal remedies such as St. John's wort is acceptable in moderationIncreases in lovastatin dose may be required for patients receiving TPV/r therapySimvastatin dosing should be reduced because of the risk for myopathy or rhabdomyolosisPatients receiving rifampin may experience loss of virologic response to other protease inhibitors

Which of the following statements is not correct regarding drug interactions with TPV/r therapy?TPV can decrease valproic acid plasma concentrations and efficacyCarbamazepine can decrease TVP plasma concentrations and efficacyAtorvastatin or simvastatin should be considered in lieu of fluvastatin therapyThe starting dose for sildenafil citrate should not exceed 25 mg every 48 hours

Medscape Medical News 2008. ©2008 Medscape

Legal Disclaimer The material presented here does not necessarily reflect the views of Medscape or companies that support educational programming on www.medscape.com. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.
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FDA Approves One Endothelin Antagonist for PAH, Nixes Another

FDA Approves One Endothelin Antagonist for PAH, Nixes Another  CME

News Author: Steve Stiles
CME Author: Yael Waknine
DisclosuresRelease Date: July 6, 2007; Valid for credit through July 6, 2008 Credits AvailablePhysicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™ for physicians;
Family Physicians - up to 0.25 AAFP Prescribed credit(s) for physicians

The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

July 6, 2007 — The US Food and Drug Administration (FDA) has given the thumbs-up to one endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH) and a provisional thumbs-down to another.

Ambrisentan (Letairis, Gilead Sciences) was approved on the strength of two phase 3 trials that suggested it significantly improves six-minute-walk test results and delays worsening of PAH, the agency announced on June 15, 2007.

On the same day, Encysive Pharmaceuticals, the maker of another drug in the same class, sitaxsentan (Thelin) announced that the FDA has for the third time rejected its application to market the drug for the same indication. But the FDA signaled its willingness to consider the results of an additional study designed to show whether the drug could improve exercise capacity, according to the company.

Ambrisentan is classified as an orphan drug, which has qualified Gilead Sciences for tax credits and marketing incentives, the FDA notes. The drug joins several other available treatments for PAH, including bosentan (Tracleer, Actelion Pharmaceuticals), another endothelin antagonist, and sildenafil (Revatio, Pfizer), the phosphodiesterase inhibitor famously available, in different packaging, for the treatment of erectile dysfunction (Viagra, Pfizer).

In its own statement, Gilead Sciences notes that ambrisentan's approval is for patients with PAH who are in World Health Organization (WHO) symptom class 2 or 3. Bosentan is indicated for patients with somewhat more severe disease, WHO class 3 or 4. The company claims that its drug may be preferable to bosentan for patients who have experienced transient, asymptomatic liver enzyme elevations on bosentan, citing supporting evidence from an uncontrolled, 36-patient open-label study.

In its story on the ambrisentan approval, the New York Times notes that the "once-a-day pill will cost $3940 a month, about the same as Tracleer." Gilead Sciences, notes Times medical reporter Andrew Pollack, said it is "establishing programs to help uninsured or underinsured patients obtain the drug."

Encysive Pharmaceuticals. FDA issues third approvable letter for Thelin (sitaxsentan sodium) [press release]. June 15, 2007. Available at: http://www.encysive.com/news_20070615.html.

Gilead Sciences. US Food and Drug Administration approves Gilead's Letairis, (ambrisentan) 5 mg and 10 mg tablets for the once-daily treatment of pulmonary arterial hypertension (WHO Group 1) in patients with WHO functional class II or III symptoms [press release]. June 15, 2007. Available at: http://www.gilead.com/wt/sec/pr_1016053.

