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ALPROSTADIL
Transdérmico de forma diferenciada para disfunção erétil
DESCRIÇÃO
Alprostadil é um isolado sintético análogo da substância endógena prostaglandina E1 (PGE1).
MECANISMO DE AÇÃO
O Alprostadil possui ação equivalente a PGE1 ligando-se em seus receptores e estimulando a produção de
mediadores, como AMPc, que promovem o relaxamento do músculo liso (vasodilatação), especificamente na região
dos corpos cavernosos, oferecendo maior aporte sanguíneo ao local e à ereção peniana. Sabe-se que o Alprostadil
em Pentravan® é considerado seguro e eficaz em pacientes com DE, principalmente quando os inibidores de PDE-5
são ineficazes, contraindicados ou quando o paciente é intolerante aos seus efeitos adversos.
INDICAÇÕES

Disfunção erétil (DE)
DOSE USUAL
Recomendação transdérmica de 100 a 400mcg ao dia, até 3 vezes por semana , com no mínimo 24 h entre as doses.
SUGESTÕES DE FÓRMULAS
Alprostadil................................................ 100mcg
Pentravan® qsp.......................................... 1 pump
Alprostadil................................................ 100mcg
Pentravan® qsp.......................................... 1 pump
Modo de uso: 1 a 3 pumps (ou conforme
orientação médica), de 5 a 15 minutos antes da
relação sexual**, podendo ser usado até 3 vezes
por semana, com 24 h entre as aplicações.
Indicação: disfunção erétil severa.
Modo de uso: 1 pump, de 5 a 15 minutos antes
da relação sexual** ou conforme orientação
médica, podendo ser usado até 3 vezes por
semana, com 24 h entre as aplicações.
Indicação: disfunção erétil leve.
*OBS: embalagem airless pen
** Modo de uso: direcionar a ponta do aplicador diretamente ao
meato uretral na glande, sem introduzir e acionar o êmbolo do
aplicador até o final (1 pump). Pode ocorrer e é comum que
parte do produto não penetre no orifício, permanecendo sobre
a pele; nesse caso, deve-se massagear suavemente até que o
produto seja absorvido (em média 15 segundos).
*OBS: embalagem airless pen
** Modo de uso: direcionar a ponta do aplicador diretamente ao
meato uretral na glande, sem introduzir e acionar o êmbolo do
aplicador até o final (1 pump). Pode ocorrer e é comum que
parte do produto não penetre no orifício, permanecendo sobre
a pele; nesse caso, deve-se massagear suavemente até que o
produto seja absorvido (em média 15 segundos).
PRINCIPAIS REFERÊNCIAS
DOMINIK G. et al. PGE1 analog alprostadil induces VEGF and eNOS expression in endothelial cells. American Journal of Physiology. v. 289, n.
5, p. 877-884. 2005. Disponível em:<http://ajpheart.physiology.org/content/289/5/H2066.short>. Acesso em: 12/07/2016, às 13:47.
ROONEY, M. et al. Long-term, multicenter study of the safety and efficacy of topical alprostadil cream in male patients with erectile dysfunction. J
Sex Med. v. 6, n. 2, p. 520-534. 2008. Disponível em:< http://www.ncbi.nlm.nih.gov/pubmed/19138370>. Acesso em: 12/07/2016, às 12:30.
ALPROSTADIL
ESTUDOS CLÍNICOS
Long-term, multicenter study of the safety and efficacy of topical alprostadil cream in male patients with erectile
dysfunction.
