Avanafil A Novel Agent For Management Biology Essay

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Erectile dysfunction is a common clinical entity that affects mainly men older than 40 years. In addition to the classical causes of erectile dysfunction, such as diabetes mellitus and hypertension, several common lifestyle factors, such as obesity, limited or an absence of physical exercise, and lower urinary tract symptoms, have been linked to the development of erectile dysfunction. The emergence of a new medication, Avanafil is a selective phosphodiesterase type-5 inhibitor used for the treatment of erectile dysfunction which has been approved in March 26, 2012. After conducting various clinical trials, Avanafil is a potential alternative to other PDE5 Inhibitor for patient with erectical dysfunction.

Introduction:

Erectile dysfunction is defined as the inability to attain or maintain a penile erection sufficient for successful vaginal intercourse1. Erectile dysfunction is a common medical disorder that primarily affects men older than 40 years of age. A recent extensive analysis of published work on the prevalence of erectile dysfunction2, on Definition/Epidemiology/Risk Factors for Sexual Dysfunction, showed that the prevalence of erectile dysfunction was 1-10% in men younger than 40 years. Prevalence of erectile dysfunction range from 2-9% in men between the ages of 40 and 49 years, it then increases to 20-40% in men aged 60-69 years. In men older than 70 years, prevalence of erectile dysfunction ranges from 50-100%3-7. Clearly, erectile dysfunction is now regarded as a major health problem for the increasingly healthy ageing population. Several cross-sectional and longitudinal studies have linked the development of erectile dysfunction to diabetes mellitus, hypertension, hyperlipidemia, metabolic syndrome, depression, and lower urinary tract symptoms8-14. Several epidemiological studies reported that erectile dysfunction is a marker of cardiovascular disease (CVD)9,12,14 . Findings from other studies have shown that certain environmental and lifestyle factors, such as smoking, obesity, and limited or an absence of physical exercise, might also be important predictors of erectile dysfunction15-17. In several studies, an extensive alteration of lifestyle habits, through modification of diet and encouragement to exercise, led to improvement of erectile dysfunction18-22.

Physiology of penile erection:

Nitric Oxide (NO), released from the endothelium and the parasympathetic nerve terminals, is the primary neurotransmitter involved in penile erection, although other transmitters can also be involved23. NO-dependent relaxation of the cavernously smooth muscles leads to compression of the subtunical small veins, occluding local venous return and resulting in an erection. Penile detumescence begins with activation of the adrenergic receptors on the cavernous arteries and trabecular smooth muscles, leading to a reduction in arterial inflow and a collapse of lacunar spaces. Decompression of the drainage venues from the cavernous bodies occurs, allowing venous drainage of the lacunar spaces and relief of the erection24.

Table 1: Main organic causes of erectile dysfunction

SR. NO.

CAUSE

EXAMPLE

1

Neurogenic

Central (cerebral or spinal cord): for example, cerebral insult, multiple sclerosis, and spinal cord injury

Peripheral: afferent (sensory neuropathy; e.g., diabetes mellitus and polyneuropathy of various other causes)

Efferent (autonomic neuropathy or after radical pelvic surgery)

2

Endocrinological

Diabetes mellitus, hypogonadism, and hyperprolactinaemia

3

Vasculogenic

Arterial: macro or micro angiopathy (e.g., atherosclerosis and trauma)

Venous: failure of the corporal veno-occlusive mechanism

Sinusoidal: failure to relax (e.g., fibrosis)

4

Drug-induced depression

Drugs: for example, some antihypertensives, antidepressants, antiandrogens and major tranquillisers

Cigarette smoking, alcoholism and recreational drug use

5

Systemic diseases and general ill health

For example, liver, renal, respiratory, and cardiovascular disease

6

Local penile (cavernous) factors

For example, cavernous fibrosis after priapism or due to other reasons, Peronei's disease and penile fracture

Table 2: Factors related to the development of psychogenic erectile dysfunction25

SR. NO.

CAUSE

EXAMPLE

1

Predisposing factors

Traumatic past experiences

Strict upbringing

Inadequate sex education

Physical and mental health problems

2

Precipitating factors

Acute relationship problems

Family or social pressures

Major life events, such as pregnancy, childbirth, or loss of a job

3

Maintaining factors

Relationship problems

Physical or mental health problems

Absence of knowledge of availability of various treatment options

Table 3: Drugs and recreational substances commonly associated with erectile dysfunction

SR. NO.

CAUSE

EXAMPLE

1

Antiandrogens

Gonadotropin-releasing hormone agonists (leuprolide, goserelin, Lupron and zoladex)

Chemotherapy (cyclophosphamide and busulfan)

Flutamide

Ketoconazole

Spironolactone

2

Antihypertensives

Thiazide diuretics

β blockers

Calcium channel blockers

3

Antiarrhythmics

Digoxin

Amiodarone

Disopyramide

4

Statins

There is controversial evidence about the effects of

Atorvastatin on erectile function56,57

5

Psychotropic drugs

Phenothiazines

Butyrophenones

6

Recreational substances

Marijuana

Opiates

Cocaine

Nicotine

Alcohol

Table 4: Risk factors and comorbidities associated with erectile dysfunction

SR. NO.