Pollack A. Gilead's drug is approved to treat a rare disease. New York Times, June 16, 2007. Available at: http://www.nytimes.com/2007/06/16/business/16gilead.html?_r=1&ref=health&oref=slogin.

http://www.fda.gov/cder/foi/label/2007/022081s000lbl.pdf

The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

Study Highlights

Ambrisentan tablets 5- and 10-mg have been approved for the treatment of PAH (WHO group 1) in patients with WHO class 2 or 3 symptoms to improve exercise capacity and delay clinical worsening.Treatment should be initiated at 5 mg once daily with/without food; uptitration to 10-mg dose should be considered as tolerated.Approval was based on data from two 12-week, double-blind, placebo-controlled, phase 3 clinical trials (ARIES-1 and ARIES-2; n = 393) showing treatment with ambrisentan significantly increased exercise capacity, as evaluated by changes in walk distance relative to baseline.ARIES-1 study results revealed placebo-adjusted mean and median changes from baseline of 31 and 27 m, respectively, for 5-mg dose (P = .008); corresponding changes for 10-mg dose were 51 and 39 m (P < .001).In ARIES-2, placebo-adjusted mean and median changes from baseline of 59 and 45 m were observed for 5-mg dose (P < .001).Treatment with ambrisentan also significantly delayed time to clinical worsening of PAH, as defined by first occurrence of death, lung transplantation, hospitalization for PAH, atrial septostomy, study withdrawal resulting from addition of other PAH therapeutic agents, or study withdrawal resulting from progressive disease.Data from long-term follow-up of ARIES ambrisentan-treated patients and an open-label extension study (n = 383) showed 95% of subjects were still alive at 1 year and 94% continued using ambrisentan monotherapy. FDA notes these uncontrolled observations do not allow comparison with patients receiving placebo and cannot be used to determine drug's long-term effect.Most commonly reported adverse events in patients receiving 2.5-, 5-, or 10-mg doses of ambrisentan vs placebo in ARIES-1 and -2 included peripheral edema (17% vs 11%), nasal congestion (6% vs 2%), sinusitis (3% vs 0%), flushing (4% vs 1%), and palpitations (5% vs 2%). Most adverse drug reactions were mild to moderate, and only nasal congestion was dose dependent.The FDA warned ambrisentan can cause elevation of liver aminotransferase levels to at least 3 times the upper limit of normal. Observed incidence was 0.8% in the 12-week trials and 2.8% in long-term open-label studies. Because these changes may indicate potentially serious liver injury, serum aminotransferase levels (and bilirubin, if aminotransferase levels are elevated) should be measured prior to treatment initiation and monthly thereafter.However, findings from an uncontrolled open-label study of 36 patients who had previously discontinued using endothelin receptor antagonists because of aminotransferase level elevations 3 times the upper limit of normal or greater suggest ambrisentan therapy may be option for patients who have had asymptomatic aminotransferase level elevations while taking other endothelin receptor antagonists after aminotransferase levels have returned to normal.Results showed at a median follow-up period of 13 months with 50% of patients receiving 10 mg/day of ambrisentan that no patients discontinued use because of aminotransferase level elevations. Most common adverse events observed were peripheral edema, headache, dyspnea, and flushing.Caution is advised with coadministration of cyclosporine A because of risk for increased ambrisentan exposure; similar care should be taken when considering concomitant therapy with strong cytochrome P 450 isoenzyme 3A and 2C19 (CYP3A and CYP2C19) inhibitors.Monthly pregnancy tests are required for women of childbearing age.Because of risks for liver injury and birth defects (pregnancy category X), ambrisentan is available only via a special restricted distribution program.

Pearls for Practice

The FDA has approved 5- and 10-mg ambrisentan tablets for the treatment of PAH (WHO group 1) in patients with WHO class 2 or 3 symptoms to improve exercise capacity and delay clinical worsening.Treatment should be initiated at a dosage of 5-mg once daily with/without food; uptitration to a 10-mg dose should be considered as tolerated.