INTRODUCTION: Alprostadil is approved for treatment of male erectile dysfunction (ED) by injection or urethral
insertion. Topical delivery of alprostadil offers an improved alternative. AIM: To evaluate the long-term safety and
efficacy of topical alprostadil cream. METHODS: This was a multicenter, open-label, long-term study in 1,161 patients
(998 double-blind rollover; 163 naïve) with ED. For the first 4 weeks, patients could administer eight doses of 200 mcg
alprostadil to the penis meatus before intercourse (up to 2 per/week). Patients then self-selected to administer 300 or
100 mcg doses if hypo-responsive or hyper-responsive, respectively, or 200 mcg if no change, for up to 9 months (2
doses/week). MAIN OUTCOME MEASURES: Safety evaluated patient/partner adverse events (AEs), changes in vital
signs, clinical laboratory tests, physical examinations, and electrocardiograms. Efficacy assessed International Index of
Erectile Function, Sexual Encounter Profile, Patient Self Assessment of Erection, and Global Assessment
Questionnaire. RESULTS: Approximately 12% of patients discontinued due to hypo-/hyper-responsiveness, 16%
withdrew consent for a variety of reasons, and less than 5% discontinued because of AEs. The majority of patients
(73%) selected 300 mcg alprostadil as the final dose. The most common AEs involved application site burning or
erythema (12.2%), meatal or glans pain (4.4%), and prolonged or painful erection (1.3%). Only 5 (0.4%) patients
reported a prolonged erection of >or=4 hours (priapism). Vaginal burning or itching (2.1%) was reported most frequently
by partners. The majority of patients (74%) demonstrated an overall improvement in erectile function on most endpoints, especially after adjusting dose strength to their individual responsiveness. CONCLUSIONS: Topical alprostadil
cream was considered effective and safe by most patients and their partners, with most AEs limited to the application
site. Dose adjustment to 300 mcg alprostadil facilitated the greatest improvement in erectile function in the majority of
patients. A separate report will integrate patient data from the open-label extension and prior double-blind studies.
An integrated analysis of alprostadil topical cream for the treatment of erectile dysfunction in 1732 patients.
OBJECTIVE: To assess the safety and efficacy of topical alprostadil cream for erectile dysfunction (ED). METHODS:
Patients with an ED score of 25 or less on the erectile function domain of the International Index of Erectile Function
(IIEF) were randomly assigned to placebo or topical alprostadil cream (100, 200, or 300 microg) for at-home use for 12
weeks in two multicenter, double-blind, parallel-group studies. Patients receiving organic nitrates and patients with
diabetes were included. Primary end points included the change in score for the erectile function domain of the IIEF and
the change from baseline for the Sexual Encounter Profile (SEP) questions 2 (vaginal penetration success) and 3
(maintenance of erection to ejaculation). Safety was based on observed and reported adverse events and clinical
laboratory results. Data from each study were pooled into a single integrated analysis. RESULTS: A total of 1732
patients received placebo (n = 434) or topical alprostadil cream at 100 microg (n = 434), 200 microg (n = 430), or 300
microg (n = 434). The mean changes from baseline to end point in IIEF erectile function (EF) domain scores were -0.7,
1.6, 2.5, and 2.4 points for each group, respectively (P <0.001). Scores on SEP questions 2 and 3 improved slightly but
significantly for all drug treatment groups compared with placebo (P <0.001). Most adverse events were localized to the
application site and resolved within 2 hours. CONCLUSIONS: Topical alprostadil cream significantly improves ED in a
broad range of patients. Most adverse events were limited to the application site and were generally well tolerated.
Clinical efficacy and safety of Vitaros©/Virirec© (Alprostadil cream) for the treatment of erectile dysfunction.
Erectile dysfunction (ED) is a very common disorder with a deep impact on patients and their partners. Several options
are now available for treating ED; oral pharmacotherapy with phosphodiesterase-5 (PDE5) inhibitors currently
represents the first-line option for many ED patients.
Vitaros©/Virirec© is new topical, non-invasive treatment for ED that offers the combination of an active drug (alprostadil,
a synthetic PGE1) with a skin enhancer that improves its local absorption directly at the site of action. Vitaros©/Virirec©
has a favorable pharmacodynamic profile and is poorly absorbed in systemic circulation. This makes it suitable in any
circumstances and results in a reduced risk of adverse events (AEs), being systemic AEs reported in only 3% of the
treated population. Its clinical efficacy has been demonstrated in both phase II and III trials, showing a global efficacy
up to 83% with the 300 μg dose in patients with severe ED significantly better than placebo. Its fast onset of action
together with its favorable toxicity profile and lack of interactions with other drugs makes Vitaros©/Virirec© a first-line
therapeutic option for patients with ED, particularly for individuals who are reluctant to take systemic treatments or with
AEs. It may also have an important role in patients not responding to PDE5 inhibitors, particularly those with ED after
radical prostatectomy.
