PHARMACOKINETICS, BIO-EQUIVALENCE AND TISSUE RESIDUES OF TWO ORAL COLISTIN FORMULATIONS IN BROILER CHICKENS

Objective: The present study was carried out to investigate and provide an overview of the pharmacokinetics, bio-equivalence and tissue residues of colistin in two oral tested products, BAC-Liquido® (Interchemi Co.) and Coline-L® (Medmac Co.) in healthy broiler chickens.Methods: The comparative pharmacokinetics, bio-equivalence, blood and tissue residues of BAC-Liquido® and Coline-L® in broiler chickens was studied after oral administration of both products in a dose of 100.000 IU colistin base/kg. b. wt once daily for 5 consecutive days.Results: Colistin in both products obeyed a two compartments open model following I. V administration. The disposition kinetics of BAC-Liquido® and Coline-L® following oral administration of 100.000 IU colistin base/kg. b. wt revealed that the maximum blood concentration [Cmax.] were 5.10 and 4.95 µg/ml and attained at [tmax.] of 5.90 and 6.40 h, respectively. Colistin in BAC-Liquido® and Coline-L® was eliminated with half-lives [t1/2β] equal to 3.15 and 2.89 h, respectively. The mean systemic bioavailability of colistin in BAC-Liquido® and Coline-L® following oral administration in healthy chickens was 3.75 and 4.05%, respectively. The blood (µg/ml) and tissue (µg/g) residues of Coline-L® and BAC-Liquido® following repeated oral administrations showed that liver, kidney; lung, breast, and thigh muscles contained the limited colistin residues. Colistin in both preparations was completely disappeared from all tissues at 24 h following the last oral dose (except liver 48 h).Conclusion: It was concluded that Coline-L® is bioequivalent to BAC-Liquido® since Cmax test/Cmax reference and AUCtest/AUCreference ratios were 0.97 and 1.06, respectively. Chickens should not be slaughtered for human consumption within treatment and could be consumed after the discontinuation of the treatment (except liver, withdrawal time 48 h) of either BAC-Liquido® or Coline-L®.Keywords: Pharmacokinetics, Colistin, Broiler chickens, Bioavailability, Tissue residue

Dopamine dysregulation in a mouse model of paroxysmal nonkinesigenic dyskinesia.

Paroxysmal nonkinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder. Patients have episodes that last 1 to 4 hours and are precipitated by alcohol, coffee, and stress. Previous research has shown that mutations in an uncharacterized gene on chromosome 2q33-q35 (which is termed PNKD) are responsible for PNKD. Here, we report the generation of antibodies specific for the PNKD protein and show that it is widely expressed in the mouse brain, exclusively in neurons. One PNKD isoform is a membrane-associated protein. Transgenic mice carrying mutations in the mouse Pnkd locus equivalent to those found in patients with PNKD recapitulated the human PNKD phenotype. Staining for c-fos demonstrated that administration of alcohol or caffeine induced neuronal activity in the basal ganglia in these mice. They also showed nigrostriatal neurotransmission deficits that were manifested by reduced extracellular dopamine levels in the striatum and a proportional increase of dopamine release in response to caffeine and ethanol treatment. These findings support the hypothesis that the PNKD protein functions to modulate striatal neuro-transmitter release in response to stress and other precipitating factors

A Transgenic Rat for Investigating the Anatomy and Function of Corticotrophin Releasing Factor Circuits.