1. Which of the following statements is not correct regarding the potential benefits of ambrisentan therapy in patients with PAH (WHO group 1) and WHO class 2 or 3 symptoms?  (Required for credit)  Ambrisentan can delay the time to clinical worsening of PAH The 20-mg dose is more effective vs the 10-mg dose for improving exercise capacity In a long-term, open-label, follow-up study, 95% of patients were alive at 1 year Ambrisentan significantly increased exercise capacity

2. Which of the following statements is correct regarding the appropriate use of ambrisentan for the treatment of PAH?  (Required for credit)  Treatment should be initiated with 5 mg of ambrisentan twice daily The risk for peripheral edema is dose dependent Monthly pregnancy tests are required for most women of childbearing age Serum aminotransferase levels should be measured every 6 weeks

Medscape Medical News 2007. ©2007 Medscape

Legal Disclaimer The material presented here does not necessarily reflect the views of Medscape or companies that support educational programming on www.medscape.com. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.
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Diagnosing Pulmonary Artery Hypertension in a Woman With Systemic Sclerosis

Summary and the Case

Summary

Background: A 42-year-old woman with limited cutaneous systemic sclerosis presented with rapid-onset dyspnea on exertion, which had developed over the previous 8 weeks. She had not experienced any dyspnea before this period. Transthoracic Doppler echocardiography performed 6 months before presentation demonstrated an estimated right ventricular systolic pressure of 32 mmHg. Lung function tests also performed at that time revealed a decreased diffusion capacity for carbon monoxide of 54% and normal lung volumes, and high-resolution CT scan of the lungs was normal.
Investigations: Physical investigation, CBC, analysis of C-reactive protein and pro-brain natriuretic peptide, transthoracic Doppler echocardiography, six-minute walk test, lung function tests including diffusion capacity for carbon monoxide, right heart catheter, high-resolution CT scan, and ventilation/perfusion scan.
Diagnosis: Pulmonary arterial hypertension associated with limited cutaneous systemic sclerosis.
Management: Treatment with oral anticoagulation therapy and the endothelin-receptor antagonist bosentan. Monitoring of adverse effects of bosentan therapy was performed using liver function tests.The Case

A 42-year-old woman was diagnosed with limited cutaneous systemic sclerosis (SSc) three years ago. At the time of diagnosis, she had suffered from Raynaud's phenomenon for six years and recurrent finger-tip ulcers during the last two winter seasons. The patient reported having no other problems, including no dyspnea on exertion. Physical examination demonstrated two small inactive ulcers at the tips of the third and fourth fingers of the left hand, acrosclerosis with a total modified Rodnan skin score of nine, and telangiectasias on the face. Physical examination did not reveal any other pathological findings. Nailfold capillaroscopy demonstrated a reduced capillary density with dilated and giant capillaries, two microhemorrhages and a few avascular areas highly suggestive of SSc. Lung function tests revealed normal lung volumes and a predicted diffusing capacity for carbon monoxide (DLCO) of 54%. High-resolution CT (HRCT) scanning of the lungs did not demonstrate pathologic findings. The right ventricular systolic pressure (RVSP), as estimated by transthoracic Doppler echocardiography (TTE) was 32 mmHg. Laboratory tests showed an antinuclear antibody titer of 1:10000 and presence of anticentromere antibodies, but not anti-topoisomerase I antibodies or other extractable nuclear antigens. Serum level of N-terminal pro-B-type natriuretic peptide (pro-BNP), which was measured at baseline for comparison at later follow-ups, was within normal limits. The patient was prescribed nifedipine and paraffin baths, and advised to avoid exposure to cold.

The patient responded well to this symptomatic treatment. The intensity and frequency of her Raynaud's attacks decreased considerably and she did not develop digital ulcers during the following years. At the first two annual follow-ups no evidence of progression of SSc was observed. The patient's modified Rodnan skin score remained unchanged, lung function tests demonstrated normal lung volumes, and her DLCO was stable. The TTE-estimated RVSPs were 28–33 mmHg, and chest X-rays were normal.

