Treatment of acute uncomplicated cystitis with faropenem for 3 days versus 7 days: multicentre, randomized, open-label, controlled trial.

OBJECTIVES: The increasing prevalence of resistant bacteria such as fluoroquinolone-resistant or extended-spectrum ß-lactamase-producing strains in pathogens causing acute uncomplicated cystitis has been of concern in Japan. Faropenem sodium is a penem antimicrobial that demonstrates a wide antimicrobial spectrum against both aerobic and anaerobic bacteria. It is stable against a number of ß-lactamases. METHODS: We compared 3 and 7 day administration regimens of faropenem in a multicentre, randomized, open-label, controlled study. RESULTS: In total, 200 female patients with cystitis were enrolled and randomized into 3 day (N = 97) or 7 day (N = 103) treatment groups. At the first visit, 161 bacterial strains were isolated from 154 participants, and Escherichia coli accounted for 73.9% (119/161) of bacterial strains. At 5-9 days after the completion of treatment, 73 and 81 patients from the 3 day and 7 day groups, respectively, were evaluated by intention-to-treat analysis; the microbiological efficacies were 58.9% eradication (43/73), 20.5% persistence (15/73) and 8.2% replaced (6/73), and 66.7% eradication (54/81), 6.2% persistence (5/81) and 7.4% replaced (6/81), respectively (P = 0.048). The clinical efficacies were 76.7% (56/73) and 80.2% (65/81), respectively (P = 0.695). Adverse events due to faropenem were reported in 9.5% of participants (19/200), and the most common adverse event was diarrhoea. CONCLUSIONS: The 7 day regimen showed a superior rate of microbiological response. E. coli strains were in general susceptible to faropenem, including fluoroquinolone- and cephalosporin-resistant strains.

A randomized clinical trial to evaluate the preventive effect of cranberry juice (UR65) for patients with recurrent urinary tract infection.

We examined the rate of relapse, as a variable index, in patients with urinary tract infection (UTI) who suffered from multiple relapses when using cranberry juice (UR65). A randomized, placebo-controlled, double-blind study was conducted from October 2007 to September 2009 in Japan. The subjects were outpatients aged 20 to 79 years who were randomly divided into two groups. One group received cranberry juice (group A) and the other a placebo beverage (group P). To keep the conditions blind, the color and taste of the beverages were adjusted. The subjects drank 1 bottle (125 mL) of cranberry juice or the placebo beverage once daily, before going to sleep, for 24 weeks. The primary endpoint was relapse of UTI. In the group of females aged 50 years or more, there was a significant difference in the rate of relapse of UTI between groups A and P (log-rank test; p = 0.0425). In this subgroup analysis, relapse of UTI was observed in 16 of 55 (29.1 %) patients in group A and 31 of 63 (49.2 %) in group P. In this study, cranberry juice prevented the recurrence of UTI in a limited female population with 24-week intake of the beverage.

Clinical effects of 2 days of treatment by fosfomycin calcium for acute uncomplicated cystitis in women.

