Pindolol binding to 5-HT1A receptors in the human brain confirmed with positron emission tomography

The augmentation effect of (–)pindolol as used in combination with SSRI to treat major depression has been ascribed to blocking of dorsal raphe nucleus cell body 5-HT autoreceptors. In this study, the radioligand [carbonyl-¹¹C]WAY-100635 and positron emission tomography were used to establish whether pindolol at a clinical dose level (10 mg s.o.d.) occupies 5-HT_1A receptors in the human brain in vivo. Three healthy males were recruited and each subject was used as his own control. The 5-HT_1A receptor occupancy was calculated for the frontal and temporal cortex and the raphe nuclei, using and a ratio analysis with the cerebellar cortex as the reference region. Maximal pindolol plasma concentration was reached within 3 h after drug administration. Two hours after pindolol administration, the regional 5-HT_1A receptor occupancy was within the range 7–21% in the three subjects. The study confirms that the 5-HT_1A-receptor may be a clinically significant target for pindolol. Received: 8 March 1999 / Final version: 15 March 1999     

The diluting effect of medical work groups on feedback efficacy in changing physician's practice

Feedback intervention has been advocated as a successful method to modify the way that physicians practice medicine. However, most studies concerned with modifying physician profiles have focused on interns and residents. The results presented here concern regular staff and therefore provide a better basis for generalization. Over a 2.5-year period, we analyzed the use of clinical resoucces by physicians practicing in four medical specialties in two hospitals. Hierarchical multiple regression models were used to control case mix in order to identify the specific effects attributable to feedback. The information failed to modify the physicians' practice profiles. Our results suggest that this failure is related to the organization of inpatient medical practice as a group effort. This mode of practice has a negative effect on feedback efficacy. First, it weakens one of the main feedback mechanisms, that is personal identification with the data. Second, it probably generates mutual adjustment among physicians, thus eliminating practice variations at the source.     

Metabolic base production and mucosal vulnerability during acid inhibition in a mammalian stomachin vitro

Acid inhibition increases gastric mucosal susceptibility to damage by luminal acid. This might be due to reduced metabolic CO₂ and bicarbonate whereas, during normal acid, secretion cytoprotective CO₂/HCO₃- production parallels acid production. Metabolic activity and mucosal damage caused by luminal acid perfusion was determined in anin vitro mouse stomach, with and without acid inhibition, and at 0%, 1%, or 5% serosal CO₂ supply. Without acid inhibition there was no mucosal damage at any level of serosal CO₂/HCO₃- supply. Acid inhibition reduced metabolic CO₂ production by 29% (P<0.004) and resulted in microscopic damage to 55% of the mucosal area and perforation in four of five stomachs (P<0.05). Although, 1% CO₂ supply completely replaced the reduction in metabolic CO₂, it did not protect against mucosal damage. Overreplacement by 5% serosal CO₂/HCO₃- was required to prevent damage. There was no correlation between luminal CO₂/HCO₃- output and mucosal damage. The protection by endogenous or exogenous CO₂/HCO₃- appears to act intracellularly rather than by intragastric or intercellular neutralization.This study was supported by Swiss National Foundation grants 32-26369.89 and 32-33626.92. The morphometry equipment was supported by a grant from the Osterreichische Nationalbank.     

Mucolytic activity of azelastine in mice and rats

The mucolytic activity of azelastine, an antiallergic/antiasthmatic drug, in mice and rats was investigated. The oral administration of test compounds 30 min before phenol red i.p. injection stimulated dye secretion in the trachea of mice. The resulting oral ED₅₀'s (mg/kg) were: azelastine, 0.16; salbutamol, 2.5;N-acetylcysteine, 61.8;S-Carboxymethyl-l-cysteine, <100; bromhexine, >100; and potassium iodide, 200. In rats, several drugs stimulated secretion of fluorescein sodium (FINa) in the tracheobronchial lumen. The resulting oral ED₅₀'s (mg/kg) were: azelastine, 0.33; terbutaline, 0.3; salbutamol, 0.89; andS-carboxymethyl-l-cysteine, 56.8. Terfenadine and diphenhydramine (1–10 mg/kg, p.o.) did not stimulate tracheal secretion in rats and mice. The mucolytic activity of azelastine may contribute to its overall effectiveness, including antitussive activity in asthmatics. Finally, this activity seems to be dissociated from its H₁-histamine receptor blocking activity.     

Dural enhancement in pituitary macroadenomas

We describe the normal dural enhancement patterns of the sellar region and determine whether the duramater is affected by pituitary macroadenomas. Dural enhancement appeared to be usually abnormal in 20 patients with pituitary macroadenoma compared with 20 control patients, mainly at the planum sphenoidale and carotid sulcus. However dural changes are subtle and their recognition requires knowledge of the normal enhancement patterns. Dural changes, reported in a variety of inflammatory and infectious dural diseases and after surgery, are not specific and may be also seen in pituitary macroadenomas. Received: 12 December 1998 Accepted: 3 November 1999     

Tratamiento del cáncer de esófago localizado y localmente avanzado: ¿algo ha cambiado?

