Role of FDA in establishing tolerable levels for dioxin and PCBs in aquatic organisms

When fishery products shipped in interstate commerce contain an environmental contaminant that presents a potential threat to public health, the Food and Drug Administration (FDA) undertakes appropriate regulatory steps to minimize exposure. These efforts range from seizure of the affected product to formal rule-making to establish a limit. The basic provision of the Food, Drug, and Cosmetic (FD&C) Act by which the agency deals with environmental contaminants in the food supply is section 402(a)(1), which deals with poisonous and deleterious substances. Poisonous and deleterious components are deemed to be "added," even if they are natural constituents of food, if any amount is present through the artifice of man. Furthermore, when the level of a naturally occurring toxin is increased in the food through handling and/or processing, the sum of all of the contaminant is deemed to be "added." Unavoidable environmental contaminants may be controlled and/or regulated under this section by the "may render injurious" standard, whereby the agency must demonstrate that there is a significant possibility that exposure to the contaminant could be injurious to human health. "Action levels" are administrative guidelines or instructions to the agency field units that define the extent of contamination at which the agency may regard food as adulterated. Except for polychlorinated biphenyls, for which there is a tolerance established by regulation, FDA has controlled contaminants in aquatic organisms by using action levels. Under section 406 of the FD&C act, the agency can also establish tolerances for unavoidably added poisonous or deleterious substances. This section allows the agency to consider the extent to which a contaminant is unavoidable in food while it limits exposure to the extent necessary to protect the public health. Section 406 requires that the tolerance be established by assessing several factors, including risk. One of these is the capability of processing technology to prevent, reduce, or otherwise control the level of the contaminant. Another factor is the necessity to avoid the needless removal of large amounts of valuable food from the market. Finally, the available analytical and sampling methods must be capable of measuring the contaminant so as to ensure the enforceability of the tolerance. Although the FDA has no statutory authority over intrastate fishing considerations, such as noncommercial fishing, it does provide advice to local or state authorities. It is the best scientific opinion the agency can give, but it is not enforceable per se. Advice is provided when requested by local and state officials where no guideline or tolerance is available, and is meant to deal with local and/or regional public health concerns.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of agomelatine in the chronic mild stress model of depression in the rat.

Chronic mild stress (CMS), a well-validated model of depression, was used to study the effects of the melatonin agonist and selective 5-HT(2C) antagonist agomelatine (S 20098) in comparison with melatonin, imipramine, and fluoxetine. All drugs were administered either 2 h before (evening treatment) or 2 h after (morning treatment) the dark phase of the 12-h light/dark cycle. Chronic (5 weeks) evening treatment with agomelatine or melatonin (both at 10 and 50 mg/kg i.p.) dose-dependently reversed the CMS-induced reduction in sucrose consumption. The magnitude and time course of the action of both drugs was comparable to that of imipramine and fluoxetine (both at 10 mg/kg i.p.); however, melatonin was less active than agomelatine at this dose. The effect of evening administration of agomelatine and melatonin was completely inhibited by an acute injection of the MT(1)/MT(2) antagonist, S 22153 (20 mg/kg i.p.), while the antagonist had no effect in animals receiving fluoxetine or imipramine. When the drugs were administered in the morning, agomelatine caused effects similar to those observed after evening treatment (with onset of action faster than imipramine) but melatonin was ineffective. Moreover, melatonin antagonist, S 22153, did not modify the intakes in stressed animals receiving morning administration of agomelatine and in any other control and stressed groups tested in this study. These data demonstrate antidepressant-like activity of agomelatine in the rat CMS model of depression, which was independent of the time of drug administration. The efficacy of agomelatine is comparable to that of imipramine and fluoxetine, but greater than that of melatonin, which had no antidepressant-like activity after morning administration. While the evening efficacy of agomelatine can be related to its melatonin receptors agonistic properties, its morning activity, which was not inhibited by a melatonin antagonist, indicates that these receptors are certainly required, but not sufficient to sustain the agomelatine efficacy. It is therefore suggested that the antidepressant-like activity of agomelatine depends on some combination of its melatonin agonist and 5-HT(2C) antagonist properties.     

