Chlorpyrifos-induced delayed polyneuropathy

Chlorpyrifos [0,0-diethyl 0-(3,5,6-trichloro-pyridyl) phosphorothioate] caused delayed polyneuropathy in man. Contrary to previous studies, we report here that it also causes delayed polyneuropathy in the hen, the animal model for this toxicity. The minimal neuropathic dose was 60–90 mg/kg p.o., corresponding to 4–6 times the estimated LD₅₀. Consequently, pralidoxime (2-PAM) in conjunction with atropine was necessary to reverse acetylcholinesterase (AChE) inhibition and cholinergic toxicity in hens given high enough doses of chlorpyrifos to cause neuropathy. Chlorpyrifos was slowly absorbed after single oral doses and the threshold of inhibition (>70%) of neuropathy target esterase (NTE), the putative target for delayed neuropathy, was reached within 5–6 days. High AChE inhibition (>90%), however, was measured within hours after dosing because of the higher potency of chlorpyrifos to inhibit this enzyme. In vitro studies showed that chlorpyrifos-oxon, the active metabolite of chlorpyrifos, was 10–20 times more active against AChE than against NTE, confirming the clinical observation. No differences were seen between human and hen enzymes in this respect. Hen and human brain homogenates contain A-esterases which hydrolysed chlorpyrifos to about the same extent in both species. In conclusion, chlorpyrifos causes delayed polyneuropathy in the hen, as was reported in man. The reasons for previous negative data in the hen are probably due to the relatively lower doses which were used. Judging from in vitro studies with hen and human enzymes, there are no differences in the two species as far as their relative sensitivity to delayed polyneuropathy. It is likely that delayed polyneuropathy would develop in both species only after severe cholinergic toxicity requiring aggressive antidotal treatment.Part of this work was presented at the 25th Annual Meeting of the Society of Toxicology held in New Orleans, LA, USA, March 1986, at the International Symposium on Biochemical and Cellular Indices of Toxicity in Occupational and Environmental Medicine held in Milan, Italy, June 1986, and at the 9th Meeting of the Peripheral Nerve Study Group, Praglia (PD), Italy, August – September, 1989     

Ipriflavone inhibits osteoclast differentiation in parathyroid transplanted parietal bone of rats

Summary Ipriflavone, a synthetic isoflavone-derived flavonoid, was shown to have inhibitory effect on bone resorption. In order to study its mechanism of action directly on bone, 46 female Wistar rats were divided into six groups and medicated orally for 25 days as follows: groups 1 and 2 were given 1% carboxymethylcellulose solution (vehicle), groups 3, 4, 5, and 6 were administered ipriflavone at doses of 0.178, 0.356, 0.712, and 1.424 mmol/kg/day (suspended in vehicle), respectively. On the 22nd day, parathyroid glands, taken from donor rats, were transplanted in contact with the outer surface of the periosteum of both the right and the left parietal bones of rats from groups 2, 3, 4, 5, and 6. The group 1 rats underwent sham operation. Bone histomorphometry, performed on the ectocranial periosteum of parietal bones, showed that absolute erosion boundary, absolute eroded area, absolute erosion depth, number of tartrate-resistant acid phosphatase (TRAP)-positive polinucleated osteoclasts, and number of TRAP-positive mononucleated cells decreased in ipriflavone-treated rats compared with group 2 rats. The reduction was roughly proportional to the increase of drug dosage and reached statistical significance in rats of groups 5 and 6. The same parameters were extremely low in group 1 rats. Mineral apposition rate did not differ in any of the groups. Significant increase of serum calcium and significant decrease of serum phosphate were found in group 2 rats compared with group 1 rats, whereas no differences from controls were detected in ipriflavone-treated animals.The results demonstrate that ipriflavone has a direct inhibitory effect upon bone resorption, probably by reducing recruitment or differentiation of osteoclasts, rather than by inhibiting the resorption activity of differentiated osteoclasts. Ipriflavone also seems to exert a protective action against parathyroid hormone (PTH) diffusion from the site of parathyroid gland transplantation.     

Lomest psychiatric case register: Old and new long-stay patients

Summary Data derived from a psychiatric case-register are presented on the attrition of the cohort of theold long-stay in-patients, and the accumulation of thenew long-stay cases in Lomest, a town in northern Italy, from 1975 to 1980. The characteristics of high user groups of out-patients attending the non-residential services are also described. The analysis seeks to provide some information on who has been left behind by the massive deinstitutionalization programme that has been carried out in Italy since 1970.     

