ABCC10, also known as multidrug-resistant protein 7 (MRP7), is the tenth member of the C subfamily of the ATP-binding cassette (ABC) superfamily. ABCC10 mediates multidrug resistance (MDR) in cancer cells by preventing the intracellular accumulation of certain antitumor drugs. The ABCC10 transporter is a 171-kDa protein that is localized on the basolateral cell membrane. ABCC10 is a broad-specificity transporter of xenobiotics, including antitumor drugs, such as taxanes, epothilone B, vinca alkaloids, and cytarabine, as well as modulators of the estrogen pathway, such as tamoxifen. In recent years, ABCC10 inhibitors, including cepharanthine, lapatinib, erlotinib, nilotinib, imatinib, sildenafil, and vardenafil, have been reported to overcome ABCC10-mediated MDR. This review discusses some recent and clinically relevant aspects of the ABCC10 drug efflux transporter from the perspective of current chemotherapy, particularly its inhibition by tyrosine kinase inhibitors and phosphodiesterase type 5 inhibitors.
Antineoplastic Agents ; Benzamides ; Benzylisoquinolines ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Erlotinib Hydrochloride ; Humans ; Imatinib Mesylate ; Imidazoles ; Multidrug Resistance-Associated Proteins ; antagonists & inhibitors ; Piperazines ; Purines ; Pyrimidines ; Quinazolines ; Sildenafil Citrate ; Sulfonamides ; Sulfones ; Taxoids ; Triazines ; Vardenafil Dihydrochloride

The phosphodiesterase type-5 inhibitors (PDE5-Is) sildenafil, vardenafil and tadalafil are widely used as first-line therapy for erectile dysfunction (ED). Since the approval of sildenafil in 1998, more than 40 million men worldwide have been successfully treated with PDE5-Is. Pharmacologically, the proven safety and high tolerance of PDE5-Is is an attractive tool to investigate further physiological functions of PDE5, for example the modulation of intracellular cyclic GMP (cGMP) pools. As cGMP is a key component of intracellular signaling this may provide novel therapeutic opportunities beyond ED even for indications in which chronic administration is necessary. The approval of sildenafil for the treatment of pulmonary hypertension in 2005 was a notable success in this area of research. A number of other potential new indications are currently in various phases of preclinical research and development. In recent years, extensive but very heterogeneous information has been published in this field. The aim of this review is to summarize existing preclinical and clinical knowledge and critically discuss the evidence to support potential future indications for PDE5 inhibitors.
Carbolines ; Cyclic GMP ; Cyclic Nucleotide Phosphodiesterases, Type 5 ; Erectile Dysfunction ; Humans ; Hypertension, Pulmonary ; Imidazoles ; Male ; Piperazines ; Purines ; Sulfones ; Triazines ; Sildenafil Citrate ; Tadalafil ; Vardenafil Dihydrochloride

Currently, phosphodiesterase type 5 (PDE5) inhibitors are the initial treatment option for erectile dysfunction. The reported efficacy of PDE5 inhibitors is about 70%, although it is significantly lower in difficult-to-treat subpopulations. Treatment failures might be due to the severity of the underlying pathophysiology, improper use of medication, unrealistic patient expectations, difficult relationship dynamics, severe performance anxiety, and other psychological problems. Physicians must address these issues to identify true treatment failures attributable to the drugs. This article discusses factors that might affect the response to PDE5 inhibitors and develops a strategy to maximize the overall efficacy of PDE5 inhibitors in initial non-responders to PDE5 inhibitors.
Carbolines ; Erectile Dysfunction ; Humans ; Imidazoles ; Male ; Performance Anxiety ; Phosphodiesterase 5 Inhibitors ; Piperazines ; Purines ; Sulfones ; Treatment Failure ; Triazines ; Sildenafil Citrate ; Tadalafil ; Vardenafil Dihydrochloride

PURPOSE: After the market launch of multiple phosphodiesterase type 5 inhibitors (PDE5Is), a considerable amount of information has emerged regarding the efficacy and the time of initiation of these drugs. In clinical situations, however, many patients with erectile dysfunction (ED) have complained about the onset of erection occurring later than expected or desired. We therefore studied the time course for initiating an erection after usage of PDE5Is. MATERIALS AND METHODS: One hundred forty-one patients who were medicated with PDE5Is > 4 times in the most recent 3 months were included for study. The patients were divided into 3 groups: sildenafil (n=51), vardenafil (n=51), and tadalafil (n=39). The choice of PDE5I was made according to the patient's and/or doctor's preferences. Regardless of the type of drug selected, the patients were recommended to have sexual stimulation 15 minutes after taking the medication. RESULTS: The onset of action of the 3 drug groups were significantly different (sildenafil, 57.0+/-38.5 min; tadalafil, 79.5+/-50.6 min; and vardenafil, 44.4+/-26.6 min; p<0.05). Psychogenic causes of ED resulted in a shorter PDE5I onset of action than organic causes of ED. Other factors, such as body mass index and international index of erectile function erectile function domain score, were shown not to differ with respect to the onset of action of PED5Is. CONCLUSION: In clinical situations, patients need more time for the onset of erections after taking PDE5Is. For restoration of a healthy sexual life, patients needs more time to achieve an erection after taking PDE5Is.
Body Mass Index ; Carbolines ; Erectile Dysfunction ; Humans ; Imidazoles ; Male ; Phosphodiesterase 5 Inhibitors ; Piperazines ; Purines ; Sulfones ; Triazines ; Sildenafil Citrate ; Tadalafil ; Vardenafil Dihydrochloride

OBJECTIVETo evaluate phosphodiesterase type 5 (PDE5) inhibitors in the management of temporary penile erectile dysfunction (ED) in patients undergoing assisted reproductive technology (ART).

