Absence of clinically important HERG channel blockade by three compounds that inhibit phosphodiesterase 5--sildenafil, Tadalafil ( Cialis ) , and Vardenafil ( Levitra ).

Compounds that inhibit phosphodiesterase 5 (PDE5) have been developed for the treatment of erectile dysfunction. Because men with erectile dysfunction frequently have comorbid cardiovascular disease, they may have limited cardiac repolarization reserve and be at risk of arrhythmia if treated with medications that prolong ventricular repolarization. The human ether-a-go-go related gene (HERG) channel is important for repolarization in human myocardium and is a common target for drugs that prolong the QT interval. We studied the ability of three compounds that inhibit PDE5--sildenafil, Tadalafil ( Cialis ) , and Vardenafil ( Levitra )--to block the HERG channel. Using a whole cell variant of the patch-clamp method, the HERG current was measured in a stably transfected human embryonic kidney cell line expressing the HERG channel. The compounds produced dose-dependent reductions in HERG current amplitude over a concentration range of 0.1 to 100 microM. The IC50 values were 12.8 microM for Vardenafil ( Levitra ) and 33.3 microM for sildenafil. Because the maximum soluble concentration of Tadalafil ( Cialis ) (100 microM) produced only a 50.9% inhibition of the HERG current amplitude, the IC50 value for Tadalafil ( Cialis ) could not be determined with the Hill equation. Tadalafil ( Cialis ) had the weakest capacity to block the HERG channel, producing a 50.9% blockade at the maximum soluble concentration (100 microM), compared with 86.2% for Vardenafil ( Levitra ) (100 microM) and 75.2% for Sildenafil Citrate ( Viagra ) (100 microM). In conclusion, the concentrations of the PDE5 inhibitors required to evoke a 50% inhibition of the HERG current were well above reported therapeutic plasma concentrations of free and total compound. None of the three compounds was a potent blocker of the HERG channel.

Testosterone regulates PDE5 expression and in vivo responsiveness to Tadalafil ( Cialis ) in rat corpus cavernosum.

OBJECTIVES: To investigate the effect of testosterone on PDE5 expression and PDE5 inhibitor Tadalafil ( Cialis ) in vivo responsiveness in a rat model. METHODS: PDE5 expression was localized by immunohistochemistry in the rat corpus cavernosum (CC) and quantified by both real-time RT-PCR and Western blot analysis in several tissues. In the in vivo study, control, castrated and testosterone (T) supplemented castrated rats were treated with acute or chronic oral Tadalafil ( Cialis ) . Erectile function was evaluated by monitoring intracavernous pressure (ICP) following electro-stimulation (ES) of the cavernous nerve and intracavernous injection of NO donor, sodium nitroprusside (SNP). RESULTS: Rat CC expressed the highest PDE5 mRNA level. PDE5 was specifically immunolocalized in endothelial and smooth muscle cells. Surgical castration induced a significant reduction of PDE5 gene and protein expression (p<0.05), and ES response at all stimulation frequencies (p<0.001). T supplementation completely restored PDE5 expression, erectile response to ES and responsiveness to PDE5 inhibitor. Both acute and chronic Tadalafil ( Cialis ) treatment were ineffective in ameliorating the ES response in castrated rats. Injection of increasing concentrations of SNP in castrated rats resulted in a statistically significant increase in ICP/MAP ratio as that observed in intact rats. In addition, Tadalafil ( Cialis ) did not amplify the SNP effect in castrated rats at all the doses tested (0.06-6 nmoles). CONCLUSIONS: Our findings demonstrate that testosterone positively regulates PDE5 expression and in vivo responsiveness to PDE5 inhibitor, Tadalafil ( Cialis ) , in the rat CC.

Interactions between grapefruit juice and cardiovascular drugs.