At the third, and most recent, annual follow-up the patient reported experiencing shortness of breath when climbing stairs. She first noted these symptoms eight weeks before the follow-up appointment and dyspnea had progressed since then. She was otherwise well and had noticed no other physical changes. On physical examination, a slightly accentuated pulmonary component of the second heart sound was noticed, but no murmurs were audible. Lung sounds were normal. No peripheral edema, ascites, hepatomegaly, or jugular vein distension were detectable. The patient's body temperature and CBC were within normal ranges, and her C-reactive protein level was not elevated. TTE was performed and revealed an estimated RVSP of 41 mmHg without evidence of left heart disease. Lung function tests demonstrated a further decrease of the DLCO from 54% to 43%, whereas lung volumes remained normal. In addition, pro-BNP level was found to be elevated to threefold higher than normal values. Right heart catheterization was used to confirm the suspected diagnosis of pulmonary arterial hypertension (PAH). The resting mean pulmonary arterial pressure in this patient was 36 mmHg, with a normal pulmonary wedge pressure of 8 mmHg, an increased pulmonary vascular resistance of 509 dynes/sec/cm5, and a cardiac index of 2.2 l/min/m2. After confirming the diagnosis of PAH by using right heart catheterization, interstitial lung disease and thromboembolic disease were excluded by HRCT and ventilation/perfusion scans. The patient was, therefore, classified as having PAH associated with limited cutaneous SSc. A six-minute walk test was performed with a result of 460 meters and a Borg dyspnea index of 3.

The patient's dyspnea progressed rapidly, with symptoms occurring after slight to moderate exercise, and her PAH was classified as New York Heart Association (NYHA) functional class III. Therapy with oral anticoagulation (phenprocoumon, prothrombin time target international normalized ratio 2.0–3.0) and the oral endothelin A and B receptor antagonist bosentan (62.5 mg twice daily for four weeks, followed by a maintenance dose of 125 mg twice daily) was initiated for the treatment of PAH. The patient responded well to the treatment, with an improvement to NYHA class II after four weeks and an increase in the six-minute walking distance from 460 to 520 meters. In addition, pro-BNP levels dropped to within 1.5 fold of the upper normal range. Bosentan therapy was well tolerated and liver function tests remained normal.  Printer- Friendly Email This

Nat Clin Pract Rheumatol.  2008;4(3):160-164.  ©2008 Nature Publishing Group
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HIV and HCV Intervention

Applications to HCV-Seropositive IDUs

HCV incidence among IDUs is consistently higher relative to that of HIV, due at least in part to its greater transmissibility; it is ten times more infectious than HIV when spread through the parenteral route (Gerberding, 1995). Worldwide, HCV prevalence among IDUs can be as high as 90 percent (Hagan and Des Jarlais, 2000), whereas HCV incidence ranges between 13 and 22 per 100 person-years (Crofts et al., 1997; Garfein et al., 1998; van Beek et al., 1998) and is highest among the susceptible pool of young IDUs. Furthermore, 20-30% of IDUs in the United States are co-infected with HIV and HCV, which can complicate the treatment of both infections. HIV infection can hasten the progression of HCV disease although it remains controversial whether or not the reverse is true (Thomas et al., 2000).

HCV infection can result in serious liver disease including cirrhosis and hepatocellular carcinoma. Approximately 80-85% of HCV infections result in a chronic carrier state where patients are infectious and capable of transmitting the virus to others (Alter et al., 1999). In some settings, morbidity and mortality attributable to HCV infections among IDUs could exceed that for HIV, since both infections are highly prevalent among drug users (Hagan and Des Jarlais, 2000). Since HCV is often acquired before HIV among IDU populations, interventions that effectively reduce high risk transmission behaviors among HCV-infected IDUs could also have a significant impact on HIV prevention (Garfein et al., 1996).

In comparison to HIV, there is limited awareness of HCV among drug users, as evidenced by the coverage of voluntary testing and counseling for both infections. In a recent study of ten publicly funded methadone maintenance treatment programs in Baltimore, MD, approximately 20% of IDUs tested HIV-seropositive, 80% of whom were aware of their infection and had sought care. On the other hand, 91% of these IDUs tested HCV-positive but three quarters had not previously been tested and were thus unaware of their infection and had not sought treatment (Loughlin et al., 2004). Clearly, IDUs will require improved HCV counseling and testing strategies as well as accessible and affordable HCV medical care.

The benefits of integrating treatment for substance abuse and HIV infection discussed above can be extended to the treatment of HCV infection. In San Francisco, Sylvestre found that HCV therapy (i.e., alpha interferon) offered in conjunction with methadone maintenance therapy was feasible, and had promising short-term outcomes (Sylvestre, 2002; Sylvestre et al., 2004). There is growing realization that patients with co-occurring HCV infection, substance use, and psychiatric illness can complete interferon treatment with careful monitoring and aggressive intervention although few programs are designed to manage these co-occurring conditions.