METHODSThis study included 75 male patients that experienced ejaculation failure due to temporary ED during ART treatment. We treated the patients with PDE5 inhibitors sildenafil, tadanafil and vardenafil, and then evaluated the hardness of penile erection using Erection Hardness Score (EHS) and analyzed the end-point efficacy.

RESULTSSildenafil was administered to 28 of the patients, tadanafil to 25, and vardenafil to 22. Of the total number of patients, 61 (81.3%) achieved effective erection, but no significant differences were observed in the rate of effectiveness among the sildenafil (24 cases, 85.7%), tadanafil (20 cases, 80.0%) and vardenafil (17 cases, 77.3%) groups (P > 0.05). After medication, 53 (70.7%) of the patients successfully ejaculated, but there were no remarkable differences in the success rate among the sildenafil (21 cases, 75.0%), tadanafil (17 cases, 68.0%) and vardenafil (15 cases, 68.2%) groups (P > 0.05). Of the 75 patients, 37 received the recommended initial dose and 38 the maximum recommended dose of PDE5 inhibitors, but no significant differences were found in the rate of successful sperm retrieval between the former (28 cases, 75.7%) and the latter group (25 cases, 65.8%) (P > 0.05). Mild adverse events, including transient flush and dizziness, occurred in 5 cases (6.7%).

CONCLUSIONPDE5 inhibitors can help temporary ED patients to achieve penile erection and ejaculation during ART treatment.

Ejaculation ; Erectile Dysfunction ; drug therapy ; Humans ; Imidazoles ; therapeutic use ; Male ; Phosphodiesterase 5 Inhibitors ; therapeutic use ; Piperazines ; therapeutic use ; Purines ; therapeutic use ; Reproductive Techniques, Assisted ; Sildenafil Citrate ; Sulfonamides ; therapeutic use ; Sulfones ; therapeutic use ; Triazines ; therapeutic use ; Vardenafil Dihydrochloride

The rate of erectile dysfunction after radical retropubic prostatectomy is from 10% to 100%. The prevalence of erectile dysfunction after nerve-sparing radical prostatectomy is more than one third. In the patients who had undergone bilateral NS, 72% responded to sildenafil, 71.7% and 59.7% responded to 20 mg and 10 mg of vardenafil respectively. For all randomized patients who received tadalafil, the mean percentage of successful penetration attempts was 54% and the mean percentage of successful intercourse attempts was 41%. For the subgroup with evidence of postoperative tumescence these values were 69% and 52%, respectively. No head-to-head trials have been performed with sildenafil, vardenafil and tadalafil in treatment of erectile dysfunction after radical prostatectomy.
Carbolines ; therapeutic use ; Erectile Dysfunction ; drug therapy ; etiology ; Humans ; Imidazoles ; therapeutic use ; Male ; Phosphodiesterase Inhibitors ; therapeutic use ; Piperazines ; therapeutic use ; Prostatectomy ; adverse effects ; Purines ; therapeutic use ; Sildenafil Citrate ; Sulfones ; therapeutic use ; Tadalafil ; Triazines ; therapeutic use ; Vardenafil Dihydrochloride

Vardenafil is a potent and highly selective phosphodiesterase type 5 (PDE5) inhibitor with a potency about 10-fold higher than sildenafil. Vardenafil can significantly improve erectile function and works rapidly. Vardenafil is a PDE5 inhibitor with the fastest onset of action among its kind so far found and works as early as 10 minutes after oral administration, providing patients with penile erection sufficient to complete an intercourse. The absolute oral bioavailability is about 15%. Vardenafil is rapidly absorbed with a median tmax of 0.7 h and a terminal half-life (t1/2) of more than 4 h. The observed pharmacodynamic properties, pharmacokinetic characteristics and good safety and tolerability profile showed that vardenafil treatment provides an effective and generally well tolerated treatment for ED.
Adolescent ; Adult ; Aged ; Animals ; Erectile Dysfunction ; drug therapy ; Half-Life ; Humans ; Imidazoles ; pharmacokinetics ; pharmacology ; Male ; Middle Aged ; Phosphodiesterase Inhibitors ; pharmacokinetics ; pharmacology ; Piperazines ; pharmacokinetics ; pharmacology ; Purines ; pharmacokinetics ; pharmacology ; Rabbits ; Sildenafil Citrate ; Sulfones ; pharmacokinetics ; pharmacology ; Triazines ; pharmacokinetics ; pharmacology ; Vardenafil Dihydrochloride