Grapefruit juice can alter oral drug pharmacokinetics by different mechanisms. Irreversible inactivation of intestinal cytochrome P450 (CYP) 3A4 is produced by commercial grapefruit juice given as a single normal amount (e.g. 200-300 mL) or by whole fresh fruit segments. As a result, presystemic metabolism is reduced and oral drug bioavailability increased. Enhanced oral drug bioavailability can occur 24 hours after juice consumption. Inhibition of P-glycoprotein (P-gp) is a possible mechanism that increases oral drug bioavailability by reducing intestinal and/or hepatic efflux transport. Recently, inhibition of organic anion transporting polypeptides by grapefruit juice was observed in vitro; intestinal uptake transport appeared decreased as oral drug bioavailability was reduced. Numerous medications used in the prevention or treatment of coronary artery disease and its complications have been observed or are predicted to interact with grapefruit juice. Such interactions may increase the risk of rhabdomyolysis when dyslipidemia is treated with the HMG-CoA reductase inhibitors atorvastatin, lovastatin, or simvastatin. Potential alternative agents are pravastatin, fluvastatin, or rosuvastatin. Such interactions might also cause excessive vasodilatation when hypertension is managed with the dihydropyridines felodipine, nicardipine, nifedipine, nisoldipine, or nitrendipine. An alternative agent could be amlodipine. In contrast, the therapeutic effect of the angiotensin II type 1 receptor antagonist losartan may be reduced by grapefruit juice. Grapefruit juice interacting with the antidiabetic agent repaglinide may cause hypoglycemia, and interaction with the appetite suppressant sibutramine may cause elevated BP and HR. In angina pectoris, administration of grapefruit juice could result in atrioventricular conduction disorders with verapamil or attenuated antiplatelet activity with clopidrogel. Grapefruit juice may enhance drug toxicity for antiarrhythmic agents such as amiodarone, quinidine, disopyramide, or propafenone, and for the congestive heart failure drug, carvediol. Some drugs for the treatment of peripheral or central vascular disease also have the potential to interact with grapefruit juice. Interaction with sildenafil, Tadalafil ( Cialis ) , or Vardenafil ( Levitra ) for erectile dysfunction, may cause serious systemic vasodilatation especially when combined with a nitrate. Interaction between ergotamine for migraine and grapefruit juice may cause gangrene or stroke. In stroke, interaction with nimodipine may cause systemic hypotension. If a drug has low inherent oral bioavailability from presystemic metabolism by CYP3A4 or efflux transport by P-gp and the potential to produce serious overdose toxicity, avoidance of grapefruit juice entirely during pharmacotherapy appears mandatory. Although altered drug response is variable among individuals, the outcome is difficult to predict and avoiding the combination will guarantee toxicity is prevented. The elderly are at particular risk, as they are often prescribed medications and frequently consume grapefruit juice.

Gateways to clinical trials.

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abetimus sodium, ademetionine, agalsidase alfa, agalsidase beta, alemtuzumab, alfimeprase, AMG-162, androgel, anidulafungin, antigastrin therapeutic vaccine, aripiprazole, atomoxetine hydrochloride; Bazedoxifene acetate, bevacizumab, bosentan; Caldaret hydrate, canfosfamide hydrochloride, choriogonadotropin alfa, ciclesonide, combretastatin A-4 phosphate, CY-2301; Darbepoetin alfa, darifenacin hydrobromide, decitabine, degarelix acetate, duloxetine hydrochloride; ED-71, enclomiphene citrate, eplerenone, epratuzumab, escitalopram oxalate, eszopiclone, ezetimibe; Fingolimod hydrochloride, FP-1096; HMR-3339A, HSV-TK/GCV gene therapy, human insulin, HuOKT3gamma1(Ala234-Ala235); Idursulfase, imatinib mesylate, indiplon, InnoVax C insulin glargine, insulin glulisine, irofulven; Labetuzumab, lacosamide, lanthanum carbonate, LyphoDerm, Lyprinol; Magnesium sulfate, metelimumab, methylphenidate hydrochloride; Natalizumab, NO-aspirin; OROS(R); PC-515, pegaptanib sodium, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, pemetrexed disodium, peptide YY3-36, posaconazole, pregabalin, PT-141, pyridoxamine; R-744, ramelteon, ranelic acid distrontium salt, rebimastat, repinotan hydrochloride, rhC1, rhGAD65, rosiglitazone maleate/metformin hydrochloride; Sardomozide, solifenacin succinate; Tadalafil ( Cialis ) , taxus, telavancin, telithromycin, tenofovir disoproxil fumarate, teriparatide, testosterone transdermal patch, tetomilast, tirapazamine, torcetrapib; Valspodar, Vardenafil ( Levitra ) hydrochloride hydrate, vildagliptin; Yttrium Y90 epratuzumab; Ziprasidone hydrochloride. 2004 Prous Science.