Interaction between central alpha 1- and alpha 2-adrenoceptors on sympathetic tone in rats

The interaction between piperoxan and alpha 2-agonists on sympathetic tone was studied in rats. The sympatho-inhibitory effect of alpha 2-agonists (clonidine, guanfacine, B-HT 933) was assessed by recording heart rate in normotensive bilaterally-vagotomized rats. Clonidine (3 micrograms/kg, i.c.v.) and B-HT 933 (100 micrograms/kg, i.c.v.) induced a bradycardia which was fully reversed by piperoxan (30 micrograms/kg, i.c.v.). However, in rats treated with guanfacine, piperoxan induced a partial recovery of the bradycardic effect. The injection of a small dose of the specific alpha 1-adrenoceptor blocking drug, AR-C 239 (10 micrograms/kg, i.c.v.) which, by itself did not modify heart rate, completely inhibited the reversal effect of piperoxan in rats treated with clonidine, B-HT 933 or guanfacine. In rat brainstem membranes, B-HT 933 was found to bind to both alpha 1- and alpha 2-adrenoceptors and was as potent as clonidine in competing for alpha 1-sites bound by [3H]prazosin. On the other hand, in bilaterally vagotomized rats, piperoxan (30 micrograms/kg, i.c.v.) induced an increase in blood pressure and heart rate which was inhibited by previous administration of AR-C 239 (10 micrograms/kg, i.c.v.). These data suggest that, by inhibiting central alpha 2-adrenoceptors, piperoxan unmasks central alpha 1-adrenoceptor stimulation by endogenous catecholamines leading to an increase in the sympathetic tone, but a full recovery in heart rate could be observed only with the mixed alpha 1- and alpha 2-adrenoceptor agonists, clonidine and B-HT 933. In addition, these data further indicate that alpha 1-adrenoceptors are implicated in a tonic control of the sympathetic nerve activity in normotensive rats.     

Almitrine bismesylate disposition in the human digestive tract

Summary The absorption of almitrine from the upper gastrointestinal tract has been evaluated in 6 healthy volunteers by an intubation technique. Almitrine bismesylate dissolved in malic acid was introduced into the stomach after homogenization with a meal containing the marker¹⁴C-polyethylene glycol (PEG) 4000. Unlabeled PEG 4000 was infused into the second part of duodenum throughout the experiment. Samples of the luminal content were collected every 15 min for four hours from the stomach and at the ligament of Treitz. Blood was also collected.Almitrine was neither absorbed from nor metabolized in the stomach. About 37% of the quantity of drug emptied from the stomach was absorbed from the duodenum. Almitrine was detected in plasma 50 min after ingestion of the meal and its plasma concentration-time profile reflected the cumulative gastric emptying rate. The metabolite tetrahydroxy almitrine was found in intestinal samples as soon as unchanged drug was detected in plasma. The intraluminal rate of formation of the metabolite increased with time.The results suggest hepatic metabolism of almitrine followed by rapid excretion of the metabolite in the bile.     

Hypofractionated stereotactic body radiation therapy (SBRT) in pediatric patients: preliminary toxicity results of a national prospective multicenter study

Objectives:While hypofractionated stereotactic body radiotherapy (SBRT) has been largely adopted in the adult setting, its use remains limited in pediatric patients. This is due, among other factors, to fear of potential toxicities of hypofractionated regimens at a young age. In this context, we report the preliminary acute (<3 months from SBRT) and middle-term (3–24 months) toxicity results of a national prospective study investigating SBRT in pediatric patients.Methods:Between 2013 and 2019, 61 patients were included. The first 40 patients (median age: 12 y, range: 3–20) who completed a 2-year-follow-up were included in the present analysis. SBRT was used for treating lung, brain or (para)spinal lesions, either as first irradiation (35%) or in the reirradiation setting (65%).Results:Acute and middle-term grade ≥2 toxicities occurred in 12.5 and 7.5% of the patients, respectively. No grade ≥4 toxicities occurred. Almost all toxicities occurred in the reirradiation setting.Conclusion:SBRT showed a favorable safety profile in young patients treated for lung, brain, and (para)spinal lesions.Advances in knowledge:SBRT appeared to be safe in pediatric patients treated for multiple oncology indications. These results support further evaluation of SBRT, which may have a role to play in this patient population in the future.     

Two hundred intrauterine exchange transfusions in severe blood incompatibilities

Two hundred intrauterine exchange transfusions were performed under local anesthesia in 107 cases of blood incompatibilities (60 fetuses with severe anemia and 47 with hydrops). Under sonographic guidance, depending on fetal and placental position, an optimal puncturing site was selected along the umbilical vein: placental insertion, fetal insertion, or fetal intraabdominal segment. Tests were immediately performed to confirm fetal origin of blood obtained and estimate hemoglobin level. Blood used for exchange transfusion was compatible with maternal blood and had a hematocrit value of 75%. Exchange transfusion was continued until a hemoglobin level of 16 gm/dl was reached. This procedure was first associated with intraperitoneal transfusions and was subsequently used independently once a month to maintain an adequate hemoglobin level. In 4 fetuses with hydrops, antenatal regression of this sign was observed in 33 cases (70.2%). Overall outcome of 107 fetuses after exchanges was 84 living neonates (78.5%), 15 deaths in utero, and eight neonatal deaths. The survival rate was 91.6% for fetuses without hydrops and 61.7% for those with hydrops. The advantage of exchange transfusion appears to be rapid and efficient correction of anemia with elimination of incompatible fetal red blood cells.     