Fosfomycin calcium is a fosfomycin antimicrobial agent with a characteristic structure. After oral administration, the drug is absorbed and excreted via the kidneys in the unchanged form, without being metabolized in the body. It is, therefore, indicated for the treatment of urinary tract diseases, including cystitis and pyelonephritis. In the present study, the clinical usefulness of fosfomycin calcium (FOSMICIN® TABLETS 500) administered orally at the dosage of 1 g (two tablets) three times daily for 2 days was examined in female patients, who were at least 20 years of age, with acute uncomplicated cystitis of bacterial origin. Of the 48 patients enrolled between February 2008 and August 2008, 39 were evaluable for efficacy and safety. Overall evaluation of the cure revealed that microbiological eradication rate (microbiological outcome) and clinical efficacy rate (clinical outcome) at 5-9 days after drug administration (visit 2) were 94.9%. Determination of the microbiological and clinical outcomes for the evaluation of recurrence at 4-6 weeks after drug administration (visit 3) were 75.8 and 85.7%, respectively. Of the 48 patients, 40 (83.3%) returned to the clinic at visit 3. The causative bacterial species for cystitis was Escherichia coli in 31 (79.5%) of the 39 patients evaluable for efficacy and safety. Adverse drug reactions observed during the administration and follow-up periods included mild diarrhea and loose stools in 1 patient each, neither requiring any specific treatment. Evaluation of cure at visit 2 in patients in whom the causative bacterial species for the infection was E. coli revealed a microbiological outcome of 93.5%, and clinical outcome was 96.8%. Furthermore, evaluation for recurrence at visit 3 revealed a microbiological outcome of 74.1% and clinical outcome of 82.1%. When the patients were divided by age into an under 60 years of age group and an over 60 years of age group, the microbiological and clinical outcomes determined for evaluation of cure at visit 2 were 96.4 and 92.9%, respectively, and the corresponding rates determined for the evaluation of recurrence at visit 3 were 87.0 and 96.0%, respectively, in the under 60 years of age group. In the over 60 years of age group, the corresponding microbiological outcome and clinical outcome rates evaluated for cure were 90.9 and 100%, respectively, and those evaluated for recurrence were 50.0 and 60.0%, respectively. These results indicate the usefulness of fosfomycin calcium administered at 1 g three times daily for 2 days for acute uncomplicated cystitis.

Centrally administered relaxin-3 induces Fos expression in the osmosensitive areas in rat brain and facilitates water intake.

The expression of the relaxin-3 gene, detected as a new member of the insulin superfamily using human genomic databases, is abundantly present in the brain and testis. Intracerebroventricularly (icv) administered relaxin-3 stimulates food intake. Icv administered relaxin (identical to relaxin-2 in humans) affects the secretion of vasopressin and drinking behavior. Relaxin-3 partly binds relaxin family peptide receptor 1, which is a specific receptor to relaxin. Thus, we hypothesized that relaxin-3 would have physiological effects in the body fluid balance. However, the effects of relaxin-3 in the body fluid balance remain unknown. In the present study, we revealed that icv administered relaxin-3 induced dense Fos-like immunoreactivity (Fos-LI) in the rat hypothalamus and circumventricular organs including the organum vasculosum of the lamina terminalis, the median preoptic nucleus, supraoptic nucleus (SON), the subfornical organ (SFO) and the paraventricular nucleus (PVN), that are related to the central regulation of body fluid balance. Icv administered relaxin-3 (54, 180 and 540 pmol/rat) also induced a significant increase in c-fos gene expression in a dose-dependent manner in the SON, SFO and PVN. Further, icv administered relaxin-3 (180 pmol/rat) significantly increased water intake, and the effect was as strong as that of relaxin-2 (180 pmol/rat). These results suggest that icv administered relaxin-3 activates osmosensitive areas in the brain and plays an important role in the regulation of body fluid balance.

Centrally administered adrenomedullin 5 activates oxytocin-secreting neurons in the hypothalamus and elevates plasma oxytocin level in rats.

We examined the effects of i.c.v. administration of adrenomedullin 5 (AM5) on the brain of conscious rats. We used porcine AM5 in the present study because rat AM5 has not been detected. We observed Fos-like immunoreactivity (LI) in the hypothalamus and brainstem of conscious rats after i.c.v. administration of AM5 (2 nmol/rat). Fos-LI, measured at 90 min post-AM5 injection, was observed in various brain areas, including the supraoptic (SON) and the paraventricular nuclei (PVN). Dual immunostaining for Fos/oxytocin (OXT) and Fos/arginine vasopressin (AVP) revealed that OXT-LI neurones predominantly colocalized Fos-LI compared with AVP-LI neurones in the SON and the PVN. Plasma OXT levels were significantly increased 5 min after i.c.v. administration of AM5 (1 nmol/rat) compared with vehicle and remained elevated in samples taken at 15 and 30 min without changes in plasma AVP levels at any time. In situ hybridization histochemistry showed that i.c.v. administration of AM5 (0.2, 1 and 2 nmol/rat) caused a marked induction of the expression of the c-fos gene in the SON and the PVN. This induction was significantly but not completely reduced by pretreatment with both the calcitonin gene-related peptide (CGRP) antagonist CGRP-(8-37; 3 nmol/rat) and the AM receptor antagonist AM-(22-52; 27 nmol/rat). Although porcine AM5 has not been detected yet in the brain, these results suggest that centrally administered porcine AM5 may activate OXT-secreting neurosecretory cells in the hypothalamus partly through AM/CGRP receptors and elicit secretion of OXT into the systemic circulation in conscious rats.

