Pharmacokinetics of VP16-213 given by different administration methods

Summary Plasma pharmacokinetics of VP16-213 were investigated after a 30–60 min infusion in 14 adult patients and six children. In adults the elimination half-life (T_1/2 ), plasma clearance (Cl_p) and volume of distribution (Vd) were respectively 7.05±0.67 h, 26.8±2.4 ml/min/m², and 15.7±1.8 l/m²; in children 3.37±0.5 h, 39.34±6.6 ml/min/m², and 9.97±3.7 l/m². After repeated daily doses no accumulation of VP16-213 was found in plasma. The unchanged drug found in the 24 h urine after administration amounted to 20–30% of the dose.In eight choriocarcinoma patients plasma levels of VP16-213 were measured after oral capsules and drinkable ampoules. The bioavailability compared to the i.v. route was variable, mean values being 57% for capsules and 91% for ampoules. In one further patient, with abnormal d-Xylose absorption results, VP16-213 was not detectable in plasma after the oral ampoule dose.Steady state levels investigated in three patients after 72 h continuous VP16-213 infusion (100 mg/m²/24 h) were around 2–5 g/ml. Levels of VP16-213 were undetectable in CSF after i.v. or oral administration.     

Some interpersonal consequences of being mentally ill or mentally retarded.

The present study was carried out at an institution for mentally retarded persons where the subjects (college students) were transported. Under the guise of being "normal," mentally ill, or mentally retarded, each of four confederates met three independent groups of subjects. The verbal reports of the subjects did not vary a great deal as a function of condition, but amount of pain inflicted in an experimental task was strikingly different. In the mentally retarded confederate condition, shocks delivered were shorter and less intense than those given in the "normal" or mentally ill confederate conditions. Since subjects had to teach the confederate, they might have been kinder in the mentally retarded confederate condition because less was expected of the learner. Evidence was also found suggesting that the social impact of stigmas depends on the personal characteristics of the stigmatized person.     

Comparison of the attitudes of Israeli therapists and lay persons to ethical dilemmas in psychotherapy

The issues of confidentiality and boundaries cause ethical dilemmas for psychotherapists. We investigated whether therapists have ethical attitudes to confidentiality and boundaries that are unique to their professional group compared with lay persons and whether gender or professional characteristics are associated with these attitudes. Clinical vignettes capturing ethical dilemmas regarding confidentiality and boundaries were presented to 93 psychotherapists of different professional backgrounds (professional group) and 55 staff and students from the fields of law and the humanities (lay group). In general, the lay group showed a greater tendency to maintain confidentiality than the professional group. Regarding boundaries, the majority of psychotherapists were against initiating any sexual relationship with current patients, former patients, students, or supervisees; the differences between the groups in this area were statistically significant. The vast majority of therapists (96.7%) disapproved of accepting money in advance compared with only 54.4% of the lay group. Analysis of the psychotherapists by professional background revealed that for the majority of the vignettes, there was no difference in attitude to confidentiality and boundaries between psychiatrists, psychologists, and social workers. The present study shows that therapists have different ethical codes from nontherapists regarding the issues of boundaries and the treatment contract. Therapists are stricter than nontherapists regarding issues of boundaries but less strict regarding issues of confidentiality, and there are some minor differences in the attitudes to these issues among different types of therapists.     

Auricular alloplastic reconstruction with osteointegrated implants: a new therapy option in microtia

Microtia has been treated over the years with autogenous tissues, although the results continue to improve, it is technically a very demanding procedure, even in the hands of a well trained surgeon. Osseointegrated implant-supported ear prosthesis, is less demanding, more straightforward, and offers a better cosmetic result. Since 1996 we have treated 8 patients with microtia types III and IV, with titanium osseointegrated implant-supported ear prosthesis in the bone of the mastoid process. The surgical procedure consists in two stages. First stage: when the three titanium screws are drill in the mastoid process of the temporal bone, with a previous CT scan of the area, that is used to measured the bone thickness. Second stage is done 3 to 6 months later. Ear remnants are removed at the beginning of the procedure, three titanium couplings are then secured to the integrated fixtures, a plastic cap is attached to each of the abutments, until healing takes place; three to four weeks later the auricular prosthesis made out of silicone over a metallic structure, will we plug in the titanium screws. Cosmetic results and patients acceptability have been good in all 8 cases, with few postoperative complications. This procedure has become and option for the patients with ear malformations.     

Value of P-glycoprotein and clinicopathologic factors as the basis for new treatment strategies in high-grade osteosarcoma of the extremities.

PURPOSE: To evaluate the prognostic value of P-glycoprotein and clinicopathologic parameters in a large series of high-grade osteosarcoma (OS) patients treated at the Rizzoli Institute. PATIENTS AND METHODS: With the use of immunohistochemistry, P-glycoprotein was assessed in 149 patients with primary, nonmetastatic, high-grade OS who were homogeneously treated with chemotherapy protocols based on doxorubicin, high-dose methotrexate, and cisplatin and the addition of ifosfamide in the postoperative phase. RESULTS: P-glycoprotein positivity was found in 47 of 149 cases (32%) and was significantly associated with a higher incidence of relapse and a worse outcome, as was age younger than 12 years and tumor volume greater then 150 mL at diagnosis. Multivariate analysis further confirmed the prognostic value of these parameters, which all were independent adverse prognostic factors. Event-free survival and proportional hazards regression analyses confirmed that overexpression of P-glycoprotein at clinical onset is the most important adverse prognostic factor for high-grade OS patients treated with these chemotherapy protocols. CONCLUSION: Increased P-glycoprotein levels, together with tumor volume and age, should be taken into consideration to identify, at time of diagnosis, subgroups of OS patients with a higher risk of recurrence. This subgroup identification will constitute the basis for drawing individualized treatment protocols on the basis of risk evaluation, with the aim of using more aggressive chemotherapy, or combination chemotherapy with other adjuvants, only in those patients for which more aggressive regimens are strictly necessary and warranted.     

