piperidines and Brain-Diseases

N-methyl-D-aspartate receptors (NMDARs) are ion channels gated by glutamate, the major excitatory neurotransmitter in the mammalian central nervous system (CNS). They are widespread in the CNS and are involved in numerous physiological and pathological processes including synaptic plasticity, chronic pain and psychosis. Aberrant NMDAR activity also plays an important role in the neuronal loss associated with ischaemic insults and major degenerative disorders including Parkinson's and Alzheimer's disease. Agents that target and alter NMDAR function may, thus, have therapeutic benefit. Interestingly, NMDARs are endowed with multiple extracellular regulatory sites that recognize ions or small molecule ligands, some of which are likely to regulate receptor function in vivo. These allosteric sites, which differ from agonist-binding and channel-permeation sites, provide means to modulate, either positively or negatively, NMDAR activity. The present review focuses on allosteric modulation of NMDARs containing the NR2B subunit. Indeed, the NR2B subunit confers a particularly rich pharmacology with distinct recognition sites for exogenous and endogenous allosteric ligands. Moreover, NR2B-containing receptors, compared with other NMDAR subtypes, appear to contribute preferentially to pathological processes linked to overexcitation of glutamatergic pathways. The actions of extracellular H+, Mg2+, Zn2+, of polyamines and neurosteroids, and of the synthetic compounds ifenprodil and derivatives ('prodils') are presented. Particular emphasis is put upon the structural determinants and molecular mechanisms that underlie the effects exerted by these agents. A better understanding of how NR2B-containing NMDARs (and NMDARs in general) operate and how they can be modulated should help define new strategies to counteract the deleterious effects of dysregulated NMDAR activity.

Topics: Allosteric Regulation; Allosteric Site; Animals; Brain Diseases; Depressive Disorder, Major; Humans; Magnesium; Neurotransmitter Agents; Pain; Piperidines; Polyamines; Protein Subunits; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Zinc

Topics: Amino Acids; Animals; Brain Diseases; Carboxylic Acids; Humans; Ibotenic Acid; Piperidines; Receptors, N-Methyl-D-Aspartate; Structure-Activity Relationship

We compared the effects of remifentanil versus fentanyl during surgery for intracranial space-occupying lesions. Patients were randomly assigned to receive either remifentanil (0.5 microg. kg(-1). min(-1) IV during the induction of anesthesia reduced to 0.25 microg. kg(-1). min(-1) after endotracheal intubation; n = 49) or fentanyl (dose per usual practice of the anesthesiologist; n = 54). Anesthesia maintenance doses of isoflurane, nitrous oxide, and opioid were at the anesthesiologist's discretion for both groups. There were no differences between opioid groups for the frequency of responses (hemodynamic, movement, and tearing) to intubation, pinhead holder placement, skin incision, or closure of the surgical wound. Adverse event frequencies were similar between groups. Times to follow verbal commands (P < 0.001) and tracheal extubation (P = 0. 04) were more rapid for remifentanil. The percentage of patients with a normal recovery score (were alert or arousable to quiet voice, were oriented, were able to follow commands, had motor function unchanged from their preoperative evaluation, were not agitated, and had modified Aldrete Scores of 9-10) at 10 min after surgery was more for remifentanil (45% vs 18%; P = 0.005). By 20 min, no difference between groups existed (P = 0.27). Anesthesiologists used more isoflurane in the fentanyl group (4.22 vs 1.93 minimum alveolar anesthetic concentration hours). Neurosurgeons, blinded to treatment group, favored the use of remifentanil. Similar frequencies of light anesthesia responses and other adverse events suggest that intraoperative depths of anesthesia were similar in the two groups. Under these conditions, emergence was more rapid with remifentanil. This is consistent with the necessity for less isoflurane use in the remifentanil group and the intrinsic rapid clearance of this opioid.. Patients given remifentanil-based anesthesia for craniotomy had faster recovery times from anesthesia than did those given fentanyl-based anesthesia.

