tacrolimus and Erectile-Dysfunction

GPI-1485 is a neuroimmunophilin ligand that binds to FK-506-binding proteins and is under development by Guilford for the potential treatment of erectile dysfunction following nerve injury during prostate resection and Parkinson's disease. In August 2002, phase II clinical trials investigating GPI-1485 for Parkinson's disease commenced, and in November 2003, further phase II trials commenced for post-prostatectomy erectile dysfunction.

Topics: Administration, Oral; Animals; Antiparkinson Agents; Clinical Trials, Phase II as Topic; Erectile Dysfunction; Humans; Male; Parkinson Disease; Patents as Topic; Prostatectomy; Structure-Activity Relationship; Tacrolimus

Radical prostatectomy (RP) is associated with erectile dysfunction, largely mediated through cavernous nerve injury. There are robust pre-clinical data supporting a potential role for neuromodulatory agents in this patient population. This study assessed tacrolimus in improving erectile function recovery rates after RP (ClinicalTrials.gov number, NCT00106392).. To define the utility of oral tacrolimus in improving erectile function recovery after nerve sparing radical prostatectomy.. A randomized, double-blind trial compared tacrolimus 2-3 mg daily and placebo in men undergoing RP. Patients had localized prostate cancer and excellent baseline erectile function, underwent bilateral nerve-sparing RP, and were followed up for at least 18 months after RP. Patients received study drug for 27 weeks and completed the International Index of Erectile Function erectile function domain (EFD) questionnaire at baseline and serially after surgery.. International Index of Erectile Function erectile function domain score.. Data were available for 124 patients (59 tacrolimus, 65 placebo); mean age was 54.6 ± 6.2 years. No patient experienced permanent creatinine or potassium elevation. At baseline, mean EFD scores were 28.6 ± 2.1 (tacrolimus group) and 29 ± 1.5 (placebo group). By week 5, mean EFD scores had dropped to 8 ± 9.4 (tacrolimus) and 9 ± 10.7 (placebo). At 18 months, mean EFD scores were 16.0 ± 11.3 (tacrolimus) and 20.2 ± 9.0 (placebo) (P = .09). Tacrolimus failed to meet significance (hazard ratio = 0.83; P = .50), with no difference in: (i) percentage of patients achieving normal spontaneous erectile function (EFD score ≥24), (ii) time to normalization of EFD score (≥24), (iii) percentage of patients capable of intercourse in response to phosphieserase type 5 inhibitor (PDE5i), and (iv) time to achieve response to PDE5i.. Despite positive animal data, oral tacrolimus as used in this trial failed to improve erectile function after nerve sparing radical prostatectomy.. The study is limited by a high attrition rate. The strengths include a randomized, placebo controlled design, extensive patient monitoring, use of medication diaries and a validated instrument as the primary outcome measure.. Despite supportive animal data, tacrolimus used in this fashion in the RP population failed to demonstrate any superiority over placebo. Mulhall JP, Klein EA, Slawin K, et al. A Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Utility of Tacrolimus (FK506) for the Prevention of Erectile Dysfunction Following Bilateral Nerve-Sparing Radical Prostatectomy. J Sex Med 2018;15:1293-1299.

Topics: Aged; Double-Blind Method; Erectile Dysfunction; Humans; Male; Middle Aged; Neurotransmitter Agents; Penile Erection; Postoperative Complications; Prostatectomy; Prostatic Neoplasms; Recovery of Function; Surveys and Questionnaires; Tacrolimus; Treatment Outcome; United States

Hypomagnesemia with urinary magnesium wasting is a well described adverse event with calcineurin inhibitor therapy. Prostate cancer is the most prevalent cancer in men in the United States. Injury to the cavernous nerves during radical prostatectomy frequently results in erectile dysfunction. Tacrolimus has been shown to be neuroprotective in the rat cavernous nerve injury model, an animal model representative of the neural injury that occurs in humans at the time of radical prostatectomy.. In a randomized, double-blind, placebo-controlled trial, the utility of tacrolimus was assessed for prevention of erectile dysfunction following bilateral nerve-sparing radical prostatectomy.. Low dose tacrolimus, associated with low trough levels, resulted in mild hypomagnesemia, which was an early and persistent finding. As early as one week after institution of therapy, mean and median serum magnesium levels were significantly lower in the tacrolimus arm as compared to the placebo arm (p<0.001 for both). While the mean and median levels were within the normal range at Week 1, 10.9% of tacrolimus-treated patients had levels <1.8mg/dL, compared to none in the placebo arm (p=0.017). Median and mean levels remained significantly different at Week 5, Month 3 and Month 6. No clinical manifestations of hypomagnesemia were noted and no subject required treatment with magnesium. Changes in serum magnesium occurred earlier than other potential metabolic adverse events described with tacrolimus (changes in serum glucose, creatinine or potassium).. These data indicate that mild hypomagnesemia is an early and sensitive biomarker for the effect of tacrolimus on the kidney.