Lower rate of preeclampsia after antioxidant supplementation in pregnant women with low antioxidant status.

OBJECTIVE: To investigate maternal and neonatal outcomes after antioxidant supplementation relatively early in pregnancy (8 to 12 weeks) for pregnant women with low antioxidant status. METHODS: A randomized, double-blind, placebo-controlled trial of daily antioxidant supplementation was performed on pregnant women screening positive for low antioxidant status at 8 to 12 weeks of gestation. Low antioxidant status was defined as a superoxidedismutase (SOD) level below 1102 U/g Hb or 164 U/mL. The supplementation group received the following antioxidants daily: vitamins A (1000 IU), B6 (2.2 mg), B12 (2.2 microg), C (200 mg), and E (400 IU), folic acid (400 microg), N-acetylcysteine (200 mg), Cu (2 mg), Zn (15 mg), Mn (0.5 mg), Fe (30 mg), calcium (800 mg), and selenium (100 microg). The control group received Fe (30 mg) and folic acid (400 microg). Maternal (preeclampsia, abortion, and hypertension) and perinatal outcomes were assessed. RESULTS: In the supplementation group (29 subjects), we observed 2 cases of preeclampsia (6.8%, 1 mild and 1 severe), 1 of IUGR (birth weight 2300 g at 38 weeks), and 1 preterm delivery. In the control group (31 subjects), there were 8 abortions, 9 cases of preeclampsia (29%, 6 mild and 3 severe) with perinatal outcome: 3 preterm delivery cases and 1 IUGR (birth weight 2030 g at 39 weeks). Preeclampsia was significantly less frequent in the supplementation group when compared to the control group (2 vs. 9 cases, p = 0.043, OR = 0.18 [95% CI: 0.03, 0.92]). Finally we focused on the prediction of preeclampsia at 8 to 12 weeks. Combined sensitivity of markers of antioxidant status (SOD slutathione peroxidase, [GPx], and total anti-oxidant status [TAS]) was 33% (false-positive rate of 4.5%). CONCLUSION: Antioxidant supplementation was associated with better maternal and perinatal outcome in pregnant women with low antioxidant status than control supplementation with iron and folate alone. In a selected population already screened positive for low SOD, preeclampsia can be detected in 33% of asymptomatic cases in the first trimester using SOD, GPx, and TAS. It seems feasible that panels of both biochemical and molecular markers may be clinically useful in the prediction of this disease.     

Synthesis and Antimuscarinic Activity of Derivatives of 2-Substituted-1,3-Dioxolanes

Geometric cis, trans isomers, derivatives of 2-substituted-1,3-dioxanes were designed and studied as antimuscarinic agents. The synthesized compounds were evaluated as perchlorides and methiodides by functional tests with rabbit vas deferens (putative M₁), guinea-pig heart (M₂) and guinea-pig ileum (M₃). The effect of the replacement of a trimethylammonium group with a dimethysulfonium in the two rings was also evaluated. Pharmacological results indicate that the 1,3-dioxane nucleus shows the highest stereoselective values on the studied receptors.     

Boerhaave syndrome. A case report and review of the literature

Spontaneous esophageal perforation (Boerhaave's syndrome) remains a difficult diagnostic and management problem with controversial recommendations regarding its treatment. The clinical manifestations of the disease are variable, and may be misleading, thus delaying accurate recognition. On the other hand, in view of the rapid onset of severe complications, particularly mediastinitis, a prompt diagnosis is essential to a better prognosis, successful operative outcome and potential survival. A case of spontaneous perforation of the thoracic esophagus penetrating the left pleural space treated within 4 hours from admission to the Emergency Room, with minimal surgical intervention is presented. Despite negative chest X-ray, a thoracic TC showed a small right sided effusion with left sided hydropneumothorax, and the definitive diagnosis was obtained by contrast study with a water soluble medium which showed the leak communicating freely with the left pleural space. The patient underwent repair by thoracic approach, the rupture was closed with a primary suture without flap reinforcement and the pleural space drained with the placement of single chest thoracostomy tube. The recovery was uneventful. The analysis of this case report and of the appropriate literature reveals that a poor prognosis is correlated with the time elapsed between the perforation and treatment. In conclusion the importance of an early aggressive surgical treatment for the Boerhaave's syndrome is emphasized, because any perforation treated more than 24 hours after the onset of symptoms, irrespective of the procedure used, is associated with a significantly higher morbility and mortality.     

Intestinal fistulas in Crohn disease

BACKGROUND: Only a part of patients suffering from Crohn's disease has enteric fistulae and a different behaviour of Crohn's disease with fistulae is reported in the literature. Aim of this paper is to evaluate if enteric fistulae are a factor conditioning mortality, morbidity and overall postoperative course, in patients with Crohn's disease. METHODS: Data on the postoperative course of 126 laparotomies for Crohn's disease, performed between November 1993 and July 1998, have been prospectively examined. Moreover, the presence of enteric fistula has been evaluated during surgery. RESULTS: Out of 126 interventions, in 58 (46%) enteric fistulae were present. Mortality (5.2% vs 0), morbidity (14.5% vs 7.3%), necessity for a temporary ostomy (20.4% vs 3.5%) were greater in those patients with fistula, as compared as those without fistula. CONCLUSIONS: In conclusion, it is suggested that Crohn's disease with fistulae is a different type of disease, with higher mortality and morbidity rates.