Topics: Anesthesia Recovery Period; Anesthetics, Intravenous; Brain Diseases; Female; Fentanyl; Hemodynamics; Humans; Male; Middle Aged; Piperidines; Prospective Studies; Remifentanil

Topics: Adenine; Adrenal Cortex Hormones; Aged; Aspergillosis; Aspergillus fumigatus; Brain Diseases; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Tomography, X-Ray Computed

Topics: Adenine; Aged; Brain Diseases; Central Nervous System Neoplasms; Female; Humans; Immunotherapy; Piperidines; Syndrome

Topics: Amyloid beta-Protein Precursor; Animals; Brain; Brain Diseases; Cholesterol 24-Hydroxylase; Cytochrome P-450 Enzyme Inhibitors; Disease Models, Animal; Drug Development; Female; Humans; Hydroxycholesterols; Longevity; Mice; Mice, Knockout; Mice, Transgenic; Mutant Proteins; Piperidines; Presenilin-1; Pyridines; Recombinant Proteins

Bing-Neel syndrome is a rare complication of Waldenström macroglobulinemia, characterized by infiltration of lymphoplasmacytic cells to the central nervous system. Multiple treatment modalities exist including purine analogs, bendamustine, high-dose methotrexate, or high-dose cytarabine. Of interest, ibrutinib, a Bruton tyrosine kinase inhibitor has also displayed efficacy in Bing-Neel syndrome. Current literature is limited for the treatment of Bing-Neel syndrome considering its rarity, and while ibrutinib is indicated for the treatment of Waldenström macroglobulinemia, it is utilized off-label for treatment of Bing-Neel syndrome. Additionally, debate exists regarding the recommended dosing strategy for ibrutinib for this indication with disease remission demonstrated at 560 mg and 420 mg. We present a case report that provides additional evidence for this debate with a patient who received 560 mg of ibrutinib initially and maintained disease control despite a dose reduction to 420 mg for tolerability. Ultimately, more data are needed to develop standardized Bing-Neel syndrome treatment strategies with specific consideration to the use of ibrutinib in this condition.

Topics: Adenine; Brain Diseases; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Syndrome; Treatment Outcome; Waldenstrom Macroglobulinemia

Topics: Adenine; Aged; Brain Diseases; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Neuroaspergillosis; Opportunistic Infections; Piperidines; Pyrazoles; Pyrimidines

Topics: Adenine; Aged; Brain; Brain Diseases; Humans; Magnetic Resonance Imaging; Male; Piperidines; Pyrazoles; Pyrimidines; Syndrome; Treatment Outcome; Waldenstrom Macroglobulinemia

Diabetic encephalopathy is an important complication of diabetes characterized by cognitive impairment, neurochemical and structural abnormalities. This study aimed to investigate the effect of coenzyme Q10 (CoQ10) and niacin as well as their combination in the treatment of encephalopathy associated with streptozotocin (STZ)- induced diabetes in rats. Glibenclamide (reference diabetic drug) and donepezil hydrochloride (acetylcholinesterase inhibitor) were also evaluated. Diabetes was induced by a single intraperitoneal injection of STZ (60 mg/kg). One month after STZ injection, diabetic rats were treated with the aforementioned drugs for two weeks. The evaluation was done through measuring glucose level, total antioxidant capacity (TAC), interleukin 6 (IL6), DNA degradation as well as serotonin and noradrenaline as neurotransmitters. The present data illustrated that combining CoQ10 and niacin exhibiting the most potent effect in improving the measured parameters and ameliorating some of diabetes complications.

Topics: Animals; Antioxidants; Blood Glucose; Brain Diseases; Cholinesterase Inhibitors; Diabetes Mellitus, Experimental; Donepezil; Glyburide; Hypoglycemic Agents; Indans; Interleukin-6; Male; Neurotransmitter Agents; Niacin; Piperidines; Rats; Rats, Wistar; Ubiquinone; Vitamins

We report the case of an aborted awake craniotomy for a left frontotemporoinsular glioma due to ammonia encephalopathy on a patient taking Levetiracetam, valproic acid and clobazam. This awake mapping surgery was scheduled as a second-stage procedure following partial resection eight days earlier under general anesthesia. We planned to perform the surgery with local anesthesia and sedation with remifentanil and propofol. After removal of the bone flap all sedation was stopped and we noticed slow mentation and excessive drowsiness prompting us to stop and control the airway and proceed with general anesthesia. There were no post-operative complications but the patient continued to exhibit bradypsychia and hand tremor. His ammonia level was found to be elevated and was treated with an infusion of l-carnitine after discontinuation of the valproic acid with vast improvement. Ammonia encephalopathy should be considered in patients treated with valproic acid and mental status changes who require an awake craniotomy with patient collaboration.

Topics: Anesthesia, General; Anesthesia, Local; Anticonvulsants; Aphasia; Benzodiazepines; Brain Diseases; Brain Mapping; Brain Neoplasms; Carnitine; Clobazam; Conscious Sedation; Consciousness Disorders; Craniotomy; Dominance, Cerebral; Frontal Lobe; Glioma; Humans; Hyperammonemia; Hypnotics and Sedatives; Intraoperative Complications; Language; Levetiracetam; Male; Middle Aged; Piperidines; Piracetam; Propofol; Remifentanil; Seizures; Temporal Lobe; Valproic Acid

Piperine (PIP) is a phytopharmaceutical with reported neuroprotective potential in Alzheimer's disease (AD). Oral PIP delivery suffers from its hydrophobicity and pre-systemic metabolism. In this article, mono-disperse intranasal chitosan nanoparticles (CS-NPs) were elaborated for brain targeting of PIP. Formula optimization was based on particle size (PS), zeta potential (ZP), polydispersity index (PDI), % entrapment efficiency (% EE), release studies, and transmission electron microscopy. AD was induced in 48 male Wistar rats on which full behavioral and biochemical testing was conducted. Brain toxicity was assessed based on Caspase-3 assay for apoptosis and tumor necrosis factor for inflammation. Spherical NPs with optimum % EE (81.70), PS (248.50 nm), PDI (0.24), and ZP (+56.30 mV) were elaborated. PIP-NPs could significantly improve cognitive functions as efficient as standard drug (donpezil injection) with additional advantages of dual mechanism (Ach esterase inhibition and antioxidant effect). CS-NPs could significantly alleviate PIP nasal irritation and showed no brain toxicity. This work was the first to report additional mechanism of PIP in AD via anti-apoptosis and anti-inflammatory effects. To conclude, mucoadhesive CS-NPs were successfully tailored for effective, safe, and non-invasive PIP delivery with 20-folds decrease in oral dose, opening a gate for a future with lower AD morbidity.

Topics: Administration, Intranasal; Alkaloids; Alzheimer Disease; Animals; Antioxidants; Apoptosis; Benzodioxoles; Brain Diseases; Caspase 3; Chitosan; Cholinesterase Inhibitors; Cognition; Drug Delivery Systems; Male; Nanoparticles; Particle Size; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Alzheimer's disease (AD) has multiple etiopathogenic factors, yet the definitive cause remains unclear and the therapeutic strategies have been elusive. Combination therapy, as one of the promising treatments, has been studied for years and may exert synergistic beneficial effects on AD through polytherapeutic targets. In this study, we tested the effects of a synthesized juxtaposition (named SCR1693) composed of an acetylcholinesterase inhibitor (AChEI) and a calcium channel blocker (CCB) on the hyperhomocysteinemia (HHcy)-induced AD rat model, and found that SCR1693 remarkably improved the HHcy-induced memory deficits and preserved dendrite morphologies as well as spine density by upregulating synapse-associated proteins PSD95 and synapsin-1. In addition, SCR1693 attenuated HHcy-induced tau hyperphosphorylation at multiple AD-associated sites by regulating the activity of protein phosphatase-2A and glycogen synthase kinase-3β. Furthermore, SCR1693 was more effective than individual administration of both donepezil and nilvadipine which were used as AChEI and CCB, respectively, in the clinical practice. In conclusion, our data suggest that the polytherapeutic targeting juxtaposition SCR1693 (AChEI-CCB) is a promising therapeutic candidate for AD.

