3,048 results on '"gamma-Aminobutyric Acid analogs & derivatives"'
Search Results
2. Back Pedaling on Baclofen: Highlighting Concerns Surrounding Baclofen use in Phenibut Withdrawal.
- Author
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Feldman R
- Subjects
- Humans, Male, Adult, GABA-B Receptor Agonists therapeutic use, Female, gamma-Aminobutyric Acid analogs & derivatives, Baclofen, Substance Withdrawal Syndrome
- Published
- 2024
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3. Comparative studies on substrate specificity of succinic semialdehyde reductase from Gluconobacter oxydans and glyoxylate reductase from Acetobacter aceti.
- Author
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Majumder TR, Inoue M, Aono R, Ochi A, and Mihara H
- Subjects
- Substrate Specificity, Kinetics, Succinate-Semialdehyde Dehydrogenase metabolism, Succinate-Semialdehyde Dehydrogenase chemistry, Succinate-Semialdehyde Dehydrogenase genetics, gamma-Aminobutyric Acid analogs & derivatives, Gluconobacter oxydans enzymology, Gluconobacter oxydans metabolism, Acetobacter enzymology, Acetobacter metabolism, Alcohol Oxidoreductases metabolism, Alcohol Oxidoreductases chemistry, Glyoxylates metabolism
- Abstract
Gluconobacter oxydans succinic semialdehyde reductase (GoxSSAR) and Acetobacter aceti glyoxylate reductase (AacGR) represent a novel class in the β-hydroxyacid dehydrogenases superfamily. Kinetic analyses revealed GoxSSAR's activity with both glyoxylate and succinic semialdehyde, while AacGR is glyoxylate specific. GoxSSAR K167A lost activity with succinic semialdehyde but retained some with glyoxylate, whereas AacGR K175A lost activity. These findings elucidate differences between these homologous enzymes., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)
- Published
- 2024
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4. Discriminative stimulus properties of two training doses of gabapentin in rats: Substitution by pregabalin, diazepam, and pentobarbital.
- Author
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Prus AJ, Van Fossen MT, Iannucci AN, Dalton AG, and Prete JN
- Subjects
- Animals, Rats, Male, Dose-Response Relationship, Drug, Cyclohexanecarboxylic Acids pharmacology, Cyclohexanecarboxylic Acids administration & dosage, Discrimination, Psychological drug effects, Drug Substitution methods, Discrimination Learning drug effects, Gabapentin pharmacology, Gabapentin administration & dosage, Pregabalin pharmacology, Pregabalin administration & dosage, Diazepam pharmacology, Diazepam administration & dosage, gamma-Aminobutyric Acid pharmacology, gamma-Aminobutyric Acid analogs & derivatives, gamma-Aminobutyric Acid administration & dosage, Pentobarbital pharmacology, Pentobarbital administration & dosage, Amines pharmacology, Amines administration & dosage, Rats, Sprague-Dawley
- Abstract
Gabapentin is used for the treatment of many conditions, including seizures, pain, and anxiety. Increasing reports of nonprescribed use suggest that gabapentin may elicit positive subjective effects. The present study was conducted to examine the subjective effects of gabapentin using rats trained to discriminate either a 30.0 mg/kg or 300.0 mg/kg dose of gabapentin versus vehicle on a two-choice drug discrimination task. Both doses of gabapentin were established as discriminative stimuli, and the 300.0 mg/kg dose was more readily established compared to the 30.0 mg/kg dose. Full substitution (> 80% gabapentin-lever responding) occurred by the training drug and by the gabapentinoid compound pregabalin. Partial substitution (> 20% gabapentin-lever responding) was shown by the opioid compounds morphine and fentanyl, and dose combinations of the opioid receptor antagonist naltrexone with the gabapentin training doses reduced the percentage of gabapentin-lever responding to below 80%. Partial substitution for both training doses of gabapentin occurred with the cannabinoid Δ⁹-tetrahydrocannabinol. The barbiturate compound pentobarbital and the benzodiazepine compound diazepam were only tested for substitution for the 300.0 mg/kg dose of gabapentin and these compounds produced full substitution. These findings demonstrate that gabapentin establishes a robust discriminative cue and exhibits stimulus effects closely similar to pregabalin, pentobarbital, and diazepam. Since pregabalin, pentobarbital, and diazepam carry a risk of problematic use and are classified as controlled substances, further evaluations of gabapentin's risks in this regard are warranted. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
- Published
- 2024
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5. GABA Analogue HSK16149 in Chinese Patients With Diabetic Peripheral Neuropathic Pain: A Phase 3 Randomized Clinical Trial.