Topics: Calcineurin Inhibitors; Double-Blind Method; Erectile Dysfunction; Humans; Magnesium; Male; Middle Aged; Prostatectomy; Prostatic Neoplasms; Tacrolimus

Sildenafil may provide an effective treatment for erectile dysfunction, frequently observed in uremic patients and after kidney transplantation. Pharmacokinetic interactions between sildenafil and tacrolimus are to be expected due to a common elimination pathway via cytochrome P450 3A4. Therefore, the pharmacokinetics during combined use of these agents were studied over 9 days.. Nine male patients (age 29-52 years) were included, who had previously participated in a recent interaction study with sildenafil given as a single dose. Comedication remained unchanged in order to avoid introducing confounding factors. In the previous study in the patients, tacrolimus blood levels with and without sildenafil were measured for pharmacokinetic analysis. In the present study, 25 mg sildenafil were coadministered daily over 9 days and tacrolimus levels were assessed at sampling times optimized using simulation. In addition, laboratory parameters and blood pressure changes were measured and adverse effects monitored.. Terminal half-lives of tacrolimus did not differ significantly and trough levels did not change when sildenafil was coadministered daily over 9 days. Mean arterial blood pressure was lower after sildenafil intake. Two patients had to reduce their antihypertensive treatment, 6 patients reported mild side effects. In 1 case, there was an asymptomatic, temporary increase in the serum concentration of gamma-GT.. There was no evidence obtained for a change in elimination half-life or average concentration of tacrolimus during repeated coadministration of sildenafil. Since blood pressure decreased, a starting dose of 25 mg sildenafil and, if necessary, adjustment of the dose of antihypertensive drugs on days when sildenafil is given has to be considered. With respect to the observed blood pressure changes, pharmacokinetic/pharmacodynamic interaction studies with other antihypertensive drugs are of critical importance in these patients.

Topics: Adult; Blood Pressure; Drug Interactions; Erectile Dysfunction; Half-Life; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tacrolimus; Vasodilator Agents

To study the pharmacokinetics of the combined use of sildenafil (which may provide an effective treatment for patients with erectile dysfunction after kidney transplantation) and tacrolimus, as interactions between them are expected because of a common elimination pathway.. Ten male patients (age 29 to 52 years) were included. Because of its importance in transplant recipients, medication remained unchanged. On day 1, tacrolimus was administered routinely, and blood samples for tacrolimus assays were drawn at predefined times. On day 2, sildenafil was added and blood was collected for assays of tacrolimus, sildenafil, and the sildenafil metabolite UK103,320 (UK) at the indicated times. Blood pressure was monitored on both study days. Sildenafil and UK were assessed by high-pressure liquid chromatography and tacrolimus was assessed by microparticle enzyme immunoassay.. No effects of sildenafil on the tacrolimus pharmacokinetics were found. However, in the patients studied, the sildenafil and UK pharmacokinetics were altered compared with the results of previous studies. The mean peak concentration of sildenafil was higher by 44% and the area under the concentration-time data increased by 90%. The elimination half-life was prolonged (4.7 hours compared with 3 hours in healthy volunteers). The area under the concentration-time data for UK was about threefold larger than in healthy volunteers, and the half-life was prolonged from 3.8 hours to 11.4 hours. Pronounced blood pressure drops were observed.. Tacrolimus or the concomitant medication or the disease itself might have altered the sildenafil and UK pharmacokinetics. Because of the drop in blood pressure, sildenafil therapy should start at the lowest dose and any antihypertensive medication should be adjusted.

Topics: Adult; Area Under Curve; Biological Availability; Blood Pressure; Drug Interactions; Drug Therapy, Combination; Erectile Dysfunction; Half-Life; Humans; Kidney Transplantation; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tacrolimus

Topics: Double-Blind Method; Erectile Dysfunction; Humans; Male; Penile Erection; Prostatectomy; Tacrolimus

Topics: Double-Blind Method; Erectile Dysfunction; Humans; Male; Prostatectomy; Tacrolimus

Topics: Erectile Dysfunction; Humans; Male; Organ Sparing Treatments; Penile Erection; Prostatectomy; Prostatic Neoplasms; Tacrolimus

For familial amyloidotic polyneuropathy (FAP) patients, several problems regarding reproduction are present. For males, erectile dysfunction and retrograde ejaculation are well known complications of the disease In addition, the risk of transferring a fatal disease to their offspring is a matter of concern for the patients. For transplanted fertile patients, the risk of side effects of immunosupression therapy causing congenital malformations must be addressed, and for female patients the additional risk of complications during pregnancy and delivery is a case of concern. After delivery, the problem of breast-feeding arises. In the Swedish population of transplanted patients, five successful pregnancies, of which male FAP recipients fathered three, are reported. All patients were on stable immunosuppressive therapy with cyclosporine or tacrolimus and prednisolone. From our experience, successful fatherhood and pregnancy is possible for liver transplanted FAP patients, as it has been reported for patients transplanted for other medical reasons.

