Viagra, Levitra or Cialis – Which works best?Part 3 check Part 1& 2
3.2. PHOSPHODIESTERASE FAMILY
PDE-5 is a member of the phosphodiesterase family,which regulates multiple cell functions throughout the human body, by catalysing the breakdown of cGMP and cAMP. cGMP and cAMP are molecules of intracellular signal transduction that lead to protein phosphorylation, modulation of enzymes, ion channels, receptors and contractile proteins, through activation of protein kinase G. The major function for phosphodiesterases in the cell is to terminate the cyclic nucleotide second messenger signal (Beavo et al 1995).
The cGMP level is a critical parameter for many cell functions, and is strictly regulated by a variety of control circuits in which phosphodiesterases play a central role. Much about this remains unexplained.
PDE-5 activity is controlled by at least two regulatory pathways.
The gene for all of the isoforms of PDE-5 known to date (A1-A2-A3) is found on chromosome 4q26 (Loughney et al. 1998, Yanka et al. 1998). In studies with human corpus cavernosum cell cultures, Lin et al were able to demonstrate that an increase in Cgmp levels over 48 hours increases the activity of the PDE5A promoter gene and therefore PDE-5 expression or PDE-5 tissue levels (Lin et al. 2002).
Moreover, an increase in the cGMP level also leads to an increase in catalytic PDE-5 activity, with cGMP in conjunction with phosphokinase G and ATP leading to PDE-5 phosphorylation, which results in an increase in the cGMP binding capacity. By means of this mechanism, Corbin et al. (2000) were able to demonstrate a 50-70% increase in catalytic PDE-5 enzyme activity after an incubation time of only 1 hour.
Besides the increase in PDE-5 expression and the increase in catalytic activity (degradation pathway), the cGMP level can also be regulated via a change in cGMP synthesis. For example, Murthy was able to show by means of cell culture experiments that an increased cGMP level leads to a reduction in sGC synthesis via phosphokinase G-mediated phosphorylation of soluble guanylate cyclase (sGC) (Murthy et al. 2001).
On the basis of these results, the following hypothesis regarding the regulation of cGMP levels would be conceivable:
An increase in the cGMP level (e.g. through prolonged PDE-5 inhibition) leads to an increase in cGMP breakdown via an increase in PDE-5 activity and expression, and to a reduction in cGMP production via a reduction of sGC activity. The mechanisms described here then might lead to a reduction in the cGMP level in the form of counter-regulation. Owing to the lack of sufficient long-term data, it is not yet possible to judge whether or not clinically relevant pharmacodynamic habituation occurs as a result of a chronic increase in the cGMP level, such as through the use of long-acting PDE-5 inhibitors like tadalafil.
Interesting long-term data for repeated use exist on the assessment of the substance sildenafil. Sildenafil has been used in German clinical trials since 1995. In England, a small group of diabetes patients was treated for 6 years; 10 out of 11 were still very pleased with the success of the treatment 6 years later (Price 1999).
In other studies, the long-term efficacy and tolerance of sildenafil were studied over a period of up to 3 years; 87-96% of ED patients proved to be pleased with sildenafil treatment, and the discontinuation ratesdue to lack of efficacy were, at 1-9%, very low (Montorsi et al. 2001, Steers et al. 2001, Gingell et al. 1999, Hackett 1999, Guliano et al. 1997, Christiansen et al. 2000, Hackett and Milledge 2001), so, at least for PDE-5 inhibitors with a relatively short half-life such as sildenafil, there is no evidence of a clinically relevant habituation effect.
3.3. CHEMICAL STRUCTURE OF CGMP AND THE PDE-5 INHIBITORS SILDENAFIL, VARDENAFIL AND TADALAFIL
As competitive inhibitors of PDE-5, the chemical structures of the substances (Fig. 1) are very similar to that of cGMP. Sildenafil and vardenafil differ only minimally in terms of their structure, as a direct comparison of the structural formulas shows. Tadalafil differs markedly from sildenafil and vardenafil in terms of its molecular structure, which is also reflected in marked pharmacokinetic differences.