Corticotrophin-releasing factor (CRF) is a 41 amino acid neuropeptide that coordinates adaptive responses to stress. CRF projections from neurons in the central nucleus of the amygdala (CeA) to the brainstem are of particular interest for their role in motivated behavior. To directly examine the anatomy and function of CRF neurons, we generated a BAC transgenic Crh-Cre rat in which bacterial Cre recombinase is expressed from the Crh promoter. Using Cre-dependent reporters, we found that Cre expressing neurons in these rats are immunoreactive for CRF and are clustered in the lateral CeA (CeL) and the oval nucleus of the BNST. We detected major projections from CeA CRF neurons to parabrachial nuclei and the locus coeruleus, dorsal and ventral BNST, and more minor projections to lateral portions of the substantia nigra, ventral tegmental area, and lateral hypothalamus. Optogenetic stimulation of CeA CRF neurons evoked GABA-ergic responses in 11% of non-CRF neurons in the medial CeA (CeM) and 44% of non-CRF neurons in the CeL. Chemogenetic stimulation of CeA CRF neurons induced Fos in a similar proportion of non-CRF CeM neurons but a smaller proportion of non-CRF CeL neurons. The CRF1 receptor antagonist R121919 reduced this Fos induction by two-thirds in these regions. These results indicate that CeL CRF neurons provide both local inhibitory GABA and excitatory CRF signals to other CeA neurons, and demonstrate the value of the Crh-Cre rat as a tool for studying circuit function and physiology of CRF neurons

Lowering blood alcohol content levels to save lives: A European case study

Road safety has become an increasing concern in developed countries due to the significant amount of fatalities and the associated economic losses. Only in 2005 these losses rose to 200,000 million euros, a considerable sum approximately 2% of GDP that easily justifies any public intervention. One measure taken by governments to address this issue is to enact stricter policies and regulations. Since drunk driving is one of the greatest concerns among public authorities in this field, several European countries have lowered their illegal Blood Alcohol Content (BAC) levels to 0.5 mg/ml during the last decade. This study is the first evaluation of the effectiveness of this transition using European panel-based data (CARE) for the period 1991-2003 with the differences-in-differences method in a fixed effects estimation that allows for any pattern of correlation (Cluster-Robust). The results reveal a positive impact on certain groups of road users and on the whole population when the policy is accompanied by enforcement interventions. Moreover, positive results appeared after a time lag of over two years. Finally, I state the importance of controlling for serial correlation in the evaluation of this type of policy.policy evaluation;, drunk driving;, differences-in-differences;, road safety;, illegal blood alcohol content levels (bac)

Drunk Driving Legislation and Traffic Fatalities: What Works and What Doesn’t?

This paper re-examines the effectiveness of Blood Alcohol Content (BAC) and Administrative License Revocation (ALR) laws in reducing traffic fatalities. Using difference-in-differences estimators of U.S. state-level data with standard errors corrected for autocorrelation, we find no evidence that lowering BAC limits to 0.08 grams/decaliter has reduced fatality rates, either in total or in alcohol-related crashes. On the other hand, ALR is found to be an effective in reducing fatalities in all specifications. Endogeneity tests using event analyses indicate temporal causality of ALR laws.

Lowering blood alcohol content levels to save lives, the european experience

Road safety has become an increasing concern in developed countries due to the significant amount of mortal victims and the economic losses derived. Only in 2005 these losses rose to 200.000 million euros, a significant amount – approximately the 2% of its GDP- that easily justifies any public intervention. One tool used by governments to face this challenge is the enactment of stricter policies and regulations. Since drunk driving is one of the most important concerns of public authorities on this field, several European countries decided to lower their illegal Blood Alcohol Content levels to 0.5 mg/ml during the last decade. This study evaluates for the first time the effectiveness of this transition using European panel-based data (CARE) for the period 1991-2003 using the Differences-in-Differences method in a fixed effects estimation that allows for any pattern of correlation (Cluster-Robust). My results show the existence of positive impacts on certain groups of road users and for the whole population when the policy is accompanied by some enforcement interventions. Moreover, a time lag of more than two years is found in that effectiveness. Finally, I also assert the importance of controlling for serial correlation in the evaluation of this kind of policies.Road Safety, Policy Evaluation, Differences-in-Differences, Drunk Driving, Illegal Blood Alcohol Content Levels (BAC).