Erectile dysfunction in young patients and elderly patients by sexual encounter profile: A comparative study.

OBJECTIVE: Demand for erectile dysfunction treatments has increased not only in elderly patients but also in young patients. Reports indicate that frequent causes of erectile dysfunction in Japan are organic disorders in elderly patients and psychogenetic disorders in young patients. METHODS: We defined patients under the age of 40 as young erectile dysfunction patients, and those over 65 as elderly erectile dysfunction patients. We divided these two groups and conducted a retrospective comparative study based on medical questionnaires. We selected 215 cases of patients under the age of 40, and 176 cases of patients over the age of 65, and created a group of young patients and a group of elderly patients. We implemented the erectile hardness score, Sexual Health Inventory for Men, and sexual encounter profile questions 2 and 3 as the patient's daily clinical journal. RESULTS: The median age of young patients was 36 years, and that of elderly patients was 70 years. With respect to Sexual Health Inventory for Men, the average score was a significantly higher score in the young patients (9.26 vs 7.10, P < 0.001). Concerning erectile hardness score, young patients showed significantly higher scores in erectile hardness score (3.15 vs 2.06, P < 0.001). In terms of sexual encounter profile question 2, 50.9% of young patients responded "yes," but 24.3% of elderly patients responded, thus indicating a significantly higher score in young patients. In terms of sexual encounter profile question 3, 6.1% of young patients responded "yes," and 0.7% of elderly patients responded "yes," indicating a significantly higher in young patients. CONCLUSIONS: The results showed that many young patients with erectile dysfunction were able to perform insertion, but were unable to maintain erection.

Investigation of Endogenous Compounds Applicable to Drug-Drug Interaction Studies Involving the Renal Organic Anion Transporters, OAT1 and OAT3, in Humans.

This study was a comprehensive analysis of metabolites in plasma and urine specimens from subjects who received probenecid, a potent inhibitor of renal organic anion transporters (OATs). Taurine and glycochenodeoxycholate sulfate (GCDCA-S) could be identified using authentic standards. Probenecid had no effect on the area under the plasma-concentration time curves of taurine and GCDCA-S, whereas it significantly inhibited their urinary excretion in a dose-dependent manner. Probenecid at 500, 750, and 1500 mg orally decreased the renal clearance (CLR) values of taurine and GCDCA-S by 45% and 60%, 59% and 79%, and 70% and 88%, respectively. The CLR values correlated strongly (r > 0.96) between the test compounds (benzylpenicillin, 6ß-hydroxycortisol, taurine, and GCDCA-S). Taurine and GCDCA-S were substrates of OAT1 and OAT3, with Km values of 379 ± 58 and 64.3 ± 3.9 µM, respectively. The Ki values of probenecid for the OAT1- and OAT3-mediated uptake of taurine and GCDCA-S (9.49 ± 1.27 and 7.40 ± 0.70 µM, respectively) were similar to those of their typical substrate drugs. The magnitude of the reduction in the CLR of taurine and GCDCA-S by probenecid could be reasonably explained using the geometric mean values of unbound probenecid concentration and Ki values. These results suggest that taurine and GCDCA-S can be used as probes for evaluating pharmacokinetic drug-drug interactions involving OAT1 and OAT3, respectively, in humans.

A Novel Selective Prostaglandin E2 Synthesis Inhibitor Relieves Pyrexia and Chronic Inflammation in Rats.

