Toxicological evaluation of long-term intravenous administration of amitraz in horses

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Acute and sustained effects of early administration of inhaled nitric oxide to children with acute respiratory distress syndrome

OBJECTIVE: To determine the acute and sustained effects of early inhaled nitric oxide on some oxygenation indexes and ventilator settings and to compare inhaled nitric oxide administration and conventional therapy on mortality rate, length of stay in intensive care, and duration of mechanical ventilation in children with acute respiratory distress syndrome. DESIGN: Observational study. SETTING: Pediatric intensive care unit at a university-affiliated hospital. PATIENTS: Children with acute respiratory distress syndrome, aged between 1 month and 12 yrs. INTERVENTIONS: Two groups were studied: an inhaled nitric oxide group (iNOG, n = 18) composed of patients prospectively enrolled from November 2000 to November 2002, and a conventional therapy group (CTG, n = 21) consisting of historical control patients admitted from August 1998 to August 2000. MEASUREMENTS AND MAIN RESULTS: Therapy with inhaled nitric oxide was introduced as early as 1.5 hrs after acute respiratory distress syndrome diagnosis with acute improvements in Pao(2)/Fio(2) ratio (83.7%) and oxygenation index (46.7%). Study groups were of similar ages, gender, primary diagnoses, pediatric risk of mortality score, and mean airway pressure. Pao(2)/Fio(2) ratio was lower (CTG, 116.9 +/- 34.5; iNOG, 62.5 +/- 12.8, p <.0001) and oxygenation index higher (CTG, 15.2 [range, 7.2-32.2]; iNOG, 24.3 [range, 16.3-70.4], p <.0001) in the iNOG. Prolonged treatment was associated with improved oxygenation, so that Fio(2) and peak inspiratory pressure could be quickly and significantly reduced. Mortality rate for inhaled nitric oxide-patients was lower (CTG, ten of 21, 47.6%; iNOG, three of 18, 16.6%, p <.001). There was no difference in intensive care stay (CTG, 10 days [range, 2-49]; iNOG, 12 [range, 6-26], p >.05) or duration of mechanical ventilation (TCG, 9 days [range, 2-47]; iNOG, 10 [range, 4-25], p >.05). CONCLUSIONS: Early treatment with inhaled nitric oxide causes acute and sustained improvement in oxygenation, with earlier reduction of ventilator settings, which might contribute to reduce the mortality rate in children with acute respiratory distress syndrome. Length of stay in intensive care and duration of mechanical ventilation are not changed. Prospective trials of inhaled nitric oxide early in the setting of acute lung injury in children are needed.

Neurohormonal, hemodynamic, and electrocardiographic evaluations of healthy dogs receiving long-term administration of doxorubicin

Objective - To evaluate diagnostic testing that could be used to establish an early diagnosis of cardiotoxicosis induced by long-term administration of doxorubicin. Animals - 13 adult mixed-breed dogs. Procedures - 7 dogs were administered doxorubicin chloride (30 mg/m2, IV, q 21 d for 168 days [cumulative dose, 240 mg/m2]), and 6 dogs received saline (0.9% NaCl) solution (5 mL, IV, q 21 d for 168 days; control group). Echocardiography, ECG, arterial blood pressure, plasma renin activity (PRA), and plasma concentrations of norepinephrine and brain natriuretic peptide (BNP) were assessed before each subsequent administration of doxorubicin and saline solution. Results - Dogs that received doxorubicin had a significant decrease in R-wave amplitude, compared with values for the control group, from 30 to 210 mg/m2. Doxorubicin-treated dogs had decreases in fractional shortening and left ventricular ejection fraction evident as early as 30 mg/m2, but significant differences between groups were not detected until 90 mg/m2 was reached. There was also a significant increase in PRA (≥ 120 mg/m2) and left ventricular end-systolic and end-diastolic dimensions (≥ 60 and ≥ 180 mg/m2, respectively). Systemic arterial pressure, remaining echocardiographic variables, and concentrations of norepinephrine and BNP had significant variations, but of no clinical importance, during doxorubicin administration. Conclusions and clinical relevance - Doxorubicin-induced cardiotoxicosis developed at 120 mg/m2, but there were no clinical signs of dilated cardiomyopathy or congestive heart failure. Echocardiography and determination of PRA were able to detect early cardiac alterations during the development of dilated cardiomyopathy, despite apparently differing degrees of sensitivity to development of doxorubicin-induced cardiotoxicosis.