Alternative nonsteroidal antiandrogen therapy for advanced prostate cancer that relapsed after initial maximum androgen blockade.

PURPOSE: Large meta-analyses have documented that maximum androgen blockade with nonsteroidal antiandrogens for advanced prostate cancer confers survival benefits, although it remains controversial. Also, we and others have reported the effectiveness of second line hormonal therapy for prostate cancer that relapses after initial hormone therapy. However, there is little clinical evidence of the effectiveness of the latter treatment strategy. Therefore, in this multicenter trial in Japan we analyzed clinical outcomes following alternative changing from 1 nonsteroidal antiandrogen to another, ie bicalutamide to flutamide and flutamide to bicalutamide, for advanced prostate cancer that relapsed after initial maximum androgen blockade. MATERIALS AND METHODS: The study included 232 patients with advanced prostate cancer who were initially treated with maximum androgen blockade, including surgical or medical castration combined with nonsteroidal antiandrogens. If a patient relapsed while on first line therapy, we discontinued antiandrogen and evaluated the patient for antiandrogen withdrawal syndrome. We then administered an alternative antiandrogen and evaluated its effect. RESULTS: The incidence of antiandrogen withdrawal syndrome after initial maximum androgen blockade was 15.5% for bicalutamide and 12.8% for flutamide. A prostate specific antigen decrease after antiandrogen withdrawal was a prognostic factor. Nonsteroidal antiandrogens as alternative therapy in patients with relapse after the initial maximum androgen blockade were effective (prostate specific antigen decrease greater than 50%) as second line maximum androgen blockade. Of 232 patients 142 (61.2%) showed a prostate specific antigen decrease in response to an alternative antiandrogen. These responders had significantly better survival than nonresponders, suggesting that responsiveness to second line therapy predicts increased survival. CONCLUSIONS: Following maximum androgen blockade with an alternative nonsteroidal antiandrogen is effective for advanced prostate cancer that has relapsed after initial maximum androgen blockade. Even a partial response to second line maximum androgen blockade was associated with improved survival. Our data support the notion that responders to second line regimens are androgen independent but still hormonally sensitive.

Single-dose treatment of male patients with gonococcal urethritis using 2g spectinomycin: microbiological and clinical evaluations.

The microbiological and clinical efficacies of a single-dose treatment of 2g spectinomycin administered by intramuscular injection were studied in 365 male patients with gonococcal urethritis. A total of 210 patients (57.5%) could be evaluated, in 28 (13.3%) of whom Chlamydia trachomatis was detected in addition to Neisseria gonorrhoeae. A single dose of spectinomycin eradicated N. gonorrhoeae in 203 (96.7%) of the 210 patients. Among patients in whom N. gonorrhoeae was eradicated, pyuria and clinical symptoms, respectively, disappeared in 92.6% (162/175) and 98.9% (173/175) of patients without concomitant C. trachomatis and in 78.6% (22/28) and 71.4% (20/28) with C. trachomatis. Minimal inhibitory concentrations (MICs) were determined for four of seven N. gonorrhoeae strains isolated after spectinomycin treatment. MICs to spectinomycin for three of the four isolates were 16 microg/mL (defined as susceptible) and the MIC of the other isolate was 128 microg/mL, indicating resistance. The resistant isolate was a multidrug-resistant strain with resistance to ciprofloxacin, tetracycline, penicillin and cephalosporins, except for ceftriaxone. The results of this study indicate that a single-dose treatment using 2g spectinomycin is effective in treating patients with urethritis caused by N. gonorrhoeae, even in the era of multidrug-resistant N. gonorrhoeae.

Effect of eviprostat on bladder overactivity in an experimental cystitis rat model.