CAUSE

EXAMPLE

1

Age

-

2

Poor physical and psychological health

-

3

Lifestyle factors

Sedentary lifestyle

Obesity

Cigarette smoking

Alcohol misuse

Recreational drug use (e.g., marijuana and heroin)

4

Metabolic risk factors and metabolic syndrome

Diabetes mellitus

Hypertension

Dyslipidaemia

Hypogonadism

Oral PDE5 are now regarded as the first-line treatment for erectile dysfunction26,27. There are now six commercially available oral PDE5-Is, which are sildenafil (Viagra; Pfizer, New York, NY, USA), Tadalafil (Cialis; Lilly, Indianapolis, IN, USA), Vardenafil (Levitra, Staxyn; Bayer, West Haven, CT, USA), Udenafil (Zydena; Dong-A Pharm Tech., South Korea), Mirodenafil (Mvix; SK Chemical, South Korea) and Avanafil (Stendra, VIVUS Inc.) Other PDE5 are under investigation for the treatments of erectile dysfunction include Lodenafil, SLx-210128. On March 26, 2012 VIVUS (Biopharmaceutical Company) announced that a Marketing Authorization application has been accepted by the European Medicines Agency.

The Brand name of Avanafil is STENDRA. STENDRA is supplied as oval, pale yellow tablets containing 50 mg, 100 mg, or 200 mg Avanafil deposed with dosage strengths. It is Store at 20-25°C (68-77°F); excursions permitted to 30°C (86°F) and Protect from light29. The recommended starting dose of Avanafil is 100 mg and should be taken orally as needed approximately 30 minutes before sexual activity. Depending on individual efficacy and tolerability, the dose can be varied to a maximum dose of 200 mg or decreased to 50 mg. The lowest dose that provides efficacy should be used. The maximum recommended dosing frequency is once per day.

Clinical trials conducted for assessing effect of Avanafil. STENDRA was evaluated in 3 randomized, double-blind, placebo-controlled, parallel group trials of up to 3 months in duration. In these 3 trials, STENDRA was taken as needed at doses of 50 mg, 100 mg, and 200 mg. Patients were instructed to take 1 dose of study drug approximately 30 minutes prior to initiation of sexual activity. Food and alcohol intake was not restricted. In addition, a subset of patients from 2 of these trials was enrolled into an open-label extension trial. In the open-label extension trial, all eligible patients were initially assigned to avanafil 100 mg. At any point during the trial, patients could request to have their dose of avanafil increased to 200 mg or decreased to 50 mg based on their individual response to treatment. The 3 primary outcome measures were the erectile function domain of the International Index of Erectile Function (IIEF) and Questions 2 and 3 from Sexual Encounter Profile (SEP). The IIEF is a 4-week recall questionnaire that was administered at baseline and at 4-week intervals during treatment. The IIEF erectile function domain has a 30-point total score, where the higher scores reflect better erectile function. The SEP included diary-based measures of erectile function. Patients recorded information regarding each sexual attempt made throughout the trial. Results are shown from the two, Phase 3, randomized, double-blind, placebo-controlled, parallel studies, one in the general ED population (Study 1) and the other in the diabetic population with ED (Study 2)33.

Results in the General ED Population (Study 1):

STENDRA was evaluated in 646 men with ED of various etiologies (organic, psychogenic and mixed). The mean age was 55.7 years (range 23 to 88 years). The population was 85.6% White, 13.2% Black 0.9% Asian and 0.3% of other races. The mean duration of ED was approximately 6.5 years. STENDRA at doses of 50 mg, 100 mg, and 200 mg demonstrated statistically significant improvement in all 3 primary efficacy variables relative to placebo33.

Table 5: Mean Change From Baseline for Primary Efficacy Variables usually ED Population (Study 1)33

QUANTITY OF DRUG

PLACEBO

(N=155)

STENDRA 50 mg

(N=154)

STENDRA 100 mg

(N=157)

STENDRA 200 mg

(N=156)

IIEF EF Domain Score

Endpoint

15.3

18.1

20.3

22.2

Change from baseline�

2.9

5.4

8.9

9.5

p-value*

-

0.0014

<0.0001

<0.0001

Vaginal Penetration (SEP2)

Endpoint

53.8%

64.3%

73.9%

77.3%

Change from baseline�

7.1%

18.2%

27.2%

29.8%

p-value*

-

0.0009

<0.0001

<0.0001

Successful Intercourse (SEP3)