Topics: Adult; Amyloid Neuropathies, Familial; Cyclosporine; Erectile Dysfunction; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Prednisolone; Pregnancy; Pregnancy Complications; Tacrolimus

Hepatic metabolism of sildenafil uses the same metabolic pathway as the calcineurin inhibitors (cyclosporine/tacrolimus), through the CYP3A4 isoenzyme. The aim of this pilot study was to evaluate the potential interaction between sildenafil therapy and circulating levels of cyclosporine and tacrolimus in a group of steady-state renal transplant recipients with erectile dysfunction.. A prospective pilot study of sildenafil interactions was carried out in 9 stable male renal transplant recipients with severe erectile dysfunction (mean age 50 +/- 8 years, range 38-64). All patients were receiving therapy with calcineurin inhibitors (5 with cyclosporine and 4 with tacrolimus). Erectile dysfunction was evaluated by clinical history, physical examination, International Index of Erectile Function (IIEF) questionnaire and the nocturnal penile tumescence test (RigiScan). Each patient received a first dose of 50 mg of sildenafil, one hour before sexual activity and a second dose at 72 hours of 50 or 100 mg according to the clinical response to the first dose. We evaluated the efficacy and safety of sildenafil and the evolution of cyclosporine-tacrolimus levels. Cyclosporine and tacrolimus trough whole blood concentrations were determined in basal conditions (before starting sildenafil) and on days 1, 4 and 7 after sildenafil therapy.. Eighty-nine percent of patients (n = 8) required a complete 100 mg dose of sildenafil. There was a positive clinical response in two-thirds of cases (6 patients). In 5 patients (55%) sildenafil administration produced a complete response, in one patient the response was incomplete, and in the remaining 3 cases (33%) no clinical response was observed. Associated side effects included self-limited tachycardia in one patient and mild visual disturbances in another. Cyclosporine and tacrolimus levels remained stable in all patients. There were no significant differences in circulating levels of cyclosporine (basal 120 +/- 47; day 1: 116 +/- 55; day 4: 123 +/- 56 and day 7: 121 +/- 56 ng/ml p = NS) or tacrolimus (basal 11.6 +/- 1.3; day 1: 11.9 +/- 1.3; day 4: 11.1 +/- 1.0 and day 7: 11.8 +/- 0.9 ng/ml p = NS) over the study period.. Sildenafil therapy is safe and effective for the treatment of erectile dysfunction in renal transplant recipients. Recommended therapeutic doses of sildenafil did not modify cyclosporine and tacrolimus trough blood levels.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Interactions; Erectile Dysfunction; Graft Rejection; Humans; Immunosuppressive Agents; Inactivation, Metabolic; Kidney Transplantation; Male; Microsomes, Liver; Middle Aged; Pilot Projects; Piperazines; Purines; Safety; Sildenafil Citrate; Sulfones; Tachycardia; Tacrolimus; Treatment Outcome; Vasodilator Agents

Topics: Animals; Axons; Erectile Dysfunction; Immunophilins; Ligands; Male; Neuroprotective Agents; Penis; Rats; Tacrolimus

The improvement of quality of life is one of the major goals in the treatment of patients after renal transplantation. While immunosuppressive therapy is present in almost all of these patients, little is known about the effects of newer immunosuppressive agents. We therefore investigated the impact of tacrolimus on life quality. From November 1997 to January 1998, a questionnaire was handed out which focussed on physical and mental problems as well as sexual capacity and the attitudes towards graft, donor and transplant related side effects. 50 kidney graft recipients treated with tacrolimus were matched to 50 patients with a cyclosporine-based immunosuppression (= controls). Values are given as mean +/- standard deviation. Tacrolimus treated patients had a mean creatinine of 1.8 +/- 0.8 mg/dl, as compared to 1.6 +/- 0.7 mg/dl in controls. The overall status of health was assessed to be good in 82% of the tacrolimus group (controls: 80%). 38% were working full-time (controls: 20%). Only 14% of patients described their physical condition as poor (16% in controls). Sexual function was good in 66% (controls: 74%) and poor in 10% (controls: 12%). Mental function was assessed to be good in 92% (controls: 82%). The majority of patients felt comfortable with their physical, sexual and mental capabilities. This was independent from the immunosuppressive regimen.

Topics: Cyclosporine; Erectile Dysfunction; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Libido; Male; Mental Processes; Middle Aged; Quality of Life; Surveys and Questionnaires; Tacrolimus