Prostaglandin E2 (PGE2) is a terminal prostaglandin in the cyclooxygenase (COX) pathway. Inhibition of PGE2 production may relieve inflammatory symptoms such as fever, arthritis, and inflammatory pain. We report here the profile of a novel selective PGE2 synthesis inhibitor, compound A [N-[(1S,3S)-3-carbamoylcyclohexyl]-1-(6-methyl-3-phenylquinolin-2-yl)piperidine-4-carboxamide], in animal models of pyrexia and inflammation. The compound selectively suppressed the synthesis of PGE2 in human alveolar adenocarcinoma cell line A549 cells and rat macrophages. In the lipopolysaccharide-induced pyrexia model, this compound selectively reduced PGE2 production in cerebrospinal fluid and showed an anti-pyretic effect. In the adjuvant-induced arthritis model, compound A therapeutically decreased foot swelling in the established arthritis. Our data demonstrates that selective suppression of PGE2 synthesis shows anti-pyretic and anti-inflammatory effects, suggesting that selective PGE2 synthesis inhibitors can be applied as an alternative treatment to nonsteroidal, anti-inflammatory drugs (NSAIDs) or COX-2-selective inhibitors.

INITIAL EXPERIENCE OF THE ENZALUTAMIDE TREATMENT FOR CASTRATION-RESISTANT PROSTATE CANCER.

(Objective) Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with castration-resistant prostate cancer (CRPC). We retrospectively evaluated clinical efficacy and safety of enzalutamide in CRPC. (Patients and methods) We reviewed clinical records of 73 patients who had received enzalutamide for the CRPC at Showa University and affiliated 7 hospitals. Enzalutamide was given at a dose of 160 mg/day, but some patients were treated at lower dose because of there age or poor performance status. Prostrate-specific antigen (PSA) response, prior docetaxel use and the previously administered agents were evaluated retrospectively. (Results) The median patients age was 77 years, the median Gleason score was 9 and the median PSA level at baseline was 26.9 ng/ml. The patients who had prior docetaxel use were 29 (39.7%) and the median of total docetaxel dose was 460 mg/body. The median number of total prior treatments (anti-androgens, Estramustine and steroid) was 3. Twenty seven (61.4%) patients with docetaxel-naïve achieved over 50% reduction of PSA level from baseline, but only 7 (24.1%) in patients previously treated with docetaxel. The most common adverse events included fatigue (24.7%), anorexia (24.7%) and the nausea (16.4%). We found a small proportion of responders to enzalutamide experienced a PSA flare. (Conclusion) Our results of the use of Enzaltamide for CRPC were similar with previous reports. PSA flare was found in some patients with CRPC who responded to enzaltamide. It should be noted that this possible PSA flare phenomenon.

6ß-Hydroxycortisol is an endogenous probe for evaluation of drug-drug interactions involving a multispecific renal organic anion transporter, OAT3/SLC22A8, in healthy subjects.

6ß-Hydroxycortisol (6ß-OHF) is a substrate of the organic anion transporter 3 (OAT3) and the multidrug and toxin extrusion proteins MATE1 and MATE-2K in the corresponding cDNA-transfected cells. This study aimed to examine the contribution of OAT3 and MATEs to the urinary excretion of 6ß-OHF in humans using the appropriate in vivo inhibitors, probenecid and pyrimethamine, for OAT3 and MATEs, respectively. Oat3(-/-) mice showed significantly reduced renal clearance of 6ß-OHF (CL(renal, 6ß-OHF)) compared with wild-type mice (18.1 ± 1.5 versus 7.60 ± 1.8 ml/min/kg). 6ß-OHF uptake by human kidney slices was inhibited significantly by probenecid to 20-45% of the control values and partly by 1-methyl-4-phenylpyridinium. 6ß-OHF plasma concentration and the amount of 6ß-OHF excreted into the urine (X(6ß-OHF)) were measured in healthy subjects enrolled in drug-drug interaction studies of benzylpenicillin alone or with probenecid (study 1), adefovir alone or with probenecid (study 2), and metformin alone or with pyrimethamine (study 3). Probenecid treatment caused a 57 and 76% increase in the area under the plasma concentration-time curve for 6ß-OHF (AUC(6ß-OHF)) in studies 1 and 2, respectively, but did not affect X(6ß-OHF). Consequently, CL(renal, 6ß-OHF) (milliliters per minute) decreased significantly from 231 ± 11 to 135 ± 9 and from 225 ± 26 to 141 ± 12 after probenecid administration in studies 1 and 2, respectively. By contrast, neither AUC(6ß-OHF) nor CL(renal, 6ß-OHF) was significantly altered by pyrimethamine administration. Taken together, these data suggest that OAT3 plays a significant role in the urinary excretion of 6ß-OHF, and that 6ß-OHF can be used to investigate the perpetrators of the pharmacokinetic drug interactions involving OAT3 in humans.