Endpoint

27.0%

41.3%

57.1%

57.0%

Change from baseline�

14.1%

27.8%

43.4%

44.2%

p-value*

-

0.0002

<0.0001

<0.0001

� Least-square estimate from ANCOVA model

* comparison to placebo for vary from baseline

Results in the ED Population with Diabetes Mellitus (Study 2)

STENDRA was evaluated in ED patients (n=390) with type 1 or type 2 diabetes mellitus in a randomized, double-blind, parallel, placebo-controlled fixed dose trial of 3 months in duration. The mean age was 58 years (range 30 to 78 years). The population was 80.5% White, 17.2% Black, 1.5% Asian, and 0.8% of other races. The mean duration of ED was approximately 6 years. In this trial, STENDRA at doses of 100 mg and 200 mg demonstrated statistically significant improvement in all 3 primary efficacy variables as measured by the erectile function domain of the IIEF questionnaire; SEP2 and SEP333.

Table 6: Mean Change From Baseline for Primary Efficacy Variables in ED Population with Diabetes Mellitus (Study 2)33

QUANTITY OF DRUG

PLACEBO

(N=127)

STENDRA 100 mg

(N=126)

STENDRA 200 mg

(N=126)

IIEF EF Domain Score

Endpoint

13.2

15.8

17.3

Change from baseline�

1.8

4.5

5.4

p-value*

-

0.0017

<0.0001

Vaginal Penetration (SEP2)

Endpoint

42.0%

54.0%

63.5%

Change from baseline�

7.5%

21.5%

25.9%

p-value*

-

0.0004

<0.0001

Successful Intercourse (SEP3)

Endpoint

20.5%

34.4%

40.0%

Change from baseline�

13.6%

28.7%

34.0%

p-value*

-

<0.0001

<0.0001

� least-square estimate from ANCOVA model

* Comparison to placebo for differ from baseline

Avanafil is the latest drug for the treatment of erectile dysfunction. No analytical method has been reported for estimation of Avanafil except LC- MS/MS which has been used in determination of Avanafil plasma concentrations was conducted at the Asian Medical Center Analytic Laboratory. Plasma concentrations of avanafil were determined by a sensitive and selective method using online solid-phase extraction (SPE) coupled to LC-MS/MS; a triple quadrupole mass spectrometer was also used. Stock solutions of avanafil and the Internal standard (IS [TA-179013C5 15N1 d2]) were prepared by dissolving 1 ng/mL of each in methanol. Twenty microliters of IS was added to each 200-μL aliquot of plasma, and the sample was transferred to an auto sampler vial, which was inserted into the online SPE (Symbiosis; Spark Holland B.V., Emmen, the Netherlands) and LC-MS/MS system (API 4000; Applied Biosystems/MDX Sciex, Toronto, Ontario, Canada) with Analyst 1.4 software (Applied Biosystems/ MDX Sciex). Chromatographic separation was conducted using a C18 column (Capcell Pak; Shiseido Co. Ltd., Tokyo, Japan; particle size, 3 μm; internal diameter, 2.0 - 50 mm). The mobile phase consisted of a mixture of 10-mM ammonium format (pH 2.5) and acetonitrile (v/v 65:35), with a flow rate of 0.3 mL/min and a column temperature of 30°C. The chromatographic run time was 5 minutes, and injection volume was optimized to 5 μL. The mass spectrometer with electrospray ionization source was operated in the positive mode. Quantitation was performed using multiple reactions monitoring of transitions of m/z 484.1 → 375.1 for avanafil and m/z 492.3 → 383.2 for IS. Avanafil concentrations were calculated from avanafil calibration curves, which were obtained by plotting the peak height ratio versus the concentration of avanafil in the calibration sample34.

The advantages of using avanafil are that it has less side effects then Viagra, Cialis and Levitr. The response time between taking a tablet and experiencing the effect is extremely fast. Preclinical studies have shown that Avanafil strongly inhibits PDE5 (half maximal inhibitory concentration = 5.2 nM) in a competitive manner and is 100-fold more potent for PDE5 than PDE6, which is found in the retina and is responsible for photo transduction. Also, Avanafil has shown higher selectivity (120-fold) against PDE6 than Sildenafil (16-fold) and Vardenafil (21-fold), and high selectivity (>10 000-fold) against PDE1 compared with Sildenafil (380-fold) and Vardenafil (1000-fold). Avanafil has also been reported to be a faster-acting drug than Sildenafil, with an onset of action as little as 15 minutes as opposed to 30 minutes for the other drugs35.

Avanafil was generally well tolerated at doses of 50 to 200 mg per day for 7 days. All adverse events were mild, and no treatment was required. So it is most effective PDE5 Inhibitor drug and it has been approved by FDA. Availability of Avanafil provides an alternative to the patients not tolerating or useful in Erectile Dysfunction/Impotence.

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