3.4. POTENCY AND SELECTIVITY OF PDE-5INHIBITORS
A review of the literature shows that the measured values for the potency and selectivity of PDE-5 inhibitors can vary, which can be demonstrated , for example, by the IC50 values (concentration at which the enzyme activity is 50% inhibited) of sildenafil (Table 2).
The reason for this is that IC50 values are dependent on the cGMP concentration, the source and extraction method of the enzymes, the reaction conditions, the number of samples, and other factors in the experimental design (Osterloh 2001). For this reason, different laboratories may obtain differing measure-
TABLE 1
TABLE 2
ment results, depending on the study conditions selected. This lack of measurement precision concerns all PDE-5 inhibitors. The IC50 of tadalafil in terms of PDE-5 has been calculated as between 0.9 nM (Angulo et al. 2001) and 6.7 nM (Baxendale et al. 2001) and the IC50 of vardenafil between 0.1 nM (Philips et al. 2002) and 0.7 nM (Saenz de Tejada et al. 2001). Accordingly, vardenafil exhibits an PDE-5 inhibitory potential approximately five times higher than that of sildenafil , which is also reflected in the dosages used in clinical trials (5, 10 or 20 mg vardenafil versus dose strengths of 25, 50 and 100 mg sildenafil).
For the assessment of efficacy and tolerance, it is therefore important to use equipotent dosages, i.e. to compare 20 mg vardenafil with 100 mg sildenafil, for example.
A single oral dose of 100 mg sildenafil produces a mean peak free sildenafil plasma concentration of 38 nM (EU-SPC VIAGRA). In order to achieve an inhibition of some 90 % in PDE–5 activity, a free drug concentration of approximatelly 25 nM is necessary (Turko et al. 1999). PDE-5 is therefore already maximally inhibited by administration of 100 mg sildenafil (Gopal et al. 2001). This applies both in resting conditionsand on stimulation of cGMP synthesis (e.g. through sexual activity). With this high efficacy, sildenafil sets the standard for other substances.
In relation to the binding potency of individual PDE-5 inhibitors to other PDE isoenzymes, there are no clear significant differences.
Considering selectivity for PDE 1-4 and 7-10 versus PDE-5, the substances discussed here show no relevant differences (Table 3). Differences are apparent in terms of PDE-6, which plays an important role in the conversion of light impulses into nerve impulses in the retina. Here, sildenafil and vardenafil show lower selectivity than tadalafil. However, since peak plasma levels of 970 nM are reached after administration of 20 mg fil (Patterson et al. 2001), it remains to be seen whether or not PDE-6 might be inhibited by these substance under clinical conditions, something which cannot currently be assessed in view of the lack of published data on plasma protein binding and the free fraction. A further difference exists in the area of PDE-11.
Here tadalafil shows only 5 times greater selectivity with respect to PDE-5, which indicates inhibition of PDE-11 by tadalafil at clinical doses (Baxendale et al. 2001). PDE-11 inhibition by tadalafil could lead to adverse effects in clinical use. So far, PDE-11 has been detected in a variety of human tissues, e.g. in the heart, pituitary gland, brain and testes. The physiological significance of PDE-11 and the possible consequences of its inhibition have not yet been established.
There is a marked difference of tadalafil versus sildenafil and vardenafil. Sildenafil and vardenafil are not expected to inhibit PDE-11.
3.5. PHARMACOKINETICS
All three substances are rapidly absorbed from the gastrointestinal tract, with peak plasma levels being attained within 1 hour in the case of sildenafil (Milligan et al. 2002) and vardenafil (Sachse and Rohde 2000) and after 2 hours in the case of tadalafil (Patterson et al. 2001), with a range of 0.5 – 12 hours for tadalafil. Absorption takes place mainly from the small intestine, with the gastric emptying time playing an important role in the onset of action.
According to the current publication situation, food intake causes no delay or reduction in tadalafilabsorption (Ibid 2001), whereas it is known to reduce and delay sildenafil absorption (Nicols et al. 2002).
