The phosphodiesterase inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil

We investigated the potency and the selectivity profile of vardenafil on phosphodiesterase (PDEs) enzymes, its ability to modify cGMP metabolism and cause relaxation of penile smooth muscle and its effect on erections in vivo under conditions of exogenous nitric oxide (NO) stimulation. PDE isozymes were extracted and purified from human platelets (PDE5) or bovine sources (PDEs 1, 2, 3, 4 and 6). The inhibition of these PDEs and of human recombinant PDEs by vardenafil was determined. The ability to potentiate NO-mediated relaxation and influence cGMP levels in human corpus cavernosum strips was measured in vitro, and erection-inducing activity was demonstrated in conscious rabbits after oral administration together with intravenous doses of sodium nitroprusside (SNP). The effects of vardenafil were compared with those of the well-recognized PDE5 inhibitor, sildenafil (values for sildenafil in brackets). Vardenafil specifically inhibited the hydrolysis of cGMP by PDE5 with an IC50 of 0.7 nM (6.6 nM). In contrast, the IC50 of vardenafil for PDE1 was 180 nM; for PDE6, 11 nM; for PDE2, PDE3 and PDE4, more than 1000 nM. Relative to PDE5, the ratios of the IC50 for PDE1 were 257 (60), for PDE6 16 (7.4). Vardenafil significantly enhanced the SNP-induced relaxation of human trabecular smooth muscle at 3 nM (10 nM). Vardenafil also significantly potentiated both ACh-induced and transmural electrical stimulation-induced relaxation of trabecular smooth muscle. The minimum concentration of vardenafil that significantly potentiated SNP-induced cGMP accumulation was 3 nM (30 nM). In vivo studies in rabbits showed that orally administered vardenafil dose-dependently potentiated erectile responses to intravenously administered SNP. The minimal effective dose that significantly potentiated erection was 0.1 mg/kg (1 mg/kg). The selectivity for PDE5, the potentiation of NO-induced relaxation and cGMP accumulation in human trabecular smooth muscle and the ability to enhance NO-induced erection in vivo indicate that vardenafil has the appropriate properties to be a potential compound for the treatment of erectile dysfunction. Vardenafil was more potent and selective than sildenafil on its inhibitory activity on PDE5.     

Vulvar carcinoma: a retrospective analysis of 80 patients

We evaluated the files of 80 women who were treated for vulvar carcinoma. In 13 women radiotherapy was used as primary treatment, in 45 cases postoperatively and in 22 women because of local recurrence. Patients older than 60 years had a significantly worse 5-year survival rate (39%) than younger women (57%) (p=0.02). The 5-year survival rate for patients with negative nodes was 72% versus 46% for the N1- and 47% for the N2-status, respectively (p=0.027). The 5-year actuarial survival rate for patients with tumor manifestation in the clitoris was 77.9% versus 26.1% for patients with tumors in the labia majora (p=0.0044). There was no difference in survival in patients who had been treated with radical vulvectomy and bilateral groin dissection plus local radiotherapy when compared with patients who had been irradiated (whole pelvis) after tumor resection alone. The 5-year survival rates and the median survival time were identical in both groups (61%/62 months). Received: 24 June 1998 / Accepted: 28 August 1998     

Beneficial clinical effects of ozonated autohemotherapy in chronically dialysed patients with atherosclerotic ischemia of the lower limbs--pilot study

Ozonated autohemotherapy is a controversial but successful method of treatment, used in particular in European countries. There are many fields in which medical ozone could be of value: treating different infections, immunodeficiency syndromes, neoplasms. Encouraging results have also been achieved in the treatment of atherosclerotic ischemia of the lower limbs. In this preliminary study, the influence of blood ozonation on the intensity of symptoms of ischemia of the lower extremities was analysed among dialysed patients with chronic renal failure. We examined 5 hemodialyzed patients and 7 patients treated with peritoneal dialysis immediately before and after 14 sessions of ozonated autohaemotherapy. Eleven patients (91.6%) reported a subjective decrease in perceived intensity of ischemic pains, or observed prolongation of intermittent claudication distance. During march tests performed on a treadmill, we found significant prolongation of intermittent claudication distance in all examined patients - 65.6% (mean value, p (< or =0.01). Patients treated with peritoneal dialysis achieved much greater improvement than did hemodialyzed patients (165% vs. 42%). We concluded that autohemotherapy with ozone, in a concentration of 34.4 mcg/ml of blood, is safe, easily applied and may be useful In the therapy of atherosclerotic ischemia of lower extremities among dialyzed patients. It could also be a complement to current treatment, especially in cases where the latter has failed.     

Verbesserte Materialgewinnung bei der Schleimhautcytologie mit Hilfe polymerer Cellulosofilter

Summary A rinse—and—suck—sound is presented, which conveys cytological material to a special filter mechanism. After Papanicolaou staining the filters are being cleared and allow a light-microscopical judgement. A reduction of the well-known possibilities of error in exfoliative cytology can be noticed.     