Esophageal cancer has a dismal prognosis and the surgical treatment only cures a small percentage of patients. The survival achieved by traditional surgical procedures is being improved with extended resections, but at the cost of greater morbidity. Concurrent radiochemotherapy can obtain results similar to those of surgery. Nowadays, locally advanced esophageal cancer should have a multimodal approach, because neoadjuvant chemotherapy, with or without radiotherapy, has demonstrated to improve the survival of chemosensitive patients. Recently, the role of hyperfractionated radiotherapy and new drugs such as paclitaxel, docetaxel and irinotecan in neoadjuvant treatment is being evaluated.     

Family history of autoimmune thyroid disease and childhood acute leukemia.

The association between a familial history of autoimmune disease and childhood acute leukemia was investigated in a French case-control study that, overall, was designed to assess the role of perinatal, infectious, environmental, and genetic factors in the etiology of childhood acute leukemia. Familial histories of autoimmune disease in first- and second-degree relatives were compared in 279 incident cases, 240 cases of acute lymphocytic leukemia (ALL) and 39 cases of acute non-lymphoblastic leukemia (ANLL), and 285 controls. Recruitment was frequency matched by age, gender, hospital, and ethnic origin. Odds ratios (OR) were estimated using an unconditional regression model taking into account the stratification variables, socioeconomic status, and familial structure. A statistically significant association between a history of autoimmune disease in first- or second-degree relatives and ALL (OR, 1.7; 95% confidence interval (CI), 1.0-2.8) was found. A relationship between thyroid diseases overall and ALL (OR, 2.0; 95% CI, 1.0-3.9) was observed. This association was more pronounced for potentially autoimmune thyroid diseases (Grave's disease and/or hyperthyroidism and Hashimoto's disease and/or hypothyroidism) (OR, 3.5; 95% CI, 1.1-10.7 and OR, 5.6; 95% CI, 1.0-31.1, respectively for ALL and ANLL), whereas it was not statistically significant for the other thyroid diseases (thyroid goiter, thyroid nodule, and unspecified thyroid disorders) (OR, 1.6; 95% CI, 0.7-3.5 and OR, 1.3; 95% CI, 0.2-7.0, respectively, for ALL and ANLL). The results suggest that a familial history of autoimmune thyroid disease may be associated with childhood acute leukemia.     

Tolerabilidad y efectividad del citrato de fentanilo oral transmucosa en el tratamiento a largo plazo del dolor irruptivo en pacientes oncológicos: estudio ECODIR

INTRODUCTION: Oral trans-mucosal fentanyl citrate (OTFC) is the one drug specifically developed for the management of breakthrough pain. This study assesses the long-term safety and efficacy of OTFC standard clinical conditions. Patients and methods. Six-month observational study performed on cancer patients with episodes of breakthrough pain. Safety was assessed by recording the advent of adverse events and efficacy by the evaluating the intensity of breakthrough pain. RESULTS: 174 cancer patients were recruited into the study. All adverse reactions reported were mild or moderate. OTFC was significantly faster (time to the commencement of pain relief: 12.7 +/- 11.4 vs 32.7 +/- 18.4 minutes; p < 0.001) and potent (post-treatment pain intensity: 3.4 +/- 1.5 vs 4.3 +/- 1.5; p < 0.001) than the previously-used drugs. CONCLUSIONS: This observational study confirms the good safety profile of OTFC as well as its effectiveness over long-term period treatment of breakthrough pain.     

Phase II trial of fortnightly irinotecan (CPT-11) in the treatment of colorectal cancer patients resistant to previous fluoropyrimidine-based chemotherapy

Introduction This phase II study investigated the anti-tumour activity and toxicity of CPT-11 (250 mg/m2 i.v. infusion over 60 minutes) administered every 2 weeks as second-line chemotherapy in patients with advanced colorectal cancer (CRC). Material and methods Patients (n=63) with histology diagnosis of advanced CRC and proven resistance to previous fluoropyrimidine therapy were enrolled. Results A total of 510 CPT-11 cycles were administered, with a mean of 8 cycles per patient (range: 1–32). The median relative dose intensity was 93%. Partial response (PR) was obtained in 11 patients (17.5%; 95%CI: 8.1%–26.7%) and 29 patients (46.0%) showed stable disease (clinical benefit of 63.5%). The median duration of response was 6.8 months (95%CI: 6.1–7.5 months), median survival was 8.8 months (95%CI: 6.3–11.5 months) and median time to disease progression was 4.5 months (95%CI: 3.9–5.0 months). Overall, this schedule of CPT-11 chemotherapy was well tolerated by the patient. Neutropenia was the most frequent grade 3/4 haematological toxicity (20.6% of patients and 4.1% of cycles). Neutropenia with concurrent fever or infection occurred in 7 patients (11.1%). Late onset diarrhoea was the most frequent grade 3/4 non-haematological toxicity (19.0% of patients and 2.3% of cycles). Other, lower-incidence, toxicities were anaemia, fever, infection, mucositis, nausea and vomiting. There were no toxic deaths. Conclusions We found that CPT-11, administered as 250 mg/m² i.v. infusion over 60 minutes every 2 weeks, was active and well tolerated schedule in the second-line chemotherapy of advanced CRC patients. This bi-weekly scheme could be used as an alternative to the weekly or the every-three-week schedule as well as in combined therapies with other chemotherapeutic agents for the treatment of advanced, metastatic, CRC.