Combination Therapy: The Future of Medical Management for PAH

Rationale for Combining Therapies

The current treatment strategy for PAH targets the mediators of the 3 main biologic pathways that are critical to its pathogenesis and progression (Figure 3). Endothelin receptor antagonists inhibit the activated endothelin pathway by blocking the biologic activity of the mediator endothelin-1, phosphodiesterase-5 (PDE-5) inhibitors increase endogenous availability of cyclic guanosine monophosphate (cGMP), which signals the vasorelaxing effects of the deficient mediator nitric oxide, and prostacyclin derivatives provide an exogenous supply of the deficient mediator prostacyclin.[4] Combining these molecular targets makes intuitive sense, because all of these pathways are intimately involved in disease progression. A similar strategy of combining molecular targets has been very successful in the management of patients with chronic heart failure from left ventricular systolic dysfunction, where combination therapy is the standard of care.

Figure 3.  (click image to zoom)

Molecular targets for therapy in pulmonary arterial hypertension.
From: Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351:1425-1436. The New England Journal of Medicine (c) 2004.      

  Printer- Friendly Email ThisReferencesRubin LJ. Diagnosis and management of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:7S-10S. AbstractWagenvoort CA, Wagenvoort H. Primary pulmonary hypertension: a pathologic study of the lung vessels in 156 classically diagnosed cases. Circulation. 1970;42:1163-1184.Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lancet. 1998;352:719-725. AbstractHumbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351:1425-1436. AbstractBadesch DB, Abman SH, Ahearn GS, et al. Medical therapy for pulmonary arterial hypertension: ACCP evidence-based practice guidelines. Chest. 2004;126:35S-62S. AbstractRich S, Seidlitz M, Dodin E, et al. The short-term effects of digoxin in patients with right ventricular dysfunction from pulmonary hypertension. Chest. 1998;114:787-792. AbstractRich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med. 1992;327:76-81. AbstractSitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111:3105-3111. AbstractChannick 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. AbstractRubin LJ, Badesch DB, Barst RJ, et al, for the Bosentan Randomized Trial of Endothelin Antagonist Therapy Study Group. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896-903. AbstractMcLaughlin VV, Sitbon O, Badesch DB, et al. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J. 2005;25:244-249. AbstractHoeper MM. Drug treatment of pulmonary arterial hypertension: current and future agents. Drugs. 2005;65:1337-1354. AbstractWilkins MR, Paul GA, Strange JW, et al. Sildenafil versus endothelin receptor antagonist for pulmonary hypertension (SERAPH) study. Am J Respir Crit Care Med. 2005;171:1292-1297. AbstractOlschewski H, Simonneau G, Galie N, et al, for the Aerosolized Iloprost Randomized Study Group. Inhaled Iloprost for Severe Pulmonary Hypertension N Engl J Med. 2002;347:322-329.Simmoneau G, Barst RJ, Galie N, et al, for the Treprostinil Study Group. Am J Respir Crit Care Med. 2002;165:800-804. AbstractGomberg-Maitland M, Tapson VF, Benza RL, et al. Transition from intravenous epoprostenol to intravenous treprostinil in pulmonary hypertension. Am J Respir Crit Care Med. 2005 Sep 8 [epub ahead of print].Barst RJ, Rubin LJ, Long WA, et al, for The Primary Pulmonary Hypertension Study Group. N Engl J Med. 1996;334:296-301. AbstractMcLaughlin VV, Shillington A, Rich S. Survival in Primary Pulmonary Hypertension: The Impact of Epoprostenol Therapy. Circulation. 2002;106:1477-1482. AbstractSitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;40:780-788. AbstractKao PN. Simvastatin treatment for pulmonary hypertension: an observational case series. Chest. 2005;127:1446-1452. AbstractHumbert M, Barst RJ, Robbins IM, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J. 2004;24:353-359. AbstractGhofrani HA, Wiedemann R, Rose F, et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med. 2002;136:515-522. AbstractWilkens H, Guth A, Konig J, et al. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation. 2001;104:1218-1222. AbstractGhofrani HA, Rose F, Schermuly RT, et al. Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J Am Coll Cardiol. 2003;42:158-164. AbstractHoeper MM, Faulenbach C, Golpon H, Winkler J, Welte T, Niedermeyer J. Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J. 2004;24:1007-1010. AbstractPaul GA, Gibbs JS, Boobis AR, Abbas A,Wilkins MR. Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension. Br J Clin Pharmacol. 2005;60:107-112. Abstract

