Comments to article Sildenafil citrate (Viagra) impairs fertilization and early embryo development in mice by Glenn et al.

15 04 2009

To the Editor:

The article entitled Sildenafil citrate (Viagra) impairs fertilization and early embryo development in mice by Glenn et al. (1) was of great interest. However, the presented data should be clarified from a teratological point of view, as it is insufficient for any further toxicological evaluation, in particular the human risk assessment. Without recording the initial number of females selected to each examined group, it is impossible to calculate the mating and fertility indexes that are crucial for Stage A of developmental toxicological studies (2). In addition, the post-implantation loss on day 4 should also be calculated.

The following data from the article are missing and should be added: mating behavior, caging duration, previous male sexual experience, copulation screening methods, as well as the drug supplier. Since sildenafil is poorly soluble in water (3), the way the administered suspension is prepared should be also explained. It is unusual to test a single dose of a drug without any further explanations of the animal pharmacokinetic and toxicological data. Due to metabolic differences, the information presented in the article on therapeutic doses being equivalent in men and mice is theoretically incorrect. According to general principles of toxicological studies, at least three different doses should be tested (2). However, in the study the drug was given as a single dose and administered only one hour before males were caged with females. A single-dose protocol, less than one full spermatogenic cycle, is unlikely to cause the male reproduction toxicity (2, 4). Since such a protocol has a high risk of false-negative results (4), the study limitations should be clearly emphasized with corresponding data of drug transfer to the semen. Without animal data on metabolism, compound concentrations in blood and semen, as well as its intracellular distribution in mice sperm, all the mentioned mechanisms of drug action are only speculations. Moreover, in the case of sildenafil, caffeine data should not be emphasized because the methyloxantine inhibits 5-phosphodiesterase in high over-therapeutic doses, but in lower, well-tolerated ones its clinical activity is secondary to influence on A1 and A2 adenosine receptors (5).

Since the authors revealed that fertilization and early embryo development is impaired by sildenafil – a well-recognized and one of the best selling drugs – all of the above stressed queries and male reproductive endpoints should be explained for better understanding of the presented data.

Franciszek Burdan MD, PhD
Experimental Teratology Unit of the Human Anatomy Department
Medical University of Lublin
Lublin, Poland

 
References:
1. Glenn DRJ, McClure N, Cosby SL, Stevenson M, Lewis SEM. Sildenafil citrate (Viagra) impairs fertilization and early embryo development in mice. Fertil Steril 2009;91:893-9.

2. International Conference on Harmonisation (ICH) Harmonised tripartite guideline (1995): Male fertility studies in reproductive toxicology. In: D’Arcy PF, Harron DWG, eds. Proceeding of third International Conference on Harmnization, Antrim: IFPMA Greystone Books Ltd, 1996: 245-52.

3. Wang Y, Chow MSS, Zuo Z. Mechanistic analysis of pH-dependent solubility and trans-membrane permeability of amphoteric compounds: application to sildenafil. In J Pharm 2008;352:217-24.

4. Clegg ED, Perreault SD, Klinefelter GR. Assessment of male reproductive toxicity. In: Hayes AW, ed. Principles and methods of toxicology. 4th ed. Philadelphia: Taylor&Francis, 2001:1263-300.

5. Mandel H.G. Update on caffeine consumption, disposition and action. Food Chem Toxicol 2002;40:1231-4.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.04.032

The Authors Declined to Respond.

Advertisements

Actions

Information

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s




%d bloggers like this: