piperidines and carbidopa--levodopa-drug-combination

Amblyopia is a developmental brain disorder in which vision is lost due to asymmetric or inadequate visual stimulation early in life. Although amblyopia is responsive to treatment if therapy is initiated early, treatment of older children and adults is usually unsuccessful due to closure of a window of cortical brain plasticity. Extensive basic research has been devoted to understanding modulators in shaping the visual cortex during the critical period of plasticity, and to providing potential clinical applications of neurotransmitters in the treatment of amblyopia. Current pharmacological treatments are reviewed from basic science research extending into clinical use, focusing on the acetylcholinesterase inhibitor donezepil, serotonin receptor inhibitor fluoxetine, dopamine precursors carbidopa-levodopa, and catecholamine modulator citicoline.

Topics: Amblyopia; Carbidopa; Cholinesterase Inhibitors; Donepezil; Dopamine Agonists; Drug Combinations; Fluoxetine; Humans; Indans; Levodopa; Neuronal Plasticity; Piperidines; Selective Serotonin Reuptake Inhibitors; Translational Research, Biomedical; Visual Cortex

The glutamatergic system is thought to contribute to the motor disturbances observed in Parkinson's disease. Blockade of glutamatergic activity by a selective antagonist of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor is associated with improvement in motor symptoms in a preclinical model of Parkinson's disease. A randomized, double-blind, double-dummy, placebo-controlled, 3-period crossover study was conducted in patients with moderate Parkinson's disease to evaluate the pharmacologic activity of MK-0657, an NR2B-selective NMDA receptor antagonist. Patients (n=16) received single oral doses of MK-0657 7 mg, carbidopa/levodopa 25/250 mg (LD) as a positive control, and placebo, after which motor function was serially evaluated by means of the Unified Parkinson's Disease Rating Scale-Motor Examination (UPDRS-ME). LD administration resulted in significant improvement in the UPDRS-ME relative to placebo (P=.025), confirming the sensitivity of the test paradigm; however, the UPDRS-ME change following MK-0657 administration showed no improvement compared with placebo (P=.110) despite exceeding the target MK-0657 plasma concentration of 400 nM. Although the administration of MK-0657 was generally well tolerated, it was associated with increases in systolic and diastolic blood pressure relative to placebo. The results of this study do not support ongoing clinical development of MK-0657 as a novel monotherapy for Parkinson's disease.

Topics: Aged; Antiparkinson Agents; Carbidopa; Drug Combinations; Female; Humans; Hypertension; Levodopa; Male; Middle Aged; Motor Activity; Parkinson Disease; Piperidines; Pyrimidines; Receptors, N-Methyl-D-Aspartate

Sulfasalazine is an anti-inflammatory agent commonly used in the treatment of autoimmune conditions such as inflammatory bowel disease and rheumatoid arthritis. Sulfasalazine is converted by gut bacteria into sulfapyridine and the clinically active metabolite 5-aminosalicylic acid (5-ASA), and its efficacy is proportional to the 5-ASA concentration within the intestinal lumen. Renal complications are commonly reported for the chemically similar 5-ASA derivative mesalamine, but are not well-known side effects of sulfasalazine therapy. We report a 72-year-old patient with Crohn's disease managed with sulfasalazine for more than 10 years who presented with severe acute kidney injury (serum creatinine, 9.7mg/dL). Renal ultrasound revealed calculi and he subsequently spontaneously voided innumerable stones, which were composed of sulfasalazine metabolites. His renal calculi cleared and serum creatinine concentration improved to 3.1mg/dL after discontinuing sulfasalazine therapy and intravenous fluid hydration. His kidney function eventually returned to baseline. This case demonstrates that renal complications, in particular nephrolithiasis, may be an under-reported but potentially serious phenomenon in patients with inflammatory bowel disease treated with sulfasalazine and that their hydration status may play an important role in this process.

Topics: Acute Kidney Injury; Aged; Anti-Inflammatory Agents, Non-Steroidal; Antiparkinson Agents; Carbidopa; Cholinesterase Inhibitors; Crohn Disease; Donepezil; Drug Combinations; Fluid Therapy; Humans; Indans; Kidney Calculi; Levodopa; Male; Parkinson Disease; Piperidines; Severity of Illness Index; Sulfasalazine; Ultrasonography

Acetylcholine and dopamine are neurotransmitters that play multiple important roles in perception and cognition. Pharmacological cholinergic enhancement reduces excitatory receptive field size of neurons in marmoset primary visual cortex and sharpens the spatial tuning of visual perception and visual cortical fMRI responses in humans. Moreover, previous studies show that manipulation of cholinergic or dopaminergic signaling alters the spatial tuning of macaque prefrontal cortical neurons during the delay period of a spatial working memory (SWM) task and can improve SWM performance in macaque monkeys and human subjects. Here, we investigated the effects of systemic cholinergic and dopaminergic enhancement on the precision of SWM, as measured behaviorally in human subjects. Cholinergic transmission was increased by oral administration of 5 mg of the cholinesterase inhibitor donepezil, and dopaminergic signaling was enhanced with 100 mg levodopa/10 mg carbidopa. Each neurotransmitter system was separately investigated in double-blind placebo-controlled studies. On each trial of the SWM task, a square was presented for 150 ms at a random location along an invisible circle with a radius of 12 degrees of visual angle, followed by a 900 ms delay period with no stimulus shown on the screen. Then, the square was presented at new location, displaced in either a clockwise (CW) or counterclockwise (CCW) direction along the circle. Subjects used their memory of the location of the original square to report the direction of displacement. SWM precision was defined as the amount of displacement corresponding to 75% correct performance. We observed no significant effect on SWM precision for either donepezil or levodopa/carbidopa. There was also no significant effect on performance on the SWM task (percent correct across all trials) for either donepezil or levodopa/carbidopa. Thus, despite evidence that acetylcholine and dopamine regulate spatial tuning of individual neurons and can improve performance of SWM tasks, pharmacological enhancement of signaling of these neurotransmitters does not substantially affect a behavioral measure of the precision of SWM in humans.

Topics: Acetylcholine; Adolescent; Adult; Carbidopa; Donepezil; Dopamine; Double-Blind Method; Drug Combinations; Female; Humans; Indans; Levodopa; Male; Memory, Short-Term; Neuropsychological Tests; Nootropic Agents; Piperidines; Psychometrics; Spatial Memory; Treatment Failure; Visual Perception; Young Adult

A 74-year-old man with parkinsonism developed progressive cognitive and behavioral dysfunction suggesting coexistent Alzheimer's disease. The intellectual and behavioral disturbances were reversed following withdrawal of his anticholinergic antiparkinsonian medication. This case demonstrates that anticholinergic drugs used to treat parkinsonism may mimic or exacerbate the clinical signs of Alzheimer's disease and suggests that these medications should be withdrawn for all parkinsonian patients who develop significant impairments of cognition or behavior.

Topics: Aged; Alzheimer Disease; Biperiden; Carbidopa; Drug Combinations; Humans; Levodopa; Male; Parkinson Disease; Piperidines