Clinical Guidelines Panel on Erectile Dysfunction: Summary Report on the Treatment of Organic Erectile Dysfunction

Purpose

The American Urological Association convened the Clinical Guidelines Panel on Erectile Dysfunction to analyze the literature regarding available methods for treating organic erectile dysfunction and to make practice recommendations based on the treatment outcomes data.

Materials and Methods

The panel searched the MEDLINE data base for all articles from 1979 through 1994 on treatment of organic erectile dysfunction and meta-analyzed outcomes data for oral drug therapy (yohimbine), vacuum constriction devices, vasoactive drug injection therapy, penile prosthesis implantation and venous and arterial surgery.

Results

Estimated probabilities of desirable outcomes are relatively high for vacuum constriction devices, vasoactive drug injection therapy and penile prosthesis therapy. However, patients must be aware of potential complications. The outcomes data for yohimbine clearly indicate a therapy with marginal efficacy. For venous and arterial surgery, based on reported outcomes, chances of success do not appear high enough to justify routine use of such surgery.

Conclusions

For the standard patient, defined as a man with acquired organic erectile dysfunction and no evidence of hypogonadism or hyperprolactinemia, the panel recommends 3 treatment alternatives: vacuum constriction devices, vasoactive drug injection therapy and penile prosthesis implantation. Based on the data to date, yohimbine does not appear to be effective for organic erectile dysfunction and, thus, it should not be recommended as treatment for the standard patient. Venous surgery and arterial surgery in men with arteriolosclerotic disease are considered investigational and should be performed only in a research setting with long-term followup available.     

Pattern of Metastases in Relation to Characteristics of Primary Tumor and Treatment in Patients with Disseminated Urothelial Carcinoma

Purpose

The anatomical pattern of recurrence and metastases in patients with urothelial cancer are described, and the relationship between treatment and features of the primary invasive tumor and the subsequent pattern of metastases is analyzed.

Materials and Methods

Between 1976 and 1991, 240 patients with recurrent or metastatic urothelial cancer were admitted to our department.

Results

The majority of the patients had recurrence within 2 years after initial diagnosis. Local recurrences and lung metastases were diagnosed significantly earlier than other metastases. Multiple sites were involved in more than half of the patients. The most common sites of recurrence were local in the bladder in 65 percent of the cases and bone in 35 percent, followed by lymph nodes in 26 percent and lung in 20 percent. The pattern of metastases was similar in patients with different histological findings, grade and location of the primary tumor. Patients younger than 60 years and those with cancer of the renal pelvis more often had distant metastases compared to older patients with bladder cancer. Local recurrences were less frequent in patients who had undergone cystectomy compared to those treated with radiotherapy only. Moreover, patients with local recurrences were likely to have metastases elsewhere.

Conclusions

Bone was the most frequent site of metastases outside the pelvis and all patients suspected to have recurrence should be examined for bone metastases. The results indicate that the pattern of recurrence and metastases are not dependent on the features of the primary tumor.     

Hereditary neuropathy with liability to pressure palsies

Summary Clinical, neurophysiological and pathological investigations were carried out in 11 affected members of 2 families with hereditary neuropathy with liability to pressure palsies (HNPP). The observations were related to findings in 261 cases of 47 families published in the literature. It was concluded that HNPP is a nosological entity characterized by the following diagnostic criteria: (1) an autosomal dominant inheritance; (2) the clinical presentation of a recurrent mononeuropathy simplex or multiplex, frequently related to an inadequate trauma to peripheral nerves; (3) a significant slowing of motor and sensory conduction velocity in clinically affected, but also in clinically unaffected nerves; (4) characteristic morphological findings in sural nerve biopsy featuring tomaculous swellings of myelin sheaths, transnodal myelination and segmental demyelination. The pathogenesis of HNPP is not clear. Hypothetical explanations of the pathogenesis of HNPP are discussed.In memory of Albert Bischoff (1921–1981), Professor of Neurology, University of Berne     

SSR181507, a dopamine D(2) receptor antagonist and 5-HT(1A) receptor agonist. I: Neurochemical and electrophysiological profile.

SSR181507 ((3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT(1A) receptors (K(I)=0.8, 0.2, and 0.2 nM for human D(2), D(3), and 5-HT(1A), respectively). In vivo, SSR181507 inhibited [(3)H]raclopride binding to D(2) receptors in the rat (ID(50)=0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D(2) antagonist and 5-HT(1A) agonist properties in the same concentration range in vitro (IC(50)=5.3 nM and EC(50)=2.3 nM, respectively, in the GTPgammaS model) and in the same dose range in vivo (ED(50)=1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced Fos immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D(2) receptor antagonism and 5-HT(1A) agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia.     

Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer.

