1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated adult zebrafish as a model for Parkinson's Disease.

Dopamine (DA) is a catecholamine neurotransmitter that works to regulate cognitive functions. Patients affected by Parkinson's Disease (PD) experience a loss of dopaminergic neurons and downregulated neural DA production. This leads to cognitive and physical decline that is the hallmark of PD for which no cure currently exists.

A review of MPTP-induced parkinsonism in adult zebrafish to explore pharmacological interventions for human Parkinson's disease.

Novel work in adult zebrafish, to recapitulate human neurodegenerative disease has proven useful in both pharmaceutical development and research on genetic disease. Due to high genetic homology to humans, affordable husbandry, relatively quick life cycle breeding times, and robust embryo production, zebrafish offer a promising model to test pharmaceutical performance in a high throughput, setting. Currently, most research in zebrafish models of Parkinson's disease induces the disease in larval or embryonic stage organisms due to ease of administration, with advancement through developmental stages taking only a matter of days.

Managing Pain in Patients With Chronic Medical Illnesses and Serious Mental Illnesses.

Objectives: This study investigated the use of opioid treatment plans that included the implementation of opioid dependence risk with a validated screening tool and opioid dependence risk tool (UDT) in a noncancer palliative pain clinic.

Methods: We retrospectively reviewed the medical records for diagnostic information, information on analgesic medications, daily morphine equivalent dose, presence of pain management agreements and opioid dependence risk tools (ORT), and UDT. We recorded hospital days and emergency department visits.

Sequential use of detergents for solubilization and reconstitution of a membrane ion transporter.

Solubilization and reconstitution of the cardiac sarcolemmal Na+/Ca2+ exchanger by use of the anionic detergent cholate and its application for reconstitution of the exchanger following solubilization with zwitterionic or nonionic detergents is described. Solubilization and reconstitution with cholate provided a 32.6-fold enrichment of Na+/Ca2+ exchange activity over sarcolemmal vesicles (5.

Stereoselective accumulation of the beta-receptor blocking drug atenolol by human platelets.

We have studied the stereochemistry of accumulation of the hydrophilic beta-adrenoceptor antagonist rac-atenolol by human platelets in vitro. The accumulation was slow, not reaching equilibrium until 90 min at 37 degrees C. The uptake was temperature dependent with the accumulation at 37 degrees C being 3-4 times greater than at 4 degrees C.

Stereoselective uptake of atenolol into storage granules isolated from PC12 cells.

Atenolol has been shown to be stored and secreted from PC12 cells by calcium-dependent and stereoselective mechanisms. The present study was designed to determine if the cytoplasmic amine storage granule was the site for storage and release of atenolol and if the drug was, in fact, an enantiomeric selective substrate for the vesicular amine transport protein. Uptake of racemic [3H]atenolol and (-)-[3H]norepinephrine was studied in a vesicular preparation of storage granules isolated from PC12 cells.

Stereoselective secretion of atenolol from PC12 cells.

Stereoselective storage and release of the cardioselective beta adrenergic receptor antagonist atenolol was studied using cultured PC12 cells as a neural model. [3H]Atenolol efflux from preloaded PC12 cells was increased 4-fold in response to membrane depolarization by elevated extracellular potassium (50 mM). [3H]Norepinephrine release was enhanced 4.

Stereoselective delivery and actions of beta receptor antagonists.

These studies have revealed that the delivery and actions of beta receptor antagonist drugs are controlled by a cascade of stereoselective processes involving multiple enzymes, transport proteins and receptors. In essence, the free concentration of the pharmacologically active (-)-enantiomer species of these drugs presented to cell surface beta receptors appears to be a function of the stereoselective clearance by hepatic cytochrome P-450 isoenzymes, enantiomer selective binding to alpha 1-acid glycoprotein and albumin and perhaps predominantly by stereoselective sequestration (and release) by the vesicular amine transport protein within adrenergic neurons. Stereoselectivity in the clearance of beta blocking drugs, which can favor either the (+)- or (-)-enantiomer, only appears to be important for the lipophilic drugs which are cleared by hepatic metabolism.