Although few empirical studies have evaluated interventions focused on HCV-seropositive IDUs, one such multicenter study is underway. Referred to as the Study to Reduce Intravenous Exposures (STRIVE), this study uses a peer-mentor approach to reduce injection related risk behaviors (e.g., distributive needle sharing) and facilitate access to HCV care. Even in the absence of proven behavioral interventions to reduce transmission behaviors among HCV-seropositive IDUs, important prevention messages should be shared with these patients. Regardless of the route of their infection, HCV-seropositive IDUs should be counseled to abstain or at least reduce their alcohol use, since alcohol can accelerate progression to HCV-related liver disease (Thomas et al., 2000). Additionally, these patients should be offered vaccines for both Hepatitis A and B, since these infections can further compromise the liver.  Printer- Friendly Email This

AIDS Behav.  2006;10(2):115-130.  ©2006 Springer
Springer Science+Business Media
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Sexual Dysfunction after Pelvic Surgery

Origination of sildenafil citrate and the other subsequent PDE-5 has revolutionized the aid of ED after RP and have become the rank care options after RP.
PDE-5 inhibitors gain the cGMP gathering in the cavernosal sinew and produce smooth yobbo tranquility.
Due to the early termination of sildenafil in 1998, this drug has been extensively investigated in our prostatectomy whole number.

Researchers at Urban center Medical building have been among the front-runners to investigate the role of viagra in RP group.
In our earlier mental object, we found that 52% (48/91) of post-RP patients responded to viagra.
Patients who underwent bilateral nerve-sparing operation have a goodness speech act than patients who underwent unilateral or non-nerve-sparing OR. In a 3-year follow-up subject area, we re-evaluated the 43/48 patients who returned the questionnaire.
Of 43 patients, 31 (72%) are hush continuing to use viagra.
This subject area indicated that most patients who initially responded to sildenafil continued to use the drug on a long-term assumption.

We also evaluated the factors affecting the efficacy of sildenafil citrate, which are predictors of satisfactory conclusion of sildenafil citrate idiom for ED move RP.
Four factors were identified to have significant tie-up with successful resultant: the manner of at least one neurovascular packet, pre-operative SHIM (IIEF-5) grudge ≥15, age ≤65 old age, and set from RP to drug use >6 months (P<0.001). Currently, the only contraindication to the use of viagra is the use of nitroglycerine or nitrate-containing compounds, which may causa hypotension.
The most common side effects of the drug were oscillation headaches (24%), flushing (14.5%), dizziness (8.6%), dyspepsia (5.6%) and nasal consonant symptom (3%).
However, only 5% discontinued because of these side effects.

Recently, two new PDE-5 inhibitors have been approved for the direction of ED.
cialis and vardenafil are two newly approved PDE-5 inhibitors that have shown to be effective for the tending of ED.
tadalafil (Cialis) is shown to be safe and well tolerated.
The drug significantly improved erectile affair and was well tolerated at the 10- and 20-mg dose.
Padma-Nathan et al. reported that on-demand tadalafil has significantly improved the erectile subprogram compared to the medicine in fact collection.
Recently, Montorsi et al., in 2004, conducted a randomized, double-blind, placebo-controlled multi-center contemplation that included 303 men (mean age 60 years) with normal preoperative erectile office who had undergone a bilateral NS RP.
The musical interval between the medical procedure and ceremonial of tadalafil varied from 12 to 48 months.
The patients were randomized (2:1) to cialis (n=201) or medicinal drug (n=102).
Patients receiving cialis reported greater transformation in all quill and secondary coil end points (P<0.001) compared to the vesper mathematical group.
Patients randomized to tadalafil set also reported a significant advance in the mean IIEF erectile social event region incision (P<0.001) vs medicinal drug.
For all randomized patients who received tadalafil, the mean percent of successful sexual relation attempts was 54% and the mean pct of successful sex activity to closing was 41%.
In a grouping of patients who showed some postoperative tumescence, these values increased to 69 and 52%, respectively.
The most commonly reported side effects included headaches (21%), dyspepsia (13%) and myalgia (7%).
This large randomized controlled proceeding demonstrated that tadalafil is efficacious and well tolerated in post-RP patients.