Topics: Animals; Brain Diseases; Calcium Channel Blockers; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Drug Therapy, Combination; Hippocampus; Homocysteine; Hyperhomocysteinemia; Indans; Male; Maze Learning; Memory Disorders; Nerve Tissue Proteins; Nifedipine; Piperidines; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Silver Staining; Tacrine

Donepezil and memantine are commonly prescribed antidementia drugs. There is a paucity of literature concerning pediatric ingestions of these drugs. We describe a case of a 2-year-old child who developed encephalopathy after an unintentional ingestion of donepezil and memantine. A 2-year-old girl was found by her family members agitated and reporting visual hallucinations. In the emergency department, she became sedated and had rightward eye deviation. She was hospitalized and had extensive neurological and infectious disease testing that was unremarkable, except for an electroencephalogram, which showed a nonspecific encephalopathy. She recovered with supportive care for 72 hours. Serum concentrations of donepezil and memantine measured on arrival were 470 ng/mL (therapeutic range, 25-50 ng/mL) and 32 ng/mL (therapeutic range, 70-150 ng/mL), respectively. This case demonstrates that unintentional ingestions of memantine and donepezil can potentially cause significant and prolonged neurological symptoms in pediatric patients.

Topics: Brain Diseases; Child, Preschool; Donepezil; Electroencephalography; Female; Hallucinations; Humans; Indans; Memantine; Piperidines

Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme for nicotinamide adenine dinucleotide (NAD) biosynthesis, and can be found either intracellularly (iNAMPT) or extracellularly (eNAMPT). Studies have shown that both iNAMPT and eNAMPT are implicated in aging and age-related diseases/disorders in the peripheral system. However, their functional roles in aged brain remain to be established. Here we showed that upon aging, NAMPT level increased in serum but decreased in brain, decreased in cortex and hippocampus but remained unchanged in cerebellum and striatum in brain, and increased in microglia but likely decreased in neuron. Accordingly, total NAD (tNAD) level significantly decreased in hippocampus, cerebellum and striatum in aged brain. Application of recombinant NAMPT, mimicking the elevated serum NAMPT level, enhanced the susceptibility of cerebral endothelial cells to ischemic injury, while inhibition of iNAMPT by FK866, a specific inhibitor, reduced intracellular NAD level and induced neuronal death. Taken together, we have revealed a region- and cell-specific change of NAMPT level in brain and serum upon aging, deduced its potential consequences, which suggests that NAMPT is a regulatory factor in aging and age-related brain diseases.

Topics: Acrylamides; Aging; Animals; Brain Diseases; Cerebellum; Corpus Striatum; Female; Hippocampus; Mice; NAD; Neurons; Nicotinamide Phosphoribosyltransferase; Piperidines; Rats

Topics: Adolescent; Brain Diseases; Carbon Monoxide Poisoning; Cognition Disorders; Donepezil; Humans; Indans; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Nootropic Agents; Piperidines

Intraoperative magnetic resonance imaging (MRI) has been used for years to update neuronavigation and for intraoperative resection control. For this purpose, low-field (0.1-0.2 T) MR scanners have been installed in the operating room, which, in contrast to machines using higher magnetic field strength, allowed the use of standard anesthetic and surgical equipment. However, these low-field MR systems provided only minor image quality and a limited battery of MR sequences, excluding functional MRI, diffusion-weighted MRI, or MR angiography and spectroscopy. Based on these advantages, a concept using high-field MRI (1.5 T) with intraoperative functional neuronavigational guidance has been developed that required adaptation of the anesthetic regimen to working in the close vicinity to the strong magnetic field. In this paper the authors present their experience with the first 80 consecutive patients who received anesthesia in a specially designed radio frequency-shielded operating room equipped with a high-field (1.5 T) MR scanner. We describe the MR-compatible anesthesia equipment used including ventilator, monitoring, and syringe pumps, which allow standard neuroanesthesia in this new and challenging environment. This equipment provides the use of total intravenous anesthesia with propofol and remifentanil allowing rapid extubation and neurologic examination following surgery. In addition, extended intraoperative monitoring including EEG monitoring required for intracranial surgery is possible. Moreover, problems and dangers related to the effects of the strong magnetic field are discussed.