OBJECTIVE: The purpose of this study was to investigate the effects of eviprostat, a phytotherapeutic drug, on bladder overactivity and inflammation in a cyclophosphamide (CYP)-induced cystitis rat model. METHODS: Female Sprague-Dawley rats received a single intraperitoneal injection of CYP (200 mg/kg) or saline. After the CYP injection, eviprostat (9, 18 or 54 mg/kg per day) or a vehicle was orally given twice each day. Four days after the CYP injection, bladder function was evaluated by cystometrograms under urethane anesthesia. In a separate group, bladder inflammation was compared between the eviprostat- or vehicle-treated animals. Furthermore, the effects of eviprostat on carbachol-induced muscle contraction were evaluated by an in vitro experiment. RESULTS: The intercontraction interval (ICI) significantly decreased in the CYP-injected rats in comparison to the saline-injected rats. In the CYP-injected group, 18 and 54 mg/kg per day of eviprostat treatment significantly increased the ICI, but did not change the maximum voiding pressure in comparison to the vehicle treatment. In the saline-injected group, no significant changes of any parameters in the cystometrograms were observed between the eviprostat- and vehicle-treated groups. CYP-induced bladder inflammation tended to be lower in the eviprostat-treated group in comparison to the vehicle-treated group. An in vitro experiment revealed that eviprostat failed to inhibit carbachol-induced muscle contraction. CONCLUSION: The oral administration of eviprostat suppressed CYP-induced bladder overactivity. The effects of eviprostat on the micturition reflex may be irrespective of antimuscarinic action. The present findings raise the possibility that eviprostat could be an effective treatment for bladder overactivity associated with inflammation.

Thalamic neural activation in the cyclophosphamide-induced visceral pain model in mice.

The afferent nociceptive information from the lower urinary tract terminates in the dorsal horn of the spinal cord, and then projects to the thalamus. In the present study, we examined the effects of visceral nociception from the lower urinary tract on the neural activity of thalamic neurons using cyclophosphamide (CP)-induced cystitis, a model of visceral nociception. The levels of c-fos mRNA as well as protein, a marker of neural activation, were investigated in the thalamus using in situ hybridization histochemistry and immunohistochemistry. The effects of pretreatment with capsaicin were also examined. In the CP-treated group, the c-fos mRNA as well as protein was significantly induced predominantly in the paraventricular area of the thalamus. The induction of c-fos mRNA exhibited a dose-dependency. The induction of c-fos mRNA of CP-treated mice was significantly inhibited by capsaicin pretreatment to deplete C-fibers. Our results indicate that visceral nociception from the lower urinary tract activates thalamic neurons and this activation is mediated in part through the activation of the capsaicin-sensitive C-fiber afferents. The present findings suggest that the levels of c-fos in the paraventricular area of the thalamus may be a useful marker for evaluating the afferent nerve activity from the lower urinary tract.

Abnormal glucose metabolism in the anterior cingulate cortex in patients with schizophrenia.

Changes in glucose metabolism were studied in the brains of schizophrenic patients treated with neuroleptics, using [(18)F]fluoro-deoxy-glucose positron emission tomography (FDG-PET). Fourteen male and eight female patients in their thirties and forties were studied in a resting state. Data from FDG-PET were processed with an anatomic standardization method, three-dimensional stereotactic surface projections (3D-SSP), which provided relative glucose metabolic values that mitigated the contamination of brain atrophy. Z-score maps indicating metabolic differences between the patient and control groups were also acquired. Metabolic values in 19 regions were evaluated in the right and left hemispheres. Patients showed decreased values in the frontal cortex, primary sensory regions and anterior cingulate cortex, more in the rostral affective subdivision than the dorsal cognitive subdivision in both hemispheres, and increased metabolic values in left and right basal ganglia, left temporal and right medial parietal regions. Values were more decreased in both anterior cingulate regions, and more increased in the right thalamus in male than female patients, suggesting gender-related dysfunction in the anterior cingulate and thalamus in schizophrenia. FDG-PET demonstrated that schizophrenia may be a disorder with a dysfunction of fronto-striatal-thalamic circuitry including the cingulate cortex.

Multiple doses of cefodizime are necessary for the treatment of Neisseria gonorrhoeae pharyngeal infection.