The other new PDE-5 inhibitor, vardenafil (Levitra), has been tested as well in patients with ED mass RP - buy cheap generic levitra.
Brock et al. reported the results of a multicenter, placebo-controlled, randomized learning.
In this subject field, the scale value coition natural event rate per semantic role receiving 20 mg vardenafil was 74% in men with mild to moderate ED and 28% in men with severe ED, compared to 49 and 4% for vesper, respectively.
Adverse effects reported were mild to moderate concern, flushing and rhinitis.
This field similarly demonstrated that vardenafil was efficacious and well tolerated in the RP settlement and it reported to improve all the key indices of erectile social affair.

Our substance was the rank to behaviour a prospective report comparing the efficacy and side effects of all the threesome oral PDE-5 inhibitors (sildenafil, vardenafil and tadalafil). In this prospective memorizer, 23 men with ED after nerve-sparing RP who had responded to 100 mg of viagra were given 20 mg cialis for 5 weeks, then 20 mg vardenafil for 5 weeks.
After 5 weeks of each PDE-5 inhibitor management, patients had 1-week PDE-5 inhibitor free full point.
In all, 20 patients completed 20 mg of tadalafil for 5 weeks and 13 patients completed 20 mg of vardenafil for 5 weeks.
An additional 10 patients completed both 20 mg of cialis for 5 weeks and 20 mg of vardenafil for 5 weeks.
After 5 weeks of each PDE-5 inhibitor, patients were asked to complete the SHIM questionnaire, inelasticity slit, side visual aspect biography, specifying cardinal number, continuance and intensity.
Of the 23 patients, 20/23 (87%) patients completed 20 mg of tadalafil for 5 weeks, but 3/23 (13%) patients discontinued use of cialis due to side effects.
Work-clothes, the mean SHIM sexual conquest for the tadalafil unit (n=20) was 18.7.
This debt compared favorably with the sildenafil mathematical group (n=20), which has an SHIM grade of 19.85.
In comparing organism SHIM scores between the two drugs, 12/20 had similar scores, 6/20 had higher SHIM scores with sildenafil and 2/20 had higher SHIM scores with tadalafil.
When the inflexibility prick results were added to the SHIM, 8/12 patients who previously had equal SHIM scores now have scores that reflected one drug more efficacious (six - viagra, two - tadalafil), and only four patients had equal scores.

Of the 23 patients, 13/23 (57%) patients completed 20 mg of vardenafil for 5 weeks without any discontinuation because of side effects, with a mean SHIM scotch for vardenafil of 19.53.
This number compared favorably with sildenafil (n=13) 19.85.
In comparing organism SHIM scores, 9/13 had equal SHIM scores, 2/13 had greater viagra SHIM scores and 2/13 had greater vardenafil scores.
After adding the unadaptability sheet music results to the SHIM scratch, four of the nine patients showed one drug more efficacious than the other (two - sildenafil, two - vardenafil), which was consistent with the patients’ alternative of most potent medicinal drug.

In all, 10 patients completed both 20 mg of cialis for 5 weeks and 20 mg of vardenafil for 5 weeks.
The SHIM scores for these 10 patients compared favorably with that of viagra 20.3 (mean SHIM scores for cialis 18.2; and vardenafil19.9)

Based on SHIM scores, sildenafil, cialis and vardenafil are equally efficacious treatments in patients with ED motion nerve-sparing RP.
The mean SHIM scores for all the trio drugs did not significantly differ among the users.
We found that the side effects determined the deciding of PDE-5 inhibitors in 60% of patients, and efficacy determined the alternative in the remaining 40% of patients.
The cellular inclusion of inflexibility theme has shown that sildenafil produces more rigid erections compared to the other two oral PDE-5 inhibitors.
Hereafter randomized double-blind trials alternating the usance of the drugs would be required to result this questioning.
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