Topics: Adolescent; Adult; Aged; Androstanols; Anesthesia, Intravenous; Anesthetics, Intravenous; Brain Diseases; Child; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Monitoring, Intraoperative; Neuromuscular Depolarizing Agents; Piperidines; Propofol; Remifentanil; Rocuronium

Reactive oxygen-derived species were previously implicated in mediation of post-traumatic brain damage; however, the efficacy of traditional antioxidants in preventing/reversing the damage is sometimes limited. The present work focused on the mechanisms underlying the neuroprotective activity of cell permeable, nontoxic, antioxidants, namely stable nitroxide radicals in an experimental model of rat closed-head injury. Brain damage was induced by the weight-drop method and the clinical status was evaluated according to a neurological severity score at 1 h and 24 h, where the difference between these scores reflects the extent of recovery. The metal chelator deferoxamine as well as three nitroxide derivatives, differing in hydrophilicity and charge, and one hydroxylamine (a reduced nitroxide) facilitated the clinical recovery and decreased the brain edema. The nitroxides, but neither the hydroxylamine nor deferoxamine, protected the integrity of the blood-brain barrier. Superoxide dismutase also improved the clinical recovery but did not affect brain edema or the blood-brain barrier. The results suggest that by switching back and forth between themselves, the nitroxide and hydroxylamine act catalytically as self-replenishing antioxidants, and protect brain tissue by terminating radical-chain reactions, oxidizing deleterious metal ions, and by removal of intracellular superoxide.

Topics: Animals; Antioxidants; Blood-Brain Barrier; Brain Diseases; Brain Edema; Deferoxamine; Head Injuries, Closed; Hydroxylamine; Male; Neuroprotective Agents; Nitrogen Oxides; Piperidines; Rats; Superoxide Dismutase

Previous studies of radiolabelled vesamicol receptor (VR) ligands suggest that the latter may be used, in conjunction with dopamine D2 antagonists, to measure changes in striatal cholinergic function in vivo. In the present study, the radiolabelled VR ligand (+)-meta-[125I]iodobenzyltrozamicol {(+)-[125I]MIBT} was used to assess striatal cholinergic function in the unilateral 6-hydroxydopamine (6-OHDA)-treated rat. In control animals, the levels of this radiotracer monitored at 3 hr post injection displayed bilateral symmetry in the striatum, cerebral cortex and cerebellum. However, in animals pretreated with the dopamine antagonist spiperone (2 mg/kg ip), the radiotracer concentration in the striatal hemisphere ipsilateral to 6-OHDA lesion increased by 23% (p = 0.068) while the concentration in the contralateral striatum was elevated by 87% (p < 0.0001). Since the nigrostriatal dopaminergic system modulates striatal cholinergic function, and dopamine D2 receptor blockade is known to result in increased striatal cholinergic function, the refractoriness of striatal cholinergic neurons following the loss of nigrostriatal dopaminergic innervation confirms the existence of a dopaminergic-cholinergic imbalance in Parkinson's disease. Therefore the combination of a D2 antagonist and radiolabelled VR ligand may provide a potentially useful method for assessing the effects of dopamine depletion in Parkinson's disease.

Topics: Animals; Brain Diseases; Cholinergic Fibers; Corpus Striatum; Disease Models, Animal; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Iodine Radioisotopes; Iodobenzenes; Ligands; Male; Oxidopamine; Parkinson Disease; Piperidines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Cholinergic; Spiperone

The possibility that compounds which interact with the putative sigma receptor might influence the dopaminergic neuropathology produced by the administration of methamphetamine (METH) to mice was investigated. (+/-)-BMY 14802 [alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol hydrochloride] attenuated METH-induced dopaminergic neuropathology whereas several other sigma-acting compounds such as R-(+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride, 1,3-di-o-tolyl-guanidine, rimcazole, clorgyline or (-)-butaclamol did not alter neurotoxicity produced by this central nervous system stimulant. (-)-BMY 14802, which has a lower affinity for the sigma site than (+)-BMY 14802, was more potent than (+)-BMY 14802 in antagonizing METH-induced neuropathology. In addition, the ketone metabolite (BMY 14786; alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanone hydrochloride), which is a major metabolite formed from (-)-BMY 14802, also attenuated the METH-induced effects. (+/-)-BMY 14802 pretreatment of mice prevented the reduction in D1 and D2 dopamine receptor number produced by the systemic administration of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and demonstrates that (+/-)-BMY 14802 and/or its metabolites interact with the dopamine receptor subtypes. Taken together, these findings suggest that the protective effect of (+/-)-BMY 14802 against METH-induced neuropathology is mediated, at least in part, through dopamine receptor antagonism. Furthermore, the failure of other sigma-acting compounds to alter METH-induced neurotoxicity indicates that the putative sigma receptor is unlikely to be an important mediator in this type of neuropathology.