Micelles in anticancer drug delivery

In recent years, the development of micelle-based carriers for cancer chemotherapy has been the object of growing scientific interest, both in academia and the pharmaceutical industry. Micelles have attracted attention in drug formulation and targeting, given that they provide a set of unique features. The core/shell structure accounts for their qualities as efficient drug delivery systems. The core provides a reservoir where hydrophobic drugs can be dissolved, and the corona confers hydrophilicity to the overall system. Sequestration of anticancer drugs in the inner core can protect them from premature degradation and allow their accumulation at tumoral sites. Micelles can be subdivided into two different groups according to their molecular weights: low-molecular-weight surfactant micelles and polymeric micelles. Although surfactant micelles such as polyethoxylated castor oil (e.g. Cremophor® EL) are commonly used to solubilize hydrophobic anticancer drugs such as paclitaxel, they have often been associated with serious adverse effects. Polymeric micelles may offer several advantages over surfactant micelles in terms of drug loading, adverse effects, stability, and targeting of tumors. Indeed, polymeric micelles can increase the circulation time of cytostatics and induce substantial changes in their biodistribution, including tumor accumulation via the enhanced permeation and retention effect. In addition, some recent studies have demonstrated that amphiphilic block copolymers (e.g. poloxamers) used for the preparation of polymeric micelles could increase the activity of several cytostatics by reversing multidrug resistance. This review first describes and compares surfactant micelle and polymeric micelle systems, already commercialized or under investigation, used to administer cytostatics. Secondly, their in vitro interactions with neoplastic cells and tissues are discussed in terms of cellular uptake and pharmacologic activity. In particular, the pharmacokinetics and biodistribution of micelles, along with the factors affecting their delivery to tumoral sites, are thoroughly discussed. Finally, in vivo studies reporting the anticancer activity and toxicity of drugs associated with micelles are reviewed.     

Cancer consultation preparation package: changing patients but not physicians is not enough.

PURPOSE: This study evaluated a cancer consultation preparation package (CCPP) designed to facilitate patient involvement in the oncology consultation. PATIENTS AND METHODS: A total of 164 cancer patients (67% response rate) were randomly assigned to receive the CCPP or a control booklet at least 48 hours before their first oncology appointment. The CCPP included a question prompt sheet, booklets on clinical decision making and patient rights, and an introduction to the clinic. The control booklet contained only the introduction to the clinic. Physicians were blinded to which intervention patients received. Patients completed questionnaires immediately after the consultation and 1 month later. Consultations were audiotaped, transcribed verbatim, and coded. RESULTS: All but one patient read the information. Before the consultation, intervention patients were significantly more anxious than were controls (mean, 42 v 38; P = .04); however anxiety was equivalent at follow-up. The CCPP was reported as being significantly more useful to family members than the control booklet (P = .004). Patients receiving the intervention asked significantly more questions (11 v seven questions; P = .005), tended to interrupt the physician more (1.01 v 0.71 interruptions; P = .08), and challenged information significantly more often (twice v once; P = .05). Patients receiving the CCPP were less likely to achieve their preferred decision making style (22%) than were controls (35%; P = .06). CONCLUSION: This CCPP influences patients' consultation behavior and does not increase anxiety in the long-term. However, this intervention, without physician endorsement, reduced the percentage of patients whose preferred involvement in decision making was achieved.     

Prolonged allograft survival through conditional and specific ablation of alloreactive T cells expressing a suicide gene

BACKGROUND: Control of antidonor activated T cells involved in allograft rejection while preserving immunocompetence is a challenging goal in transplantation. Engineered T cells expressing a viral thymidine kinase (TK) suicide gene metabolize the nontoxic prodrug ganciclovir (GCV) into a metabolite toxic only to dividing cells. We evaluated this suicide gene strategy for inducing transplantation tolerance in mice. METHODS: Transgenic mice expressing TK in mature T cells were analyzed for (i) specific T-cell depletion under GCV treatment upon various stimulations; (ii) outcome of allogeneic nonvascularized skin or heart allografts under a short 14-day GCV treatment initiated at the time of transplantation; and (iii) the capacities of T cells from such allotransplanted mice to proliferate in mixed lymphocyte reactions and to induce graft-versus-host disease in irradiated recipients with the genetic background of the donor allograft. RESULTS: Upon in vitro or in vivo GCV treatment, only activated dividing TK T cells but not B cells were efficiently depleted. Acute rejection of allogeneic grafts was prevented and a significant prolongation of graft survival was obtained, although associated with signs of chronic rejection. Prolonged skin graft survival correlated with decreased in vitro and in vivo T-cell reactivities against donor alloantigens, whereas overall immunocompetence was preserved. CONCLUSIONS: Efficient and specific depletion of alloreactive TK T cells can be achieved by administrating GCV. These results open new perspectives for the control of allogeneic graft rejection using suicide gene therapy.     