PURPOSE: The purpose of this study was to establish the feasibility and efficacy of preoperative radiotherapy (RT) with concurrent capecitabine and oxaliplatin (XELOX-RT) in patients with rectal cancer. PATIENTS AND METHODS: Thirty-two patients with locally advanced (T3/T4) or low-lying rectal cancer received preoperative RT (total dose, 50.4 Gy). Capecitabine was administered concurrently at 825 mg/m2 bid on days 1 to 14 and 22 to 35, with oxaliplatin starting at 50 mg/m2 on days 1, 8, 22, and 29 with planned escalation steps of 10 mg/m2. End points of the phase II study included downstaging, histopathologic tumor regression, resectability of T4 disease, and sphincter preservation in patients with low-lying tumors. RESULTS: Dose-limiting grade 3 gastrointestinal toxicity was observed in two of six patients treated with 60 mg/m2 of oxaliplatin. Thus, 50 mg/m2 was the recommended dose for the phase II study. Toxicities observed at this dose level were generally mild, with only two cases of short-lived grade 3 diarrhea. Myelosuppression, mainly leukopenia, was restricted to grade 2 in 19% of patients. T-category downstaging was achieved in 17 (55%) of 31 operated patients, and 68% of patients had negative lymph nodes. Pathologic complete response was found in 19% of the resected specimens. Radical surgery with free margins could be performed in 79% of patients with T4 disease, and 36% of patients with tumors < or = 2 cm from the dentate line had sphincter-saving surgery. CONCLUSION: Preoperative XELOX-RT is a feasible and well tolerated treatment. This regimen is proposed for phase III evaluation comparing standard fluorouracil-based therapy with XELOX chemoradiotherapy.     

Pattern of dissemination and survival following isolated locoregional recurrence of breast cancer

Purposes: The study evaluates prognostic factors for dissemination and survival in patients with local or regional recurrence of breast cancer. Furthermore, the aim was to define subgroups of patients at different risk of developing metastases in specific anatomical sites. Patients and methods: The study included 140 patients with isolated local or regional node recurrence, who entered a prospective study for staging of patients with first recurrence of breast cancer in the period 1983–85. The primary treatment was a simple mastectomy; node positive patients received adjuvant radiotherapy and chemotherapy or tamoxifen.If possible, the locoregional recurrence was treated with surgery and/or radiotherapy, otherwise by systemic therapy. Results: Median follow up was 10.4 years; 78 patients developed distant metastases (soft tissue, 32%; bone, 45%; viscera 40%). Median time to dissemination was 4.4 years, and the ten year dissemination rate was 72%. Median time to dissemination was 3.7 years for patients with recurrence in the regional nodes compared to 6.5 years for patients with chest wall recurrence only, p = 0.05. No specific time sequence (temporal pattern) was observed in the anatomical distribution of metastases, and the anatomical site of recurrence could not be predicted by any of the prognostic factors. At follow up, 93 patients had died. The median survival was 5.6 years and 30% were alive after 10 years. Forty-three of the 99 patients who received local therapy only did not develop metastases. Fifteen of these patients died without evidence of metastatic disease while 28 patients were still alive without distant recurrence after a median follow up time of 9.3 years (range, 6.5–11.9 years). Level of LDH and the number of positive regional nodes (NPOS) at primary diagnosis were significant independent prognostic factors for survival after recurrence. Conclusions: Approximately one third of the patients receiving local treatment only, were alive and without distant metastases up to ten years after locoregional recurrence, indicating that there is a subset of patients which may be long term survivors after local treatment only (surgery or radiotherapy). The duration of survival can be estimated by LDH and NPOS, but the model needs validation in a separate data set before clinical use.     

Social austerity versus structural reform in European health systems: a four-country comparison of health reforms.

Cost containment has captured the attention of health policymakers in most OECD countries, and deliberations about creating powerful financial incentives dominate health care politics. Some European health systems are now implementing hospital payment schemes that mirror the U.S. model of diagnosis-related groups (DRGs) and are raising premiums and copayment levels in an effort to limit public expenditures. Though financial incentives may indeed help rein in health expenditures, focusing predominantly on financial incentives hinders due consideration of needed structural reforms that improve the continuity, quality, and appropriateness of health care service delivery. This article focuses on the structural specifics of two legally enacted health insurance systems (Germany and Austria) and two national health systems (Great Britain and Denmark) to discuss the influence of structural characteristics on cost-containment efforts. Structural reform strategies discussed include increasing reliance on general practitioners, improving coordination of community and hospital-based specialty care, addressing the stark divide between ambulatory and hospital-based care that exists in some European health systems, and improving continuity of care by better integrating medical and social care sectors. Also discussed is the relative focus on financial incentives versus structural deficits in recent European-health care reform strategies.     

Assessment of the combined approach of N-alkylation and salt formation to enhance aqueous solubility of tertiary amines using bupivacaine as a model drug.

Quaternary prodrug types of poorly water-soluble tertiary amines have been shown to exhibit significantly enhanced solubilities as compared to the parent amine. In the present study the combined effect of N-alkylation and salt formation to enhance aqueous solubility of tertiary amines have been investigated using bupivacaine as a model compound. X-ray structure analyses of selected salts were included to investigate the potential existence of correlations between salt solubility and crystal packing modes. Alkyl groups were methyl, ethyl, propyl, and butyl and the derivatives were isolated as their iodide salts. Chloride, mesylate, formate, acetate, glycolate, and tosylate salts were obtained by anion exchange of the N-methyl-bupivacaine derivative. N-Alkylation and salt formation afforded quaternary ammonium salts possessing pH-independent aqueous solubilities far exceeding that of the parent tertiary amine (up to a factor of 3200 at pH 8). A moderate reduction in solubility with increasing length of the alkyl chain was observed for the iodide salts of the N-alkylated bupivacaine derivatives. In case of the N-methyl-bupivacaine derivative variation of the counterion had a significant impact on the solubility with the iodide salt being 200 times less soluble than the chloride salt. X-ray analysis revealed that both the alkyl substituent and the anionic counterion influenced salt packing modes, however, in an unpredictable manner making establishment of quantitative correlations between crystal packing and solubility difficult even for a series of closely related derivatives.