Topics: Animals; Anticonvulsants; Antipsychotic Agents; Brain Diseases; Butaclamol; Carbazoles; Dizocilpine Maleate; Dopamine; Dopamine Agents; Drug Interactions; Drug Synergism; Guanidines; Ligands; Male; Methamphetamine; Mice; MPTP Poisoning; Neostriatum; Piperidines; Psychotropic Drugs; Pyrimidines; Receptors, Dopamine; Receptors, sigma; Stereoisomerism; Tyrosine 3-Monooxygenase

The recent finding that ifenprodil binds with high affinity to sigma sites suggests that other sigma agents may have ifenprodil-like cerebroprotectant and functional N-methyl-D-aspartate (NMDA) antagonist effects. The present study, compared the in vivo effects of ifenprodil and the sigma agents, BMY 14802, caramiphen and haloperidol, in three tests sensitive to NMDA antagonists and purported cerebroprotectant drugs. When administered at or below the rotorod TD50 dose, all four compounds significantly increased survival time in an hypoxic environment (4% O2 in nitrogen). Caramiphen and ifenprodil (ED50 = 52 and 61 mg/kg, respectively) also blocked maximal electroshock-induced seizures, whereas BMY 14802 and haloperidol were ineffective. Finally, caramiphen (ED50 = 95 mg/kg) antagonized seizures and lethality induced by administration of NMDA (250 mg/kg, IP). BMY 14802, haloperidol and ifenprodil only partially antagonized NMDA-induced seizures, but did enhance the anticonvulsant potency of the noncompetitive NMDA antagonist, MK-801. Together, these findings suggest that sigma agents may have cerebroprotective effects.

Topics: Animals; Anticonvulsants; Brain Diseases; Electroshock; Haloperidol; Hypoxia; Male; Mice; Mice, Inbred Strains; N-Methylaspartate; Nimodipine; Piperidines; Postural Balance; Pyrimidines; Receptors, Opioid; Receptors, sigma; Seizures

Two sibling cases of cerebrotendinous xanthomatosis with parkinsonism were reported. One was a woman of 39 years old, and another was her sister of 36 years old. In both cases, febrile convulsion appeared on 1.5 year old, and mental deterioration, ataxic -spastic gait, cataract and swelling of Achilles tendons developed in order since entrance into elementary school. Five years ago, while they were in hospital at the first time, they were diagnosed as cerebrotendinous xanthomatosis by mental disturbance, cerebellar ataxia, pyramidal tract sign, histologically xanthomatous granuloma of Achilles tendons and hypercholestanolemia and family history of autosomal recessive trait. After the second admission, parkinsonism was noticed in addition to those findings above. Parkinsonism consisted of the following: Resting tremor of parkinsonian type, mild muscle rigidity of forearm and intrinsic-plus hand were observed in the elder sister, and generalized severe rigidity and bradykinesia in the younger sister. In both cases, brain CT showed the pontocerebellar atrophy, and the bilateral low density area in corona radiata, posterior portion of internal capsule, cerebral peduncle, tegmentum of midbrain and deep matter of cerebellum. Brain MRI also showed abnormal intensity in the same regions as on the brain CT. Administration of anti-parkinsonian drugs was challenged for the parkinsonism. Oral L-dopa test (500 mg) moderately improved parkinsonism in both cases. Therapy of diphenylpyraline hydrochloride (10 mg/day) entirely inhibited parkinsonian tremor and mild rigidity in the elder sister but was less effective for severe rigidity in the younger sister than administration of L-dopa.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Achilles Tendon; Adult; Brain Diseases; Female; Humans; Magnetic Resonance Imaging; Parkinson Disease; Piperidines; Tomography, X-Ray Computed; Xanthomatosis