Effect of the fluoroquinolone antibacterial agent DX-619 on the apparent formation and renal clearances of 6ß-hydroxycortisol, an endogenous probe for CYP3A4 inhibition, in healthy subjects.

PURPOSE: To examine the effect of the fluoroquinolone DX-619 on CYP3A4 and urinary excretion of 6ß-hydroxycortisol, an endogenous probe of hepatic CYP3A4 activity, in healthy subjects. METHODS: The effect of DX-619 on CYP3A4 was examined in human liver microsomes. The apparent formation and renal clearance of 6ß-hydroxycortisol (CL(6ß-OHF) and CL(renal,6ß-OHF), respectively) were determined in placebo- and DX-619-treated subjects. 6ß-hydroxycortisol uptake was determined in HEK293 cells expressing OAT1, OAT3, OCT2, MATE1, and MATE2-K. RESULTS: DX-619 was a mechanism-based inhibitor of CYP3A4, with K(I) and k(inact) of 67.9 ± 7.3 µmol/l and 0.0730 ± 0.0033 min(-1), respectively. Pharmacokinetic simulation suggested in vivo relevance of CYP3A4 inhibition by DX-619. CL(6ß-OHF) and CL(renal,6ß-OHF) were decreased 72% and 70%, respectively, on day 15 in DX-619-treated group compared with placebo (P < 0.05). 6ß-hydroxycortisol was a substrate of OAT3 (K(m) = 183 ± 25 µmol/l), OCT2, MATE1, and MATE2-K. Maximum unbound concentration of DX-619 (9.1 ± 0.4 µmol/l) was above K(i) of DX-619 for MATE1 (4.32 ± 0.79 µmol/l). CONCLUSIONS: DX-619 caused a moderate inhibition of hepatic CYP3A4-mediated formation and significant inhibition of MATE-mediated efflux of 6ß-hydroxycortisol into urine. Caution is needed in applying CL(6ß-OHF) as an index of hepatic CYP3A4 activity without evaluating CL(renal,6ß-OHF).

Validation studies on blood collection from the jugular vein of conscious mice.

A method for blood collection from the jugular vein of mice without anesthesia was compared with a tail-incision technique. Jugular vein blood collection allowed withdrawal of almost 15% of the circulating blood volume at a time in less than 1 min. Hemolysis, hematocrit, and plasma thrombin-antithrombin complexes (a marker of blood coagulation) were higher in samples collected from the tail vein than the jugular vein. Mice produced similar plasma corticosterone levels after serial blood collection by either method. Tail incision led to a slight but significant increase in C-reactive protein levels. Using the jugular venipuncture technique, we then performed a pharmacokinetic study and an oral glucose tolerance test. Plasma concentrations of levofloxacin, an antimicrobial agent, were dose-dependently elevated after oral administration, and linear increases in C(max) and AUC were observed. We also confirmed that overall glucose excursion is significantly decreased in mice treated with exendin 4, a glucagon-like peptide 1 agonist. These results indicate that the jugular venipuncture is a useful technique from the point of view of no requirement for anesthetics, serial blood collection at short intervals, large volume of blood collection, quality of sample and animal welfare. This technique is of particular interest for studies that examine time-dependent changes in blood variables.

Helicobacter pylori eradication by sitafloxacin-lansoprazole combination and sitafloxacin pharmacokinetics in Mongolian gerbils and its in vitro activity and resistance development.