Chronic administration of risperidone in a rat model of schizophrenia: A behavioural, morphological and molecular study

In the present work we analyzed the effect of the chronic administration of risperidone (2mg/kg over 65 days) on behavioural, morphological and molecular aspects in an experimental model of schizophrenia obtained by bilateral injection of ibotenic acid into the ventral hippocampus of new-born rats. Our results show that during their adult lives the animals with hippocampal lesions exhibit different alterations, mainly at behavioural level and in the gene expression of dopamine D2 and 5-HT2A receptors. However, at morphological level the study performed on the prefrontal cortex did not reveal any alterations in either the thickness or the number of cells immunoreactive for c-Fos, GFAP, CBP or PV. Overall, risperidone administration elicited a trend towards the recovery of the values previously altered by the hippocampal lesion, approaching the values seen in the animals without lesions. It may be concluded that the administration of risperidone in the schizophrenia model employed helps to improve the altered functions, with no significant negative effects. © 2013.

US Food and Drug Administration approval of generic versions of complex biologics: implications for the practicing physician using low molecular weight heparins

Low-molecular-weight heparins (LMWHs) have shown equivalent or superior efficacy and safety to unfractionated heparin as antithrombotic therapy for patients with acute coronary syndromes. Each approved LMWH is a pleotropic biological agent with a unique chemical, biochemical, biophysical and biological profile and displays different pharmacodynamic and pharmacokinetic profiles. As a result, LMWHs are neither equipotent in preclinical assays nor equivalent in terms of their clinical efficacy and safety. Previously, the US Food and Drug Administration (FDA) cautioned against using various LMWHs interchangeably, however recently, the FDA approved generic versions of LMWH that have not been tested in large clinical trials. This paper highlights the bio-chemical and pharmacological differences between the LMWH preparations that may result in different clinical outcomes, and also reviews the implications and challenges physicians face when generic versions of the original/innovator agents are approved for clinical use.

In vivo study of laser irradiation of fractionated drug administration based mechanism for effective photodynamic therapy in rat liver

Up-regulation of stress-activated proteins in cancer cells plays a protective role against photodynamic induced apoptosis. Post photodynamic therapy extracted normal rat liver tissue usually shows a fraction of surviving cells, the photodynamic resistant cells, residing in the necrotic region. To treat these photo-dynamic resistant cells a technique has been proposed based on fractionated drug administration of diluted photosensitizer, keeping the net concentration (5 mg/kg) constant, and subsequently varying drug light interval (DLI). Flourescence measurements were made for the presence of photosensitizer in a tissue. For qualitative analysis both histological and morphological studies were made. Although preliminary aim of this approach was not achieved but there were some interesting observation made i.e. for higher dilution of photosensitizer there was a sharp boundary between necrotic and normal portion of tissue. An increase in the absorption coefficient (alpha) from 2.7 -> 2.9 was observed as photosensitizer was diluted while the corresponding threshold dose (D (th)) persistently decreases from (0.10 -> 0.02) J/cm(2) when irradiated with a 635 nm laser fluence of 150 J/cm(2).

Chemotherapy patients' perceptions of drug administration safety

To explore chemotherapy patients' experiences of drug administration safety and to investigate the relationship between perceptions of risk and harm from error, staff safety practices, and patients' engagement in error prevention strategies.

Changes in volumetric BMD of radius and tibia upon antidepressant drug administration in young depressive patients

To determine longitudinal changes in trabecular volumetric BMD (vBMD) at tibia and radius in young depressive patients under antidepressants using pQCT.