Betahistine dihydrochloride in the treatment of peripheral vestibular vertigo

The present study compares the efficacy and safety of betahistine dihydrochloride to that of a placebo in recurrent vertigo resulting from Meniere's disease (MD) or in paroxysmal positional vertigo (PPV) of probable vascular origin. The design was double-blind, multicentre and parallel-group randomised. Eleven Italian centres enrolled 144 patients: 75 of the patients were treated with betahistine (41 MD/34 PPV) and 69 with placebos (40 MD/29 PPV). The betahistine dosage was 16 mg twice per day for 3 months. Compared to the placebo, betahistine had a significant effect on the frequency, intensity and duration of vertigo attacks. Associated symptoms and the quality of life also were significantly improved by betahistine. Both the physician's judgement and the patient's opinion on the efficacy and acceptability of the treatment were in agreement as to the superiority of betahistine. The effective and safe profile of betahistine in the treatment of vertigo due to peripheral vestibular disorders was confirmed.     

Medical treatment reverses cytokine pattern in allergic and nonallergic chronic rhinosinusitis in asthmatic children

A Th2 cytokine pattern has recently been reported both in allergic and nonallergic chronic rhinosinusitis in asthmatic children. The aim of the study was to evaluate the cytokine pattern in chronic rhinosinusitis in allergic and nonallergic asthmatic children before and after medical treatment. Thirty asthmatic children were evaluated, 18 males and 12 females (mean age 9.1 years). Sixteen were allergic and 14 were nonallergic. All children were asthmatic and suffered from chronic rhinosinusitis, whose diagnosis was confirmed by endoscopy. All of them were treated with amoxicilline-clavulanate (20 mg/kg b.i.d.) and fluticasone propionate aqueous nasal spray (100 µg daily) for 14 days; a short course of oral corticosteroid was also prescribed (deflazacort 1 mg/kg daily for 2 days, 0.5 mg/kg daily for 4 days and 0.25 mg/kg daily for 4 days). Rhinosinusal lavage and nasal cytology were performed in all subjects before and after medical treatment. IL4 and IFNγ were measured by immunoassay and inflammatory cells were counted by conventional staining. Thirteen allergic children and 12 nonallergic children showed a negative endoscopy after the treatment. Allergic subjects showed a significant decrease of IL4 (p = 0.0002) and a significant increase of IFNγ (p = 0.03) after the treatment. Nonallergic children showed a significant decrease of IL4 (p = 0.0007) and a nonsignificant increase of IFNγ. A significant reduction of the inflammatory infiltrate was detected in all asthmatic children (p < 0.05). This study confirms a Th2 polarization in chronic rhinosinusitis both in allergic and nonallergic asthmatic children. Moreover, the medical treatment of chronic rhinosinusitis reversed the cytokine pattern from a Th2 towards a Th1 profile both in allergic and nonallergic children.     

Molsidomine antagonizes L-NAME-induced acquisition deficits in a recognition memory task in the rat.

The present study was designed to investigate the role of nitric oxide (NO) on the acquisition of a recognition memory task in the rat. For this purpose, the effects on memory exerted by pre-training administration of the NO synthase inhibitor L-NAME (N(omega)-nitro-L-arginine methyl ester) and the NO donor molsidomine (N-[ethoxycarbonyl]-3-[4-morpholinosydnomine]) were assessed by using the object recognition task, a working memory paradigm based on the differential exploration of a new and familiar object. In a first dose-response study, it was found that L-NAME (10, 30, and 60 mg kg(-1), i.p.) at 30 but not at 10 mg kg(-1) disrupted animals performance, whereas the dose of 60 mg kg(-1) induced side effects. Molsidomine (2 and 4 mg kg(-1), i.p.) at 4 but not at 2 mg kg(-1), antagonized the L-NAME-induced performance deficits. These results indicate that NO is involved in the acquisition of a recognition memory task.     