A meta-analysis of behavioral parent training for children with attention deficit hyperactivity disorder

This meta-analysis examined the effect of behavioral parent training on child and parental outcomes for children with attention deficit hyperactivity disorder. Meta-analytic procedures were used to estimate the effect of behavioral parent training on children with attention deficit hyperactivity disorder. Variables moderating the intervention effect were examined. Forty studies were included and generated an overall moderate effect size at post-treatment and a small effect size at follow-up. The majority of outcome categories were associated with a moderate effect size at post-treatment that decreased to a small effect size at follow-up. Parenting competence was the only outcome that had a large effect, which decreased to moderate at follow-up. The strength of the effect differed between questionnaire and observation measures. Behavioral parent training is an effective intervention for children with attention deficit hyperactivity disorder. Sustainability of the effects over time is a problem that awaits further scrutiny. Recommendations for further research and clinical practices are provided.     

A simple method for transposing MRI information to simulation films. Technical note]

BACKGROUND: The use of MRI information in the treatment planning process is still expensive and time consuming. Electro-optical devices or specially designed post-processing software in here the risk of picture distortion. PATIENTS AND METHODS: Between June 1998 and June 1999 in 48 patients with brain tumors and 11 patients with carcinoma of the prostate CT treatment planning and MRI were performed with identical patient positioning using the same devices as in the simulation. The transposition of organ and tumor volumes between MRI and simulation film takes place by overlying both on the brightening screen by using a grid. MRI and simulation films must be produced using an identical magnification factor. RESULTS: For 9 patients with brain tumors and 2 patients with a carcinoma of the prostate the transposition of MRI information on the simulation films showed the necessity of a modification of the shielding or the treatment portals. CONCLUSIONS: The simple method of direct transposition of MRI structures into simulation films allows to accomplish a verification of the portals and conformation which result of the treatment planning process. Moreover an individualized shielding can also directly be realized.     

Patients' assessment of the importance of measures relevant for treatment in lumbar disc herniations and their satisfaction--a prospective study

In modern health system hospital is integral part of patients treatment. The hospital competes with an ubiquitous medical supply of adjacent institutions and general doctors. As a part of the medical supply chain a hospital may not exist as an "island" itself. Necessity in health politics and economics leads to image and advertisement strategies for a long term survival of hospitals. An analysis of medical output in patients treatment will build the basis for future development and strategies. By a questionnaire 170 patients suffering from a lumbar disc herniation were asked before starting medical treatment about their expectations and at the end of hospitalisation about their contentment with their stay in hospital. The very high expectations in medical treatment and nursing were fulfilled by the clinical staff. Here all patients were much more content they expected priorly. But the patients valued a distinct deficit in contentment in the co-treatment by other clinical faculties of the hospital. The reason of these results were explained by big distances inside the hospital and long time waiting between medical examinations. Our results show that intensive care by physicians and nurses increase contentment of patients. An additional improvement of patients judgement about hospital services will be possible by introduction of a routine co-treatment of other medical faculties.     

Effects of two selective phosphodiesterase type 5 inhibitors,sildenafil and vardenafil,on object recognition memory and hippocampal cyclic GMP levels in the rat

The present study investigated the effects of two cyclic GMP-specific phosphodiesterase enzyme type 5 inhibitors, sildenafil and vardenafil, on the memory performance in the object recognition task. Both compounds were given per orally (1, 3 and 10 mg/kg sildenafil; 0.1, 0.3, 1 and 3 mg/kg vardenafil) immediately after the exposure to two identical objects. The memory for the objects was tested 24 h later. Vehicle-treated rats spent equal times exploring a new and the familiar object demonstrating that they did not remember the familiar one. However, sildenafil improved the object discrimination performance of the rats with a high discrimination performance at a dose of 3 mg/kg. Rats treated with vardenafil also showed an improved object discrimination performance. Compared with sildenafil, vardenafil appeared to be even more potent in this respect since it already produced a high discrimination performance at a dose of 0.3 mg/kg. The effects of both compounds on cyclic GMP and cyclic AMP accumulation were studied in rat hippocampal slices incubated in vitro. Cyclic GMP levels were increased after incubation with the highest concentration of 100 microM vardenafil (together with 0.1 mM sodium nitroprusside), although no changes in cyclic GMP levels were detected after incubation with different concentrations of sildenafil. Both compounds had no effect on cyclic AMP levels. Additional cyclic GMP immunocytochemistry showed that incubation with vardenafil (in the presence of sodium nitroprusside) resulted in a concentration-dependent staining of cyclic GMP. Staining was predominantly found in neuronal fibres in the hippocampal CA2/CA3 region. It was already detected at a concentration of 0.1 microM vardenafil. Also positive fibres were detected after incubation with sildenafil but at a higher concentration of 10 microM. Taken together, these results suggest that inhibition of phosphodiesterase enzyme type 5 improves object recognition memory. This effect might be explained by increased levels of central cyclic GMP.