Peripheral Female Genital Arousal as Assessed by Thermography Following Topical Genital Application of
Alprostadil vs Placebo Arousal Gel: A Proof-of-Principle Study Without Visual Sexual Stimulation.
INTRODUCTION: Female sexual arousal disorder is a pathophysiologic state characterized clinically by persistent or
recurrent inability to attain or maintain an adequate lubrication-swelling response of sexual excitement until completion
of sexual activity. Prior clinical experience with alprostadil products for men with erectile dysfunction supports its use in
women with female sexual arousal disorder. AIM: To compare the effect of topical alprostadil with over-the-counter
(OTC) lubricant on female genital arousal in the absence of visual sexual stimuli. METHODS: Healthy premenopausal
women without sexual dysfunction were recruited from the community to participate in the study. Of 17 women who
consented, 10 were enrolled and completed the trial. The mean age of subjects was 32 years (range = 27-43). Study
drug or placebo was applied topically to the genitals. Continuous temperature monitoring was performed. Participants
completed questionnaires assessing genital sensation, effect, intensity, and duration. MAIN OUTCOME MEASURES:
Change in temperature from baseline in vestibule, clitoris and vulva. RESULTS: In all 10 subjects, topical alprostadil
induced a statistically significant increase in temperature of the vestibule, clitoris, and vulva compared with the OTC
lubricant. The most rapid difference in genital temperature between placebo and alprostadil was seen on the vulva,
which demonstrated a significant difference at approximately 9 minutes. There was a significant difference in
temperature seen for the vestibule and clitoris at 11 and 19 minutes, respectively. Sixty percent of women reported
being aware or conscious of genital sensations with topical alprostadil, but not with OTC lubricant. Discordance was
noted in 30% of subjects who reported being aware or conscious of genital sensations with the two treatments and 10%
who reported not being aware or conscious of genital sensations with either treatment. CONCLUSION: Topical
alprostadil administered to healthy premenopausal women induced statistically significant, sustained increases in genital
temperatures of the vestibule, clitoris, and vulva within 20 minutes compared with OTC lubricant.
Alprostadil for the treatment of erectile dysfunction.
Erectile dysfunction (ED) is a common medical condition affecting over 20 m men in the United States. Efficacious
medical therapy for the treatment of erectile dysfunction has been available since the early 1980s and can be divided
into local pharmacotherapy and systemic therapy. Alprostadil, a synthetic form of prostaglandin E1, is a useful local
pharmacotherapeutic agent for the treatment ED. Alprostadil is presently available for administration as an
intracavernosal injection or an intraurethral suppository. Local alprostadil therapy is effective at restoring the ability to
participate in intercourse in up to 70% of men with ED. The principle side-effects of alprostadil are local, with few
systemic reactions. The mechanism of alprostadil, its efficacy in clinical trials and side-effects are examined to outline
the utility of alprostadil for the treatment of ED.
PGE1 analog alprostadil induces VEGF and eNOS expression in endothelial cells.
Endothelial nitric oxide synthase (eNOS), VEGF, and hypoxia-inducible factor 1-α (HIF-1α) are important regulators of
endothelial function, which plays a role in the pathophysiology of heart failure (HF). PGE1 analog treatment in patients
with HF elicits beneficial hemodynamic effects, but the precise mechanisms have not been investigated. We have
investigated the effects of the PGE1 analog alprostadil on eNOS, VEGF, and HIF-1α expression in human umbilical
vein endothelial cells (HUVEC) using RT-PCR and immunoblotting under normoxic and hypoxic conditions. In addition,
we studied protein expression by immunohistochemical staining in explanted hearts from patients with end-stage HF,
treated or untreated with systemic alprostadil. Alprostadil causes an upregulation of eNOS and VEGF protein and mRNA
expression in HUVEC and decreases HIF-1α. Hypoxia potently increased eNOS, VEGF, and HIF-1α synthesis. The
alprostadil-induced upregulation of eNOS and VEGF was prevented by inhibition of MAPKs with PD-98056 or U-0126.