Chronic administration of methylphenidate produces neurophysiological and behavioral sensitization.

The electrophysiological properties of acute and chronic methylphenidate (MPD) on neurons of the prefrontal cortex (PFC) and caudate nucleus (CN) have not been studied in awake, freely behaving animals. The present study was designed to investigate the dose-response effects of MPD on sensory evoked potentials recorded from the PFC and CN in freely behaving rats previously implanted with permanent electrodes, as well as their behavioral (locomotor) activities. On experimental day 1, locomotor behavior of rats was recorded for 2 h post-saline injection, and sensory evoked field potentials were recorded before and after saline and 0.6, 2.5, and 10 mg/kg, i.p., MPD administration. Animals were injected for the next five days with daily 2.5 mg/kg MPD to elicit behavioral sensitization. Locomotor recording was resumed on experimental days 2 and 6 after the MPD maintenance dose followed by 3 days of washout. On experimental day 10, rats were connected again to the electrophysiological recording system and rechallenged with saline and the identical MPD doses as on experimental day 1. On experimental day 11, rat's locomotor recording was resumed before and after 2.5 mg/kg MPD administration. Behavioral results showed that repeated administration of MPD induced behavioral sensitization. Challenge doses (0.6, 2.5, and 10.0 mg/kg) of MPD on experimental day 1 elicited dose-response attenuation in the response amplitude of the average sensory evoked field potential components recorded from the PFC and CN. Chronic MPD administration resulted in attenuation of the PFC's baseline recorded on experimental day 10, while the same treatment did not modulate the baseline recorded from the CN. Treatment of MPD on experimental day 10 resulted in further decrease of the average sensory evoked response compared to that obtained on experimental day 1. This observation of further decrease in the electrophysiological responses after chronic administration of MPD suggests that the sensory evoked responses on experimental day 10 represent neurophysiological sensitization. Moreover, two different response patterns were obtained from PFC and CN following chronic methylphenidate administration. In PFC, the baseline and effect of methylphenidate expressed electrophysiological sensitization on experimental day 10, while recording from CN did not exhibit any electrophysiological sensitization.

Agriculture, Rural Development, Food and Drug Administration, and related agencies appropriations for 2011 : hearings before a Subcommittee of the Committee on Appropriations, House of Representatives, One Hundred Eleventh Congress, second session /

Mode of access: Internet.

Agriculture, Rural Development, Food and Drug Administration, and related agencies appropriations for 2013 : hearings before a Subcommittee of the Committee on Appropriations, House of Representatives, One Hundred Twelfth Congress, second session /

Shipping list no.: 2012-0266-P (pt. 1A), 2012-0262-P (pt. 1B), 2012-0267-P (pt. 1C), 2012-0317-P (pt. 2), 2013-0006 (pt. 3), 2013-0008-P (pt. 4), 2013-0027-P (pt. 5), 2013-0033-P (pt. 6), 2013-0042-P (pt. 7), 2013-0038-P (pt. 9).

Agriculture, Rural Development, Food and Drug Administration, and related agencies appropriations for 2012 : hearings before a Subcommittee of the Committee on Appropriations, House of Representatives, One Hundred Twelfth Congress, first session /

Shipping list number: 2011-0276-P (pt. 1A), 2011-0274-P (pt. 1B), 2011-0283-P (pt. 1C), 2011-0318-P (pt. 2), 2011-0339-P (pt. 4), 2011-0366-P (pt. 5), 2011-0375-P (pt. 6), 2011-0367-P (pt. 7), 2011-0372-P (pt. 8), 2012-0014-P (pt. 9).

Interagency coordination in drug research and regulation. Hearings before the Subcommittee on Reorganization and International Organizations of the Committee on Government Operations, United States Senate, Eighty-eighth Congress, first session. Agency coordination study, pursuant to S. Res. 27, 88th Cong. Review of cooperation on drug policies among Food and Drug Administration, National Institutes of Health, Veterans' Administration, and other agencies. Mar. 20-June 26, 1963.

Mode of access: Internet.