CLINICAL PHARMACOLOGY

Mechanism of Action
Maca's reported beneficial effects for sexual function could be due to its high concentration of proteins and vital nutrients though Maca contains a chemical called p-methoxybenzyl isothiocyanate, which reputedly has aphrodisiac properties. Maca may contain phyto-estrogens as occurs in other plants. Phyto-estrogens may have estrogenic or anti-estrogenic activities (Kuiper et al. 1998).Recently; remarkable progress has been made in our understanding of the role of sex steroids in human male physiology. A possible role of estrogens in both human male fertility and sexuality has also been suggested by recent studies (Rochira et al. 2001). A well-established effect of estrogens has been provided by recent studies on male rodents, which show impaired sexual behavior and fertility as a consequence of estrogen defect (O’Donnell et al. 2001). The emerging physiological role of estrogens in male fertility suggests that estrogenic substances should be considered ‘male hormones’ (O’Donnell et al. 2001). At this time it is difficult to conclude that treatment with Maca contributes a male hormone in the form of phytoestrogens which would lead to improvement in sexual function. Further studies will be required to clarify the mechanism of action of Maca on male sexuality and fertility. Maca, when used appropriately, appears to be relatively safe.

Fertility-enhancing properties of maca are thought to be due to aromatic isothiocyanates hydrolyzed from these glucosinolates. Furthermore, benzyl isothiocyanate has been reported to inhibit breast, stomach and liver cancer in rats. Aphrodisiacal properties are attributed to the prostaglandins, sterols and amides of polyunsaturated fatty acids The most confounding question about maca's effect is its ability to influence sexual performance without affecting serum hormone levels such as luteinizing hormone, follicle stimulating hormone, prolactin, testosterone and estradiol It is therefore assumed that maca acts on the receptors for these hormones Both methanolic and acqueous extracts of Maca exhibit estrogenic activity in vitro Alkaloids purified from the maca root are thought to affect the hypothalamic-pituitary axis, explaining why maca can induce effects in both sexes

Muira puama  (Ptychopetalum olacoides )is a small tree native to the Brazilian Amazon where the stems and roots are used as a tonic for neuromuscular problems. A root decoction is used externally in massages and baths for paralysis and beriberi. Oral use of tea made from the roots for sexual impotence, rheumatism, and GI problems has been noted
Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and  increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function byincreasing the amount of cGMP. Gioxil-36 inhibits PDE5. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 by Gioxil-36 has no effect in the absence of sexual stimulation.
Studies in vitro have demonstrated that Gioxil-36  is a selective inhibitor of PDE5. PDE5 is found in corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, cerebellum, and pancreas. In vitro studies have shown that the effect of Gioxil-36  is more potent on PDE5 than on other phosphodiesterases. These studies have shown that Gioxil-36  is >8,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. Gioxil-36  is >8,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. Additionally, Gioxil-36  is 600-fold more potent for PDE5 than for PDE6, which is found in the retina and is responsible for phototransduction. Gioxil-36  is >7,000-fold more potent for PDE5 than for 10 PDE8, PDE9, and PDE10. Gioxil-36  is 14-fold more potent for PDE5 than for PDE11A1 and 40-fold more potent for PDE5 than for PDE11A4, two of the four known forms of PDE11. PDE11 is an enzyme found in human prostate, testes, skeletal muscle and in other tissues. In vitro, Gioxil-36  inhibits human recombinant PDE11A1 and, to a lesser degree, PDE11A4 activities at concentrations within the therapeutic range. The physiological role and clinical consequence of PDE11 inhibition in humans have not been defined.

Pharmacokinetics

Absorption
Gioxil-36 well absorbed from an oral dose, with about 70 percent ending up in the bloodstream.   After single oral-dose administration, the maximum observed plasma concentration (Cmax) of Gioxil-36  is achieved between 30 minutes and 6 hours (median time of 2 hours). Absolute bioavailability of Gioxil-36 l following oral dosing has not been determined.
The rate and extent of absorption of Gioxil-36 are not influenced by food; thus Gioxil-36 may be taken with or without food.
 
Distribution
The mean apparent volume of distribution following oral administration is approximately 63 L, indicating that Gioxil-36 l is distributed into tissues. At therapeutic concentrations, 94% of Gioxil-36 l in plasma is bound to proteins.  Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.

Metabolism
Gioxil-36 l is predominantly metabolized by CYP3A4 to a catechol metabolite. The catechol metabolite undergoes extensive methylation and glucuronidation to form the methylcatechol and methylcatechol glucuronide conjugate, respectively. The major circulating metabolite is the methylcatechol glucuronide. Methylcatechol concentrations are less than 10% of glucuronide concentrations. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations. 
Elimination
Following a single dose of 420mg  Gioxil-36 in normal weight and obese subjects, fecal and urine excretion of the unabsorbed product was found to be the major route of elimination. The mean oral clearance for Gioxil-36  is 2.5 L/hr and the mean terminal half-life is 17.5 hours in healthy
subjects. Gioxil-36 l is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).

Special Populations
Geriatrics: Plasma concentrations of Maca and Muira puama  were similar between elderly (ages 61 to 75yr) and younger (ages 17-30) subjects following a single dose of 240mg  oral Gioxil-36 . In general, dose selection for the elderly should be cautious, reflecting the greater frequency for decreased hepatic, renal, or other product therapy.
Pediatrics: Gioxil-36 has not been evaluated in individuals less than 18 years old.

Patients with Diabetes Mellitus:  In male patients with diabetes mellitus after a 240 mg Gioxil-36 dose, exposure (AUC) was reduced approximately 19% and Cmax was 5% lower than that observed in healthy subjects. No dose adjustment is warranted