Consistently, the expression of eNOS and VEGF was increased, and HIF-1α was reduced in failing hearts treated with
alprostadil. The potent effects of alprostadil on endothelial VEGF and eNOS synthesis may be useful for patients with
HF where endothelial dysfunction is involved in the disease process.
Evaluation of percutaneous absorption performance for human female sexual steroids into pentravan cream.
There is a lack of studies on Pentravan cream, a widespread transdermal vehicle which is used by compounding
pharmacies. The purpose of this study was to evaluate this transdermal vehicle. The permeation performance for
progesterone, estradiol, and estriol in formulations containing each of those drugs separately, as well as an association
of estradiol + estriol (Biest), was evaluated regarding their compounding process and their potential biological
application. An excised female human skin model was used to predict the permeation and the retention of the active
compounds in every skin layer in lieu of conventional tape stripping. Progesterone was the drug with the highest
permeation (37.02 mcg cm(-2) at the end of the experiment). Estradiol and estriol in Biest had permeations
approximately 4-fold lower (9.44 mcg cm(-2) for estradiol-Biest and 14.02 mcg cm(-2) for estriol-Biest), and the profiles
of estradiol in Eemuls and in Biest were almost the same (9.46 mcg cm(-2) for Eemuls). All permeations followed
pseudo- first order kinetics. For progesterone, using the percentage of permeation by dose, one can infer that a patient
using the 1-g emulsion dose released by the pump containing 50 mg of progesterone will have 38.4 mg of progesterone
liberated into his bloodstream, gradually and continuously for 48 hours. The results indicate that the vehicle was able to
provide percutaneous absorption rates compatible with and higher than clinical treatment needs. Using the same
rationale, the Eemuls would deliver practically the entire amount of estradiol load per dose (1.0 mg), approximately 0.5
mg of estradiol per day. As for the Biest, the dosing used would deliver almost 0.5 mg estradiol/day and 2.0 mg estriol/
day. Thus, according to the results, human female sexual hormones incorporated in the oil-in-water vanishing cream
base and applied topically are expected to exert their biological activities systemically with good efficacy due to their
satisfactory permeation through human skin. However, one must take into account that a high quantity of drug was
delivered. Thus, to avoid patient overdose, care has to be taken regarding the quantity of emulsion used.
In vitro percutaneous absorption of ketoprofen and testosterone: comparison of pluronic lecithin organogel vs.
pentravan cream.
An in vitro human percutaneous absorption study was conducted to assess the delivery of ketoprofen and testosterone
from two base formulations, a Pluronic lecithin organogel and Pentravan Cream. Each formulation was applied to ex
vivo human trunk skin (from three skin donors) on triplicate sections mounted onto Franz Diffusion Cells. Following a 5mcL/cm2 applied dose, serial dermal receptor solutions were collected over 48 hours. For both compounds, a greater
rate and extent of absorption was found from the Pentravan formulation than from the Pluronic lecithin organogel
formulation: 3.8-fold greater for ketoprofen, 1.7-fold greater for testosterone, for amount absorbed.
Current role of local treatments for erectile dysfunction in the real-life setting.
PURPOSE OF REVIEW: Local treatments for erectile dysfunction include intraurethral alprostadil as well as topical
alprostadil cream. They are alternative treatment options to oral or intracavernosal treatments that could overcome
unmet needs in patient treatment. RECENT FINDINGS: Intraurethral and topical alprostadil are two local methods of
delivering an erectogenic drug to the patient. They have an established efficacy and a safety profile without important
systemic adverse events. Efficacy data show that they result in significantly improved erections sufficient for sexual
intercourse compared with placebo. Comparative efficacy data to other treatments are very limited. There are no specific
contraindications to other drugs. They can be offered to patients who do not tolerate or do not respond to oral treatment.