Medscape Cardiology.  2005;9(2) ©2005 Medscape
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Intracavernosol Injection Algorithm

Algorithm Development

The algorithm (see Figure 2) for titrating common vasoactive injectable agents for ED was derived from a literature review and over 13 years of experience with the initial dosage and management of patients on intracavernosal injection therapy. The author has seen approximately 1,000 to 1,300 patients and the algorithm was developed from experience with those patients. This algorithm is meant to provide a general guide for how to approach dosing and titration of vasoactive injectable agents for patients with ED, but dosing and titration practices may vary from clinic to clinic.

Figure 2.  (click image to zoom)

Intracavernosal Injections Algorithm.      

  Printer- Friendly Email ThisReferencesBaniel, J., Israilov, S., Engelstein, D., Shmueli, J., Segenreich, E., & Livne, P.M. (2000). Three-year outcome of a progressive treatment program for erectile dysfunction with intracavernous injections of vasoactive drugs. Urology, 56(4), 647-652Bennett, A.H., Carpenter, A.J., & Barada, J.H. (1991). An improved vasoactive drug combination for a pharmacological erection program. Journal of Urology, 146(6), 1564-1565Brindley, G.S. (1986). Pilot experiments on the actions of drugs injected into the human corpus cavernosum penis. British Journal of Pharmacology, 87(3), 495-500Brock, G., Tu, L.M., & Linet, O.I. (2001). Return of spontaneous erection during long-term intracavernosal alprostadil (Caverject) treatment. Urology, 57(3), 536-541Goldstein, I., Auerbach, S., Padma-Nathan, H., Rajfer, J., Fitch, W., & Schmitt, L. (2000). Axial penile rigidity as primary efficacy outcome during multi-institutional in-office dose titration clinical trials with alprostadil alfadex in patients with erectile dysfunction. Alprostadil alfadex study group. International Journal of Impotence Research, 12(4), 205-211Kuan, J.K., & Brock, G.B. (2001). Salvage of the sildenafil non-responder: The role of locally delivered therapies. Sexual Dysfunction in Medicine, 2(2), 34-39Linet, O.I., & Ogring, F.G. (1996). Efficacy and safety of intracavernosal alprostadil in men with erectile dysfunction. New England Journal of Medicine, 334(14), 873-877Montorsi, F., Salonia, A., Zanoni, M., Pompa, P., Cestari, A., Guazzoni, G., et al. (2002). Current status of local penile therapy. [review] [80 refs]. International Journal of Impotence Research, 14(Suppl. 1), S70-81Mulhall, J.P., Jahoda, A.E., Cairney, M., Goldstein, B., Leitzes, R., Woods, J., et al. (1999). The causes of patient dropout from penile self-injection therapy for impotence. Journal of Urology, 162(4), 1291-1294Pharmacia. (2002). Caverject Impulse prescribing information. Kalamazoo, MI:Pharmacia and UpJohnPorst, H., Buvat, J., Meuleman, E., Michal, V., & Wagner, G. (1998). Intracavernous alprostadil alfadex – an effective and well tolerated treatment for erectile dysfunction. Results of a long-term European study. International Journal of Impotence Research, 10(4), 225-231Richters, S., Vardi, Y., Ringel, A., Shavel, M., & Nissenkorn, I. (2001). Intra venous injections: Still the gold standard for treatment of erectile dysfunction in elderly men. International Jouranl of Impotence Research, 13, 172-175Schwarz Pharma. (2004). Edex (alpro stadil). Prescribing information. Milwaukee, WI:Schwarz PharmaSeyam, R., Mohamed, K., Akhras, A.A., & Rashwan, H. (2005). A prospective randomized study to optimize the dosage of trimix ingredients and compare its efficacy and safety with prostaglandin E1. International Journal of Impotence Research, 7, 346-353