A total of 293 strains of Helicobacter pylori, including strains resistant to levofloxacin, clarithromycin, metronidazole, or amoxicillin, were examined for in vitro susceptibility to 10 antimicrobial agents. Among these agents, sitafloxacin (a fluoroquinolone) showed the greatest activity (MIC(90), 0.06 µg/ml), with high bactericidal activity and synergy in sitafloxacin-lansoprazole (a proton pump inhibitor) combination. In a Mongolian gerbil model with a H. pylori ATCC 43504 challenge, marked eradication effects were observed at ≥1 mg/kg for sitafloxacin, ≥10 mg/kg for levofloxacin, and ≥10 mg/kg for lansoprazole, reflecting MIC levels for each agent (0.008, 0.25, and 2 µg/ml, respectively). The therapeutic rates were 83.3% for the sitafloxacin (0.3 mg/kg)-lansoprazole (2.5 mg/kg) combination and 0% for either sitafloxacin or lansoprazole alone. The maximum serum concentration (C(max)) of sitafloxacin was 0.080 ± 0.054 µg/ml at 30 min, when orally administered at 1 mg/kg. The simultaneous administration of lansoprazole resulted in no difference. In the resistance development assay, MICs of levofloxacin increased 64- to 256-fold with gyrA mutations (Ala88Pro and Asn87Lys), while MICs of sitafloxacin only up to 16-fold with the Asn87Lys mutation. The data suggest that sitafloxacin exhibited superior anti-H. pylori activity with low rates of resistance development in vitro and that, reflecting high in vitro activities, sitafloxacin-lansoprazole combination exhibited strong therapeutic effects in Mongolian gerbils with a C(max) of sitafloxacin that was 10-fold higher than the MIC value at a 1-mg/kg administration.

Functional characterization of multidrug and toxin extrusion protein 1 as a facilitative transporter for fluoroquinolones.

Many fluoroquinolones are mainly eliminated by urinary excretion, in which tubular secretion by carrier-mediated transport systems has been suggested to be involved. In the present study, we examined the possibility that multidrug and toxin extrusion protein (MATE) 1, which is abundantly expressed in the kidney, might be involved in that, using rat MATE (rMATE) 1 expressed in MDCKII cells. It was found that rMATE1 can transport fluoroquinolones such as ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, norfloxacin (NFX), pazufloxacin, and tosufloxacin. Although rMATE1 has been known as an apical organic cation/H(+) antiporter, detailed investigation of rMATE1-mediated uptake of NFX has revealed that it is not sensitive to intracellular acidification by treatments using NH(4)Cl or nigericin, suggesting that the transmembrane proton gradient is not involved in its transport as a driving force. However, it was dependent on extracellular pH, being greatest at pH 7.0 and smaller at both acidic and basic pH in agreement with the profile of zwitterionization of NFX. The basal-to-apical transcellular transport of NFX in rMATE1-expressing MDCKII cells was greater than that in mock cells and insensitive to acidification of the apical medium, demonstrating proton gradient-independent functionality of rMATE1 in NFX efflux. Finally, rMATE1-mediated NFX uptake at pH 7.4 was saturable with the Michaelis constant of 55.3 microM and inhibited by cationic compounds, such as TEA and cimetidine. These results suggest that rMATE1 mediates the transport of NFX by a facilitative manner. MATE1 may play a key role in the renal tubular secretion of fluoroquinolones.

MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 7: highly soluble and in vivo active quaternary ammonium analogue D13-9001, a potential preclinical candidate.

A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives, substituted at the 2-position with piperidines bearing quaternary ammonium salt side chains, were synthesized and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin (LVFX) and the beta-lactam aztreonam (AZT) in Pseudomonas aeruginosa. Attachment of the charged entity using an N-ethylcarbamoyloxy linker led to the discovery of the highly soluble compound 22 (D13-9001), which maintained good potency in vitro and displayed excellent activity in vivo in a rat pneumonia model of P. aeruginosa.