Relationship between steady-state depression of calcium-dependent action potentials and competition for binding sites by nifedipine, nitrendipine, and PY 108-068.

The objective of the present study was to determine the time-courses for depression and recovery of calcium-mediated action potentials in canine Purkinje fibers following exposure to dihydropyridine (DHP) calcium channel antagonists and to determine if the reported discrepancy (up to 1,000 X) between I50 values for inducing physiologic effects in isolated tissues and the dissociation constant (Kd) for [3H]nitrendipine binding to membrane sites could be reduced when physiologic measurements were made under experimentally determined steady-state conditions. Changes in dV/dtmax of slow calcium-mediated action potentials (20 mM KCl, 10(-6) M isoproterenol) were recorded at 10-min intervals during exposure (2-4 h) to nifedipine, nitrendipine, and PY 108-068 (10(-9) M-4 X 10(-8) M). Time to steady state was slow, with half-life t1/2 values of 40 min (nifedipine), 84 min (nitrendipine), and 81 min (PY 108-068).

Sodium and potassium permeability of membrane vesicles in a sarcolemma-enriched preparation from canine ventricle.

Vesicles in a highly enriched sarcolemma preparation from canine ventricle were found to develop membrane potentials in response to outwardly directed potassium and inwardly directed sodium concentration gradients. The magnitude of the potential measured by the fluorescent dye diS-C3-(5) suggested a sodium-to-potassium permeability ratio between 0.2 and 1.

Association of in vivo and in vitro propranolol levels in canine Purkinje fibers with antiarrhythmic effects.

This study has determined the propranolol content of Purkinje fibers associated with antiarrhythmic and electrophysiological actions of the drug both in vivo and in vitro. The minimum effective tissue content of propranolol that consistently reversed a sustained ouabain-induced ventrivular tachycardia in vivo after i.v.

Antiarrhythmic activity of p-hydroxy-N-(2-diethylaminoethyl) benzamide (the p-hydroxy isostere of procainamide) in dogs and mice.

p-Hydroxy-N-(2-diethylaminoethyl)benzamide (2), the p-hydroxy isostere of procainamide (1), shows antiarrhythmic activity against acontine-induced atrial arrhythmia and lowers mean arterial blood pressure after iv infusion in dogs. In isolated canine Purkinje fibers, phenolic 2 in a bath concentration of 20 mug/ml significantly reduced the rate of phase O depolarization, prolonged the repolarization time, and reduced automaticity. These in vitro and the above in vivo activities of phenolic 2 were similar to those observed for procainamide (1).

Correlation of the electrophysiological and antiarrhythmic properties of the N-acetyl metabolite of procainamide with plasma and tissue drug concentrations in the dog.

N-acetylprocainamide (NAPA), a major metabolite of procainamide (PA) in man, has been reported recently to be biologically active. The present study compares the electrophysiological and antiarrhythmic effects of NAPA and PA and correlates their activity with plasma and tissue drug concentrations. In isolated canine Purkinje fibers, NAPA, in bath concentrations of 10 and 20 mg/l reduced automaticity and prolonged repolarization time.

Further studies regarding the structure activity relationships of beta-adrenoceptor antagonists.

1. The ortho (M66,527) and para (M66,368) analogues of 1-t-butylamino-3-(methoxyphenoxy)-2-propanol and para substituted tertiary butylphenoxy-1-N-isopropylamine-3 propanol-2 oxalate acid (L8429) were tested in dogs for their beta-adrenoceptor blocking activity.2.

The effects on cardiac muscle and nerve of a fluorinated decahydroquinoline derivative, L7810, rapidly absorbed after oral administration.

1. L7810 (4-carbamoyloxy-1-(4-(4-fluorophenyl)-4-oxobutyl) decahydroquinoline, has a local anaesthetic action on frog nerve 1.75 times that of procaine.