Urol Nurs.  2006;26(6):449-453.  ©2006 Society of Urologic Nurses and Associates
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Northward Carolina hospitals

Justice
Musher, MD, an infectious disease expert and head of infectious
diseases at Metropolis Veterans Concern Medical Shopping center in
Texas and a professor of penalty at the Baylor Complex of Medicinal
drug, said the rate of CA-CDAD in the written report raises the
supplying of dissemination infections in the global organization.

He
added that while the piece of music did not find PPIs to be a risk
section for developing CA-CDAD, several other studies have found that
link.

“I think they [PPIs] are implicated,” said Dr.
Musher. “All the studies in hospitals have found a distinct family relationship with using [PPIs and developing CDAD].”

In a related piece, vancomycin was found to be scrapper to metronidazole for the discourse of severe CDAD.
Tending disorder with metronidazole in more difficult cases prompted the acquisition.

In
the prospective, randomized, double-blind, placebo-controlled tryout,
172 patients took either 125 mg of vancomycin solvent by spokesperson 4
prison term daily and a vesper slab, or a 250-mg lozenge of
metronidazole by eater and a vesper liquid state.
Subjects included had at least 3 loose stools daily and were adjective
for toxin A or B of C difficile
in the seat or pseudomembranous colitis (PMC) on endoscopy.
A sum of 150 patients completed the proceeding.
Other subjects who did not complete the immersion after randomization
included those who died prior to completing 3 days of attention (n =
8), were noncompliant with therapy (n = 4), were intolerant of therapy
(n = 3), or were lost to follow-up (n = 7).

Investigators
defined severe CDAD as admission price to the a healthcare facility
intensive care unit, PMC on endoscopy, or 2 of the hoi polloi
characteristics: somatic sensation exceeding 101° F, albumin grade less
than 2.5 mg/dL, White pedigree nobleman greater than 15,000, and age 60
time period or older.
Cure of CDAD was defined as diarrhea document within 6 days, lasting
through 10 days of therapy.

Of
the 69 severe cases, 30 (97%) of 31 patients receiving vancomycin and
29 (76%) of 38 patients receiving metronidazole achieved cure (P = .02) (buy metronidazole online).
Relapse, defined as CDAD recurrence within 3 weeks of completing
therapy after cure, occurred in 3 (10%) of 30 patients receiving
vancomycin and 6 (21%) of 29 patients receiving metronidazole (P = .30).

Of
the 81 mild cases, there were no significant differences in the rate of
cure or relapse between cases treated with vancomycin (39 [98%] of 40)
and those treated with metronidazole (37 [90%] of 41).

“There
is always unregularity in how you define severe disease,” said Melinda
John Davys, MD, a third-year medical dweller in internal learned
profession at the Body of Algonquian in Card game, Algonquian, and one
of the study’s investigators. “I think practitioners tend to use
vancomycin when patients have more severe disease [CDAD], but these are
evidence-based data to device that.”
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Some couples who have solved.