They can be also combined to oral treatment as a salvage therapy before proceeding to intracavernosal injections. The
major advantages of them are the patient-friendly modality of delivering and the presence of minor local adverse events
that are self-limited and mild in nature. Priapism or prolonged erections are very rare with local treatments. SUMMARY:
Local treatments can have an important role as a first-line treatment for erectile dysfunction or in drug combinations
mainly because of their excellent safety profile.
REFERÊNCIAS
COSTABILE, R. A. Alprostadil for the treatment of erectile dysfunction. Expert Opin Investig Drugs. v. 8, n. 6, p. 877-884. 1999. Disponível
em:<http://www.ncbi.nlm.nih.gov/pubmed/15992137>. Acesso em: 12/07/2016, às 13:22.
DOMINIK G. et al. PGE1 analog alprostadil induces VEGF and eNOS expression in endothelial cells. American Journal of Physiology. v. 289, n.
5, p. 877-884. 2005. Disponível em:<http://ajpheart.physiology.org/content/289/5/H2066.short>. Acesso em: 12/07/2016, às 13:47.
GOLDSTEIN, S. W. et al. Peripheral Female Genital Arousal as Assessed by Thermography Following Topical Genital Application of Alprostadil vs
Placebo Arousal Gel: A Proof-of-Principle Study Without Visual Sexual Stimulation. Sex Med. doi: 10.1016/j.esxm.2016.03.026. 2016. Disponível
em:<http://www.ncbi.nlm.nih.gov/pubmed/27090169>. Acesso em: 12/07/2016, às 12:57.
LEHMAN, P. A.; RANEY, S. G. In vitro percutaneous absorption of ketoprofen and testosterone: comparison of pluronic lecithin organogel vs.
pentravan cream. Int J Pharm Compd. v. 16, n. 3, p. 248-252. 2012. Disponível em:< http://www.ncbi.nlm.nih.gov/pubmed/23050302>. Acesso em:
14/07/2016, às 14:05.
MOISIDIS, K.; KALINDERIS, N.; HATZIMOURATIDIS, K. Current role of local treatments for erectile dysfunction in the real-life setting. Curr Opin
Urol. v. 26, n. 2, p. 123-128. 2016. Disponível em:<http://www.ncbi.nlm.nih.gov/pubmed/26716564>. Acesso em: 12/07/2016, às 13:31.
MONCADA, I.; CUZIN, B. Clinical efficacy and safety of Vitaros©/Virirec© (Alprostadil cream) for the treatment of erectile dysfunction. Urologia. v.
82, n. 2, p. 84-92. 2015. Disponível em:<http://www.ncbi.nlm.nih.gov/pubmed/?hl=pt-BR&term=Moncada+I.%2C+Cuzin+B.%3BUrologia%2C2015>.
Acesso em: 12/07/2016, às 12:40.
PADMA-NATHAN H.; YEAGER J. L. An integrated analysis of alprostadil topical cream for the treatment of erectile dysfunction in 1732 patients.
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POLONINI, H. C. et al. Evaluation of percutaneous absorption performance for human female sexual steroids into pentravan cream. Int J Pharm
Compd. v. 18, n. 4, p. 332-340. 2014. Disponível em:< http://www.ncbi.nlm.nih.gov/pubmed/25508641>. Acesso em: 12/07/2016, às 14:16.
ROONEY, M. et al. Long-term, multicenter study of the safety and efficacy of topical alprostadil cream in male patients with erectile dysfunction. J
Sex Med. v. 6, n. 2, p. 520-534. 2008. Disponível em:< http://www.ncbi.nlm.nih.gov/pubmed/19138370>. Acesso em: 12/07/2016, às 12:30.