- Author
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Guo X, Zhang T, Yuan G, Zeng W, Hu Q, Ma J, Li Y, Li H, Zhang Y, Liu J, Bian F, Zhang W, Zhang F, Pang S, Li Y, Wu X, Tang X, Zhang K, Pan T, Hu H, Cheng Z, Wang Y, Gao J, and Sun J
- Subjects
- Humans, Male, Female, Middle Aged, Double-Blind Method, China, Aged, Adult, Analgesics therapeutic use, Treatment Outcome, Pain Measurement, East Asian People, Diabetic Neuropathies drug therapy, gamma-Aminobutyric Acid analogs & derivatives, gamma-Aminobutyric Acid therapeutic use, gamma-Aminobutyric Acid administration & dosage, gamma-Aminobutyric Acid adverse effects, Pregabalin therapeutic use
- Abstract
Importance: Many patients with diabetic peripheral neuropathic pain (DPNP) experience inadequate relief, despite best available medical treatments. There are no approved and effective therapies for patients with DPNP in China., Objective: To evaluate the efficacy and safety of capsules containing γ-aminobutyric acid (GABA) analogue HSK16149 in the treatment of Chinese patients with DPNP., Design, Setting, and Participants: This phase 2 to 3 adaptive randomized clinical trial was multicenter, double blind, and placebo and pregabalin controlled. The trial started on December 10, 2020, and concluded on July 8, 2022. In stage 1, various doses of HSK16149 were evaluated to determine safety and efficacy for stage 2. The second stage then validated the efficacy and safety of the recommended dose., Intervention: In stage 1, enrolled patients (n = 363) were randomized 1:1:1:1:1:1 to 4 HSK16149 doses (40, 80, 120, or 160 mg/d), pregabalin (300 mg/d), or placebo. In stage 2, patients (n = 362) were randomized 1:1:1 to receive HSK16149, 40 or 80 mg/d, or placebo. The final efficacy and safety analysis pooled data from patients receiving the same treatment., Main Outcomes and Measures: The primary efficacy end point in stage 1 was the change from baseline in average daily pain score (ADPS) at week 5. The primary efficacy end point in stage 2 was the change from baseline in ADPS at week 13. When the final statistical analysis was performed, the P values calculated from the independent data of each phase were combined using the weighted inverse normal method to make statistical inferences., Results: Of 725 randomized patients in the full-analysis set (393 men [54.2%]; mean [SD] age, 58.80 [9.53] years; 700 [96.6%] of Han Chinese ethnicity), 177 received placebo; 178, HSK16149, 40 mg/d; 179, HSK16149, 80 mg/d; 66, HSK16149, 120 mg/d; 63, HSK16149, 160 mg/d; and 62, pregabalin, 300 mg/d. A total of 644 patients (88.8%) completed the study. The 40- and 80-mg/d doses of HSK16149 were recommended in stage 2. At week 13, the ADPS mean (SD) change from baseline was -2.24 (1.55) for the 40-mg/d and -2.16 (1.79) for 80-mg/d groups and -1.23 (1.68) for the placebo group, showing statistical significance for both HSK16149 doses vs placebo (both P < .001). In a safety set (n = 726), 545 patients (75.1%) had adverse events, which were generally mild to moderate, with dizziness and somnolence being the most common., Conclusions and Relevance: Forty- and eighty-mg/d doses of HSK16149 were recommended for treating patients with DPNP in China. The efficacy of HSK16149 capsules was superior to placebo in all groups for relieving DPNP and appeared well tolerated., Trial Registration: ClinicalTrials.gov Identifier: NCT04647773.