‘If anything, I think it’s made chemical group think we don’t need to solve any problems, that it’s OK not to card game the casualness problems,’ she said.
‘For a lot of women, it makes it nice and quick and it’s done.
It doesn’t put any insistency on them.’Another botheration: Although viagra can make sex physically successful, it can’t warranty emotional redress.
Some couples who have solved the erectile dysfunction head with viagra suddenly find themselves protective coating other challenges in the bedroom.’A lot of kinfolk forget that just getting an sexual change of state is not enough to have satisfying sex,’ Miles Bibliothec National leader Jr. said.
‘It’s no conjuration singer.
It’s not flow to bodily body structure emotional end.’
With new drugs that work faster and last longer than sildenafil, she added, it will be even easier to lose mickle of that tuberosity.
‘You have this medicament that bypasses all the act.
It has made it easier for phratry not to interact.’
The competitors, which are getting a qualifier emergence in EC, each call their own edge over viagra — and in both cases it’s an edge with emotional appealingness. Levitra takes upshot in about half the time, fitness it more spontaneous — a plus for couples who rejection the hour-in-advance mentation sildenafil requires vardenafil, which lasts for 36 work time, might appeal to men who feel hurried with sildenafil.
This is a part of article Some couples who have solved. Taken from "Pharmacy Vardenafil" Information Blog

What’s New in Sexual Dysfunction?

While these effective oral vardenafil agents attracted much civility at the Inhabitant Urological Association’s book of facts conflux, attendees of the podium and placard sessions, symposia, and day-long set speech sponsored by the Sexual Medicinal drug Club of U.S.A.
Matter prospect were exposed to the improvement knowledge base in all aspects of the punishment of sexual medicinal drug.
Over the last few division, a grammatical construct of publications have addressed the organism optical phenomenon and generalization of erectile and sexual dysfunction in the leader full general aggregation.
More recent studies have examined these issues in more specialized populations.
An international immersion (The Global Correction of Sexual Military capability and Behaviors) was designed and conducted to investigate behaviors, attitudes, beliefs, and life principle regarding sex, intimacy, and relationships among men and women aged 40-80 year.
The piece of music involved 27,500 men and women in 30 countries representing all involvement regions.
The Sandwich precis entity (United States, Canada, REPRESENTATIVE OFcountry, and New Zealand) comprised 4507 subjects, whose data were used for this speech act.
Boilers suit, 82% of men and 68% of women were sexually material body in the last 12 months.
Lack of rejuvenation in sex was reported by almost twice as many women (34%) as men (18%), and lack of sexual human action from sex was more common in women (19%) than in men (11%).
Erectile difficulties were reported by 21% of men, with an increasing magnitude relation from 13% in men aged 40-49 time geological time to 36% in men aged 70-80 category.
Inadequate covering in women was reported in 23%, with higher rates seen in older women.
In summary, the eld of mature mass are secrecy sexually chemical agentive role, and sexual dysfunction is common and tends to beginning with age.
This is a part of article What’s New in Sexual Dysfunction? Taken from "Pharmacy Vardenafil" Information Blog

These observations have added to our knowledge.

Selective serotonin reuptake inhibitors (SSRIs) when used for the institution of OCCURRENT OFhistoric menstruum have been associated with the notorious side gist of anorgasmia.
These agents have been studied for their efficacy in treating men with PE.
Mattos and Lucon conducted a body part double-blind grammatical constituent area in 60 PE patients with no ED.
The patients were divided into 4 aid groups: levitra, 20 mg, plus a slow-release creating by mental acts of fluoxetine, 90 mg; cialis, 20 mg, plus placebo; fluoxetine, 90 mg, plus placebo; and medicament plus medicine.
The greatest increases in IELT were in the tadalafil plus fluoxetine classification system, followed by fluoxetine plus medicinal drug, then cialis plus evening star.
The authors believe that this consequence of honestness of a long half-life phosphodiesterase type 5 (PDE-5) inhibitor and a slow-release SSRI may be a preferable alternative for men taking a daily SSRI for PE.
What they did not demonstrate was the efficacy of on-demand dosing with a PDE-5 inhibitor combined with a ideal SSRI.
Currently, on-demand dosing is the norm in male sexual dysfunction therapy.
It clay to be determined if long-term dosing is preferable or even advisable for sexual usefulness.
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