Bipiperidyl mustard and a neurotoxic triamine are known to cause edematous and/or necrotizing lesions in particular areas of hypothalamus and dorsal medulla but not in spinal cord. Experimental allergic encephalomyelitis (EAR) causes widespread inflammatory lesions that are especially numerous in spinal cord. When the chemical toxicants were administered to rats during the acute phase of EAE, mortality was increased. This was due to a specific interaction between EAE and chemical toxicants leading to the development of necrotizing vasculitis and parenchymal necrosis near EAE lesions in spinal cord or brain. The interaction decreased as the EAE lesions healed. Another neurotoxic chemical, dipiperidinoethane, did not produce this phenomenon. These effects of EAE are probably related to damage to the vessel walls and the blood-brain barrier. The present work may increase the versatility of EAE as a model for multiple sclerosis if the EAE lesions can be enlarged progressively by repeated exposures to the toxicant.

Topics: Animals; Blood-Brain Barrier; Brain; Brain Diseases; Encephalomyelitis, Autoimmune, Experimental; Female; Mustard Compounds; Necrosis; Piperidines; Polyamines; Rats; Rats, Inbred Lew; Spinal Cord

The present study is concerned with the question of whether or not amphiphilic drugs (chloroquine, quinacrine, perhexiline) that fail to induce general lipidosis in the central nervous system (CNS) of adult rats can produce lipidosis in a circumventricular organ (area postrema) not furnished with a blood-brain barrier. Chlorphentermine known to induce general lipidosis in CNS of adult rats served as reference compound. All drugs, when chronically applied in high oral doses, induced significant perikaryal lipidosis in the area postrema. In the adjacent nuclei (nucleus tractus solitarii, nucleus dorsalis nervi vagi, nucleus nervi hypoglossi, nucleus gracilis), only chlorphentermine caused generalized lipidosis, whereas the other drugs had either limited or no effects. The present findings strongly suggest that the exemption, of most regions of the CNS of adult rats, from lipidosis induced by chloroquine and others is due to hindered drug distribution across the blood-brain barrier, rather than being due to non-susceptibility of central neurons toward the lipidosis-inducing action of the drugs.

Topics: Animals; Blood-Brain Barrier; Brain Diseases; Chloroquine; Chlorphentermine; Female; Lipidoses; Male; Medulla Oblongata; Microscopy, Electron; Perhexiline; Piperidines; Quinacrine; Rats; Time Factors

Topics: Brain Diseases; Cerebellum; Female; Humans; Iatrogenic Disease; Middle Aged; Parkinson Disease, Secondary; Perhexiline; Piperidines; Polyradiculopathy; Retinal Hemorrhage

Topics: Adolescent; Adult; Anticonvulsants; Antipsychotic Agents; Bipolar Disorder; Brain Diseases; Cerebrovascular Disorders; Child; Epilepsy; Humans; Hypertension; Hypnotics and Sedatives; Intracranial Arteriosclerosis; Middle Aged; Phenothiazines; Piperidines; Schizophrenia; Seizures

Topics: Antipsychotic Agents; Brain Diseases; Brain Injuries; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Hyperkinesis; Intellectual Disability; Male; Mental Disorders; Phenothiazines; Piperidines; Schizophrenia, Childhood

Topics: Biopsy; Body Temperature; Body Weight; Brain Diseases; Calcium; Child; Child, Preschool; Chlorides; Creatine; Dehydration; Diabetes Insipidus; Diagnosis, Differential; Diet; Diuresis; Feeding and Eating Disorders; Female; Humans; Hydrochlorothiazide; Hypothalamus; Infant; Kidney; Male; Mineralocorticoid Receptor Antagonists; Obesity; Osmolar Concentration; Osmosis; Piperidines; Potassium; Sodium; Urography; Vasopressins

Topics: Brain; Brain Diseases; Humans; Piperidines; Propiophenones; Tolperisone