Microdiscectomy in the treatment of lumbar disc herniation

The authors report their experience with short- and medium-term microdiskectomy for the treatment of lumbar disc herniation. It is based on 760 operations performed between 1985 and July 1999: expulsed hernias and those of large size with intense pain symptoms and/or neurologic deficit were treated. During the same period of time, the authors used enzymatic and percutaneous nucleolysis according to Onik for smaller hernias. The incidence of satisfactory results was high (90.1%), in agreement with the results published in the literature. There was a low incidence of complications (4.6%), and of these 2.8% had a benign spontaneous evolution; 1% was prevented during surgery, 0.5% was prevented with subsequent surgery, while only 0.2% was the cause of definitive failure. Unsatisfactory results were constituted by the sequelae of complications (1 discitis, 4 liquoral cysts, 1 error in level not diagnosed intraoperatively), stenosis of the lateral recess not diagnosed pre- or intraoperatively, and thus not treated; in 6.1% of cases there was no plausible justification. The microsurgical technique above all reduces the duration of hospitalization (5 days on the average, but with 91% of cases dismissed on day 3), and allows for a rapid return to work activity (after 63 days for patients who are not employees, but with a return after 20 days in 95% of cases).     

Concomitant boost radiation and concurrent cisplatin for advanced head and neck carcinomas. Preliminary results of a phase II, single-institutional trial

INTRODUCTION: This study aims to asses the effectiveness and toxicity of boost radiotherapy concomitant and concurrent cisplatin for patients with locally advanced head and neck cancer (LAHNC). MATERIAL AND METHODS: There were 30 patients included in a prospective, phase II single-institution trial and of whom, 29 were at AJCC stage IV and 1 at stage III. Treatment consisted of radiotherapy acceleration fractionation with concomitant boost, 72 Gy, and 2 cycles of concomitant cisplatin (20 mg/m2/day continuous infusion; days 1-5 and 29-33). Amifostine, (i.v. 200 mg/m2) was administered to 26 prior to the first fraction of radiotherapy. Endpoints of the study were quality-of-life (QL), overall survival, and local control of disease. RESULTS: Complete response (CR) was achieved in 23 patients (77%), 2 patients had partial response (PR) (7%), 4 had no response (13%), and 1 was not evaluated for response. The 2-year overall survival and loco-regional control were 60% and 56%, respectively. Main toxicity was grade 3 or 4 mucositis in 93% of the patients. QL scores (questionnaire QLQC30; version 3.0) and the HN cancer module QLQ-HN35) showed a worsening in areas related to the treatment e.g. dry mouth, problems stretching the mouth, and sticky saliva. CONCLUSIONS: this combination modality is active, but toxic, in the treatment for LAHNC. Concomitant boost radiotherapy is probably, not the best radiotherapy schema for combining with chemotherapy in LAHNC.     

Irinotecan in combination with fluorouracil in a 48-hour continuous infusion as first-line chemotherapy for elderly patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors study.

PURPOSE: Elderly patients constitute a subpopulation with special characteristics that differ from those of the nonelderly and have been underrepresented in clinical trials. This study was performed to determine the efficacy and safety of irinotecan (CPT-11) in combination with fluorouracil (FU) administered as a 48-hour continuous infusion twice a month in elderly patients. PATIENTS AND METHODS: Patients > or = 72 years old with metastatic colorectal cancer, Eastern Cooperative Oncology Group performance status of 0 to 1, no geriatric syndromes, and no prior treatment were treated every 2 weeks with CPT-11 180 mg/m2 plus FU 3,000 mg/m2 in a 48-hour continuous infusion. RESULTS: By intent-to-treat analysis, in 85 assessable patients, the objective response rate was 35% (95% CI, 25% to 46%), and stable disease was 33% (95% CI, 23% to 44%). Median time to progression was 8.0 months (95% CI, 6.0 to 10.0 months), and median overall survival time was 15.3 months (95% CI, 13.8 to 16.9 months). Toxicity was moderate. Grade 3 and 4 neutropenia, diarrhea, and asthenia were observed in 21%, 17%, and 13% of patients, respectively. Only one case of neutropenic fever occurred. There were two toxic deaths, one was a result of grade 4 diarrhea and acute kidney failure, and the other was a result of massive intestinal hemorrhage in the first cycle. The study of prognostic factors did not reveal any predictive factor of response. Response to treatment and baseline lactate dehydrogenase were the main factors conditioning progression-free and overall survival. CONCLUSION: Twice a month continuous-infusion CPT-11 combined with FU is a valid therapeutic alternative for elderly patients in good general condition.