A single dose of cefodizime (CDZM), ceftriaxone (CTRX), or spectinomycin (SPCM) is recommended for the treatment of gonococcal urethritis or uterine cervicitis in the era of multidrug-resistant Neisseria gonorrhoeae; namely, cefozopran-resistant N. gonorrhoeae (CZRNG). N. gonorrhoeae pharyngeal infection is not so rare in Japan; however, the proper treatment regimen for this infection is not clear. We previously found that a single dose of CDZM completely eradicated multidrug-resistant N. gonorrhoeae in patients with urethritis and uterine cervicitis, so we tried a single 1.0-g dose of CDZM for the treatment of N. gonorrhoeae pharyngeal infection, including infections with CZRNG. The eradication rate of N. gonorrhoeae from the pharynx was 63.0% with a single 1.0-g dose of CDZM, while the rate for CZRNG with the same dose of CDZM was 38.5%. N. gonorrhoeae was completely eradicated from the pharynx when patients received one or two additional doses of CDZM. Therefore, we concluded that two to three doses of CDZM were necessary for the treatment of N. gonorrhoeae pharyngeal infection including infection with CZRNG.

Single dose of cefodizime completely eradicated multidrug-resistant strain of Neisseria gonorrhoeae in urethritis and uterine cervicitis.

Cefodizime (CDZM) has strong antimicrobial activity to Neisseria gonorrhoeae in vitro. However, multidrug-resistant N. gonorrhoea emerged and has been increasing in Japan. To know the effectiveness of CDZM on gonococcal urethritis and uterine cervicitis even in the era of multidrug-resistant N. gonorrhoeae, a clinical trial of single-dose therapy of CDZM for gonococcal urethritis and uterine cervicitis was conducted. N. gonorrhoeae was eradicated from 100% of patients with gonococcal urethritis and uterine cervicitis by a single dose of CDZM. In conclusion, CDZM is one of most suitable drugs for the treatment of gonococcal genital infection in the era of multidrug-resistant N. gonorrhoeae.

Effects of nitric oxide synthase isoform deletion on oxytocin and vasopressin messenger RNA in mouse hypothalamus.

The effects of neuronal, endothelial, or inducible nitric oxide synthase gene disruption on the expression of oxytocin and vasopressin gene were examined in the hypothalamus (paraventricular, supraoptic, suprachiasmatic, and anterior commissural nuclei) and extrahypothalamus (bed nucleus of the stria terminalis). The oxytocin messenger RNA levels in the anterior commissural nucleus of neuronal nitric oxide synthase knockout mice were significantly higher than in control mice, but not in endothelial or inducible nitric oxide synthase knockout mice. In contrast, no significant effects of neuronal, endothelial, or inducible nitric oxide synthase gene disruption on oxytocin and vasopressin messenger RNA levels in the other hypothalamic and extrahypothalamic nuclei were observed. These results suggest that neuronal nitric-oxide-synthase-derived nitric oxide may be involved in the regulation of oxytocin gene expression in the anterior commissural nucleus.

Upregulation of CRH gene expression and downregulation of arginine vasopressin gene expression in the hypothalamus of bilateral nephrectomized rats.

The expression of the corticotropin-releasing hormone (CRH) gene and the arginine vasopressin (AVP) gene in the hypothalamus examined in bilateral nephrectomized rats by in situ hybridization histochemistry. The expression of the CRH gene was significantly increased in the parvocellular part of the paraventricular nucleus (PVN) 12 and 20 h after bilateral nephrectomy in comparison with that after sham operation. The plasma concentration of adrenocorticotropic hormone (ACTH) in nephrectomized rats was significantly higher than that in sham operated rats 20 h after surgery. In contrast, the expression of the AVP gene in both the parvocellular and magnocellular parts of the PVN and throughout the supraoptic nucleus (SON) was significantly decreased 20 h after bilateral nephrectomy in comparison with that after sham operation. These results suggest that nephrectomy-induced upregulation of the CRH gene with elevation of plasma ACTH may be due to the activation of the hypothalamo-pituitary adrenal (HPA) axis.