Impact of medical practice guidelines on the assessment of patients with acute coronary syndrome without persistent ST segment elevation.

OBJECTIVE: To assess the impact of introducing clinical practice guidelines on acute coronary syndrome without persistent ST segment elevation (ACS) on patient initial assessment. DESIGN: Prospective before-after evaluation over a 3-month period. SETTING: The emergency ward of a tertiary teaching hospital. PATIENTS: All consecutive patients with ACS evaluated in the emergency ward over the two 3-month periods. INTERVENTION: Implementation of the practice guidelines, and the addition of a cardiology consultant to the emergency team. MAIN OUTCOME MEASURES: Diagnosis, electrocardiogram interpretation, and risk stratification after the initial evaluation. RESULTS: The clinical characteristics of the 328 and 364 patients evaluated in the emergency ward for suspicion of ACS before and after guideline implementation were similar. Significantly more patients were classified as suffering from atypical chest pain (39.6% versus 47.0%; P = 0.006) after guideline implementation. Guidelines availability was associated with significantly more formal diagnoses (79.9% versus 92.9%; P < 0.0001) and risk stratification (53.7% versus 65.4%, P < 0.0001) at the end of initial assessment. CONCLUSION: Guidelines implementation, along with availability of a cardiology consultant in the emergency room had a positive impact on initial assessment of patients evaluated for suspicion of ACS. It led to increased confidence in diagnosis and stratification by risk, which are the first steps in initiating effective treatment for this common condition.     

An association of pleuropulmonary blastoma and cystic nephroma: possible genetic association.

The association of pleuropulmonary blastoma and cystic nephroma is an uncommon entity, with only 4 cases of such an association in the same patient described in English literature. We report a 5th histologically documented case in a 32-month-old boy. The boy underwent a pulmonary biopsy that showed a pleuropulmonary blastoma and a nephrectomy that showed a cystic nephroma. The pleuropulmonary mass showed an important regression with postbiopsy chemotherapy, allowing subsequent tumorectomy. To date very little is known about this rare entity, and a genetic link between these 2 tumors is hypothesized.     

Is a prophylactic treatment by erythropoietin relevant to reduce red blood cell transfusion in the pediatric intensive care unit?

OBJECTIVE: An adult trial reported the efficacy of recombinant human erythropoietin in critically ill patients with a 19% decrease in red blood cell transfusion. Our aim was to evaluate the relevance of this prophylactic treatment in children hospitalized in a pediatric intensive care unit (PICU). DESIGN: Cohort study from January 1995 to December 2004. SETTING: University hospital PICU. PATIENTS: Children between 1 month and 18 yrs of age. INTERVENTIONS: We searched through a prospective databank for all children hospitalized in the PICU for > or =4 days (potential recipients of erythropoietin, as proposed in the adult trial) and transfused with red blood cells after day 7 following PICU entry (in whom erythropoietin might prevent anemia, according to results of the adult trial). MEASUREMENTS AND MAIN RESULTS: We found that 799 of 2,578 children (31%) were hospitalized for > or =4 days. The study group comprised 787 patients who were hospitalized for > or =4 days in the PICU and for whom full records were available. One hundred eighty-three children in this study group were transfused during their stay in the PICU (median age, 7 months; weight, 6.60 kg). Hemoglobin levels before transfusion (mean +/- sd) were 7.7 +/- 1.5 g/dL. These transfused children represented 23% of the study group and 7% of the total PICU admissions. Forty-seven children (6% of the study group, 2% of the total PICU admissions) were transfused with red blood cells after 7 days of hospitalization and could have benefited from a prophylactic treatment with erythropoietin. Relative risk to benefit of a prophylactic treatment by erythropoietin was higher in cases of mechanical ventilation (relative risk, 1.18) and inotropic treatment (relative risk, 1.72) and if the main diagnosis involved dermatological (relative risk, 3.03) or oncologic disease (relative risk, 3.94). CONCLUSIONS: If we applied the results of the adult trial to our PICU, we would have to treat 31% of the children with prophylactic erythropoietin and thereby expect a reduction of one red blood cell transfusion for every 17 treated patients.