Since, at a therapeutic dosage, sildenafil has adequate latitude in terms of maximum inhibition of PDE-5, a good clinical effect is also obtained on ingestion after food intake. Ingestion on an empty stomach produces a more rapid onset of action, whereas ingestion after or with a meal produces a slower onset of action (Corbin and Francis 2002).
The bioavailability of sildenafil is approx. 41 % (Nichols et al. 2002). After a single oral dose of 100 mg sildenafil, a total mean plasma concentration of approximatelly 440 ng/ml is achieved, the plasma protein binding is 96 %, which means that there is a mean free sildenafil peak plasma concentration of 18 ng/ml. For tadalafil (20 mg) and vardenafil (20 mg) total mean plasma concentrations are 378 ng/ml (Patterson et al. 2001) respectively 19 ng/ml (Sachse and Rhode 2000). Data concerning plasma protein binding or mean free peak plasma concentrations have not yet been published. The mean half-lives of sildenafil and vardenafil are 3 - 4 hours (Sachse and Rohde 2000) and that of tadalafil, approximatelly 18 hours (Patterson et al.
2001). Tadalafil can still be detected in the blood 5 days after ingestion (Patterson et al. 2001), which means that accumulation might be possible, if tadalafil would be taken regularyly and in short intervals.
Approximatelly 50 % of all drugs are metabolized via the cytochrome-P 450 system (Eichelbaum and Burk 2001), which exhibits a great deal of genetic polymorphism. The elimination of sildenafil (Hyland et al. 2001), vardenafil (Rohde et al. 2001) and tadalafil ((Patterson et al. 2001) takes place overwhelmingly via the liver, mostly via the cytochrome enzyme P450 (CYP3A4). CYP3A4 expression varies up to a factor of 50 between various individuals, and in vivo enzyme function by at least a factor of 20 (Özdemir et al. 2000).
5. CONCLUSION
As knowledge stands at present, PDE-5 inhibitors are the method of choice for the treatment of erectile dysfunction, alongside treatment for the underlying disease.
Sildenafil has proven to be an effective and well tolerated drug. Studies with a follow-up period of up to 4 years have been conducted. The success rate of sildenafil varies in the group of ED patients with an or- 442 EUROPEAN JOURNAL OF MEDICAL RESEARCH October 29, 2002 ganic underlying disease between 43% in patients who have undergone radical prostatectomy and 85% in patients with a neurological disease, and amounts to a mean of 82% (Guay et al. 2001). The treatment success rate can be increased by repeated usage attempts (McCullough et al. 2001). Vardenafil and tadalafil demonstrate efficacy data that can be presumed to be approximate to those of sildenafil. Since near maximum inhibition of PDE-5 is already achieved with sildenafil (Turko et al. 1999),an increase in efficacy is not to be expected with vardenafil and tadalafil.
As yet, we need more data to assess the adverse effects of vardenafil and tadalafil, particularly in longterm
use and in high-risk groups. Sildenafil has already been used in over 20 million men in over 110 countries (Pfizer Inc. data on file) and is one of the best studied pharmacological substances around. For example, 1095 scientific publications are available on Medline, the database of the National Institute of Health, using the keyword sildenafil, 24 publications using vardenafil and 3 publications using tadalafil (as at August 25, 2002). Some 4 years after the market launch of sildenafil, the postmarketing data show a high degree of concordance with the efficacy and safety data obtained in the clinical licensing studies (Sadovsky et al. 2001). The Office of Drug Safety of the FDA (Federal Drug Administration) collected and analyzed reports of death in men prescribed sildenafil from its marketing in March 1998. In conclusion there did not appear to be an increase in death due to myocardial infarction above expected numbers in the same age groups compared to sildenafil users (Wysowski DK et al. 2002).
This adventage in terms of knowledge and safety data makes sildenafil a safe and reliable treatment for patients with erectile dysfunction. Whether tadalafil or vadenafil are complementary to sildenafil or not will be shown the years following market introduction.