- Published
- 2024
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6. Use of kersetin and fisetin flavonoids in combination with pregabalin and gabapentin in the treatment of neuropathic pain.
- Author
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Karabacak E, Eken H, Dallali I, and Arslan R
- Subjects
- Animals, Male, Rats, Amines administration & dosage, Amines therapeutic use, Amines pharmacology, Rats, Wistar, Dose-Response Relationship, Drug, Disease Models, Animal, Cyclohexanecarboxylic Acids administration & dosage, Cyclohexanecarboxylic Acids therapeutic use, Hyperalgesia drug therapy, Pregabalin administration & dosage, Pregabalin therapeutic use, Gabapentin administration & dosage, Gabapentin therapeutic use, Gabapentin pharmacology, Neuralgia drug therapy, Flavonoids administration & dosage, Flavonoids pharmacology, Flavonoids therapeutic use, Flavonols pharmacology, Flavonols administration & dosage, Flavonols therapeutic use, Analgesics administration & dosage, Analgesics therapeutic use, Analgesics pharmacology, Quercetin administration & dosage, Quercetin pharmacology, Quercetin therapeutic use, Drug Therapy, Combination, gamma-Aminobutyric Acid administration & dosage, gamma-Aminobutyric Acid therapeutic use, gamma-Aminobutyric Acid analogs & derivatives
- Abstract
We purposed to explore the consequences of the use quercetin and fisetin alone and in combination with pregabalin and gabapentin, which are used in the management of neuropathic pain, and on neuropathic pain in general. The anti-allodynic effect of various doses (5, 10, and 20 mg/kg) of quercetin and fisetin, both singly and in combination with pregabalin and gabapentin, was evaluated by developing a neuropathic pain model induced by chronic constrictive nerve damage in rats. The effectiveness of these flavonoids was investigated by combining them with gabapentin (50 mg/kg) and pregabalin (15 mg/kg), choosing the effectual dose of 10 mg/kg and the dose of 5 mg/kg, which did not show significant antiallodynic effects. In groups combined with gabapentin and pregabalin, it was determined that they showed a significant antiallodynic effect compared with 50 mg/kg gabapentin and 15 mg/kg pregabalin. In conclusion, in our combination studies, it was observed that the effectiveness of gabapentin and pregabalin, was increased and the duration of effect was prolonged when used with lower doses of flavonoids. Based on these findings; it is possible to say that quercetin and fisetin are potential agents that can be used alone or in combination with other effective treatments to alleviate neuropathic pain., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
- Published
- 2024
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7. Economic Evaluation of anti-epileptic Medicines for Autistic Children with Epilepsy.
- Author
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Tinelli M M, Roddy A, Knapp M, Arango C, Mendez MA, Cusack J, Murphy D, Canitano R, Oakley B, and Quoidbach V
- Subjects
- Humans, Child, Carbamazepine therapeutic use, Carbamazepine economics, Spain, Ireland, Italy, Gabapentin therapeutic use, Oxcarbazepine therapeutic use, England, Male, gamma-Aminobutyric Acid therapeutic use, gamma-Aminobutyric Acid economics, gamma-Aminobutyric Acid analogs & derivatives, Female, Amines therapeutic use, Amines economics, Anticonvulsants therapeutic use, Anticonvulsants economics, Epilepsy drug therapy, Epilepsy economics, Cost-Benefit Analysis, Autistic Disorder drug therapy, Autistic Disorder economics
- Abstract
We examine the cost-effectiveness of treating epilepsy with anti-epileptic medicines in autistic children, looking at impacts on healthcare providers (in England, Ireland, Italy and Spain) and children's families (in Ireland). We find carbamazepine to be the most cost-effective drug to try first in children with newly diagnosed focal seizures. For England and Spain, oxcarbazepine is the most cost-effective treatment when taken as additional treatment for those children whose response to monotherapy is suboptimal. In Ireland and Italy, gabapentin is the most cost-effective option. Our additional scenario analysis presents the aggregate cost to families with autistic children who are being treated for epilepsy: this cost is considerably higher than healthcare provider expenditure., (© 2023. The Author(s).)
- Published
- 2024
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8. Phenibut: Review and Pharmacologic Approaches to Treating Withdrawal.
- Author
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Penzak SR and Bulloch M
- Subjects
- Humans, Benzodiazepines therapeutic use, Benzodiazepines pharmacology, Substance Withdrawal Syndrome drug therapy, gamma-Aminobutyric Acid therapeutic use, gamma-Aminobutyric Acid analogs & derivatives
- Abstract
β-Phenyl-γ-aminobutyric acid (phenibut) is an analog of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) that was first synthesized in Russia in the early 1960s. It is marketed as a nootropic (smart drug) to improve cognitive performance, and to treat generalized and social anxiety, insomnia, and alcohol withdrawal. The use of phenibut is legal in the USA and it is widely available online without a prescription. Increased public awareness of phenibut has led to a growing number of reports of acute intoxication and withdrawal. In this review, we describe the pharmacology of phenibut, the presentation and management of acute intoxication, and regulatory issues, placing particular emphasis on the treatment of acute withdrawal, for which there are no comparative studies. Among 29 cases of phenibut withdrawal, patients were successfully treated with baclofen, benzodiazepines, and phenobarbital, as individual agents or in various combinations. Ancillary medications included antipsychotics, dexmedetomidine, gabapentin, and pregabalin. After stabilization, a number of patients did well on baclofen tapers, whereas others were weaned off benzodiazepines or phenobarbital. Phenobarbital may be preferred over baclofen, or used as an added agent, in patients at risk for seizures. As long as phenibut remains legal, cases of phenibut intoxication and withdrawal are likely to increase. As urine or plasma drug screening for phenibut is not widely available, it is vital that clinicians obtain a detailed medication history in patients presenting to the emergency department with nonspecific symptoms that may represent phenibut intoxication or withdrawal. Further, clinicians may wish to consult an addiction specialist or toxicologist in these situations., (© 2024, The American College of Clinical Pharmacology.)
- Published
- 2024
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9. Phenibutan-an Illegal Food Supplement With Psychotropic Effects and Health Risks.
- Author
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Bonnet U, Scherbaum N, Schaper A, and Soyka M
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- Humans, Germany, Dietary Supplements adverse effects, Psychotropic Drugs poisoning, Psychotropic Drugs adverse effects, Female, Adult, Male, gamma-Aminobutyric Acid adverse effects, gamma-Aminobutyric Acid therapeutic use, gamma-Aminobutyric Acid poisoning, gamma-Aminobutyric Acid analogs & derivatives
- Abstract
Background: Phenibut (β-phenyl-γ-aminobutyric acid) is an analog of the neurotransmitter gamma-aminobutyric acid (GABA). Like abapentin and pregabalin, it inhibits α2-δ-subunits of voltagedependent presynaptic calcium channels. The potential harm resulting from the use of these gabapentinoids is currently a matter of debate., Methods: This review is based on pertinent publications retrieved by a selective literature search and on cases reported to the Giftinformationszentrum-Nord (GIZ-Nord), a poison information center at the University of Göttingen, Germany., Results: Phenibut is a prescription drug in Russia but its production, possession, use, trafficking, or administration is illegal in Germany. The phenibut toxicity syndrome resembles that of gabapentinoids and GABA mimetics: benzodiazepine-like with - drawal symptoms including epileptic seizures, delirium and paradoxical activation have been described, as have cases of abuse and dependence. A few cases of use in the setting of multidrug abuse, and of phenibut-related death, have been described to date in the USA. The GIZ-