PURPOSE: We analyzed the prescriptions of alpha-blockers and phosphodiesterase 5 inhibitors (PDE5Is) in the urology department as well as in other departments of the general hospital. METHODS: We investigated the frequency of prescription of alpha-blockers and PDE5Is from 3 general hospitals from January 1, 2007 to December 31, 2009. For alpha-blockers, data were collected from patients to whom alpha-blockers were prescribed from among patients recorded as having benign prostatic hyperplasia according to the 5th Korean Standard Classification of Diseases. For PDE5Is, data were collected from patients to whom PDE5Is were prescribed by the urology department and by other departments. Alpha-blockers were classified into tamsulosin, alfuzosin, doxazosin, and terazosin, whereas PDE5Is were classified into sildenafil, tadalafil, vardenafil, udenafil, and mirodenafil. RESULTS: Alpha-blockers were prescribed to 11,436 patients in total over 3 years, and the total frequency of prescriptions was 68,565. Among other departments, the nephrology department had the highest frequency of prescription of 3,225 (4.7%), followed by the cardiology (3,101, 4.5%), neurology (2,576, 3.8%), endocrinology (2,400, 3.5%), pulmonology (1,102, 1.6%), and family medicine (915, 1.3%) departments in order. PDE5Is were prescribed to 2,854 patients in total over 3 years, and the total frequency of prescriptions was 10,558. The prescription frequency from the urology department was 4,900 (46.4%). Among other departments, the endocrinology department showed the highest prescription frequency of 3,488 (33.0%), followed by the neurology (542, 5.1%), cardiology (467, 4.4%), and family medicine (407, 3.9%) departments in order. CONCLUSIONS: A high percentage of prescriptions of alpha-blockers and PDE5Is were from other departments. For more specialized medical care by urologists is required in the treatment of lower urinary tract symptoms and erectile dysfunction.
Adrenergic alpha-1 Receptor Antagonists ; Carbolines ; Cardiology ; Cyclic Nucleotide Phosphodiesterases, Type 5 ; Doxazosin ; Endocrinology ; Erectile Dysfunction ; Hospitals, General ; Humans ; Imidazoles ; Lower Urinary Tract Symptoms ; Male ; Nephrology ; Neurology ; Phosphodiesterase 5 Inhibitors ; Piperazines ; Prazosin ; Prescriptions ; Prostatic Hyperplasia ; Pulmonary Medicine ; Purines ; Pyrimidines ; Quinazolines ; Sildenafil Citrate ; Sulfonamides ; Sulfones ; Tadalafil ; Triazines ; Urology ; Vardenafil Dihydrochloride

Sociopsychological factors play a critical role in the pathogenesis of erectile dysfunction (ED). An optimal therapeutic regimen is supposed to bring sociopsychological benefits to both the patients and their partners. Psychological and Interpersonal Relationship Scales (PAIRS) is an effective measure for evaluating the impact of ED on the psychological aspects and interpersonal relationship of the patients and their partners, as well as for predicting the satisfaction of ED patients with the treatment. PAIRS scores on the effects of phosphodiesterase type 5 inhibitors on ED show a significant decrease in sexual activity-related time concerns of the patients treated with tadalafil, as compared with those medicated with sildenafil or vardenafil. This also underlies the preference of the patients and their partners for tadalafil in clinical practice. The drug attribute associated with the decreased time concerns is the long and outstanding efficacy of tadalafil for up to 36 hours.
Carbolines ; therapeutic use ; Erectile Dysfunction ; drug therapy ; psychology ; Female ; Humans ; Imidazoles ; therapeutic use ; Interpersonal Relations ; Male ; Phosphodiesterase Inhibitors ; therapeutic use ; Piperazines ; therapeutic use ; Purines ; therapeutic use ; Sildenafil Citrate ; Sulfones ; therapeutic use ; Tadalafil ; Time Factors ; Treatment Outcome ; Triazines ; therapeutic use ; Vardenafil Dihydrochloride

Recently published articles on interstitial lung disease (ILD) have focused on the accurate diagnosis of idiopathic pulmonary fibrosis (IPF), serum biomarkers, acute exacerbation of IPF, the prognostic factors of ILD and the trial of new treatment. In particular, reports on the serum biomarkers such as CC-chemokine ligand 18, surfactant protein, circulating fibrocytes, and acute exacerbation of IPF are sufficient to be mentioned here. Pirfenidone therapy is the most important trial for the treatment of IPF. Other newer treatment trials such as interferon-gamma, sildenafil and imatinib have been reported to be unsuccessful. On the other hand, the sirolimus trial for lymphangioleiomyomatosis is promising. Combined pulmonary fibrosis and emphysema and IgG4-related disease are established to be the new disease entities of ILD.
Benzamides ; Biomarkers ; Emphysema ; Hand ; Idiopathic Pulmonary Fibrosis ; Interferon-gamma ; Lung Diseases, Interstitial ; Lymphangioleiomyomatosis ; Piperazines ; Pulmonary Fibrosis ; Purines ; Pyridones ; Pyrimidines ; Sirolimus ; Sulfones ; Imatinib Mesylate ; Sildenafil Citrate