The homocamptothecin BN 80915 is a highly potent orally active topoisomerase I poison

BN 80915, a lead compound of the homocamptothecin (hCPT) family, has entered clinical trials. BN 80915 is a difluoro-hCPT where the six-membered alpha-hydroxylactone ring of camptothecin (CPT) is replaced by a seven-membered beta-hydroxylactone ring. Preclinical data reported here show that in spite of the modification to the crucial E-ring of CPTs, BN 80915 retains topoisomerase I poisoning activity as shown in living HT29 cells as well as in cell-free assays, where BN 80915 always performs better than SN-38 or TPT. In antiproliferative assays BN 80915 is also very potent as evidenced by IC50s values consistently lower than those of SN38 in sensitive cell lines as well as in their related multidrug-resistant lines overexpressing P-glycoprotein or multidrug resistance-associated protein. Furthermore, in human plasma, in contrast to CPT analogs, the hydrolysis of BN 80915 is slow, leading to improved plasma stability, and irreversible, thus avoiding toxicity related to the accumulation of active principle during excretion in the urinary tract. These findings may account for the good in vivo efficacy observed in PC3 xenograft experiments where BN 80915 administered orally at very low doses doubled the tumor growth delay in comparison to CPT-11 administered i.p. Altogether, these results strongly support further development of BN 80915.     

Radiothérapie d''un hémangiome massif du foie chez une enfant d''un mois et demi

We report the case of a six-week-old baby who underwent irradiation for a giant hepatic hemangioma. After medical treatment including corticosteroids and interferon, no response was observed. She progressed to respiratory failure, requiring the use of mechanical ventilation. An emergency radiation therapy of the liver was decided. We observed a rapid improvement of the child, with the recovery of autonomous breathing without mechanical ventilation and a normalization of cardiac functions. Two months later, a partial left hepatic embolization was needed due to a progression of a localized blood flow. Six months later, she finally came back home. Cardiac output was normal and hepatomegaly began to regress. One year later, ponderal status is satisfactory, and it remains a localized hepatic right lobe hypertrophy without functional consequence.     

Fractionated irradiation of cerebellopontine angle neurinoma: 12 years' experience of the Bordeaux University Hospital Center]

PURPOSE: To evaluate retrospectively the long-term results of fractionated radiation therapy (RT) in cerebello-pontine angle neurinomas (CPA). METHODS AND MATERIAL: From January 1986 to October 1995, 29 patients with stage III and IV neurinomas were treated with external fractionated RT. One patient was irradiated on both sides and indications for RT were as follows: (1) general contraindications for surgery (16 patients); (2) hearing preservation in bilateral neurinomas after controlateral tumor exeresis (six patients); (3) partial tumor removal (five patients); and, (4) non-surgical recurrence (three patients). A three to four fields technique with coplanar static beams and conformal cerobend blocks was used; doses were calculated on a 95 to 98% isodoses and were given five days a week for a median total dose of 51 Gy (1.8 Gy/fraction). Most patients were irradiated with 6 to 10 MV photons). RESULTS: Median follow-up was 66 months (seven to 120 months). Seven patients died, two with progressive disease, five from non-tumoral causes. Tumor shrinkage was observed in 13 patients (43.3%), stable disease in 14 (46.6%), and tumor progression in three. Two patients underwent total tumor removal after RT (one stable and one growing tumor). Hearing was preserved in four out of six patients. No patient experienced facial or trigeminal neuropathy. CONCLUSION: Fractionated RT is a well tolerated and efficacious treatment of large non-surgical CPA neurinomas.     

Dose de tolérance à l’irradiation des tissus sains : l’os chez l’adulte

Radiation tolerance for bone tissue has been mostly evaluated with regard to bone fracture. Main circumstances are mandibula osteoradionecrosis, hip and costal fracture, and patent or radiologic fractures in the treated volume. After radiation therapy of bone metastasis, the analysis of related radiation fracture is difficult to individualize from a pathologic fracture. Frequency of clinical fracture is less than 5% in the large series or cohorts and is probably underevaluated for the asymptomatic lesions. Women older than 50 years and with osteoporosis are probably the main population at risk. Dose–effect relations are difficult to qualify in older series. Recent models evaluating radiations toxicity on diaphysa suggest an important risk after 60 Gy, for high dose–fraction and for a large volume.     

Long-term effects of therapeutic education for patients with rheumatoid arthritis

IntroductionThe objective of this study was to assess the effects of an educational program on the course of rheumatoid arthritis (RA) after 3 years.MethodsFrom December 2002 to December 2003, 39 RA patients participated in a 3-day education program delivered to groups of four or five patients. Effects of the program were evaluated after 3 years in 33 patients, comparatively to baseline, based on the following variables: knowledge of RA (self-questionnaire), disease activity (DAS 28), functional impairment (health assessment questionnaire [HAQ]) and quality of life (arthritis impact measurement scale 2 [AIMS2], short-form). We also compared patient knowledge in the educational program participants and in 38 controls with RA. Direct questions were used to evaluate the program after 3 years.ResultsPatient knowledge 3 years after the education program was significantly improved compared to baseline (P < 0.0001) and was significantly better than in the controls (P < 0.0001). Disease activity was significantly lower in the education group after 3 years than at baseline (DAS28, 3.1 vs. 3.8, P < 0.005). Neither the HAQ nor the AIMS2 scores changed significantly after 3 years compared to baseline. The replies to the direct questions indicated a very high level of overall satisfaction with the educational program.ConclusionAn educational program tailored to patient needs can produce lasting improvements in knowledge of the disease and may help to control the activity of RA. These results warrant the development of education programs for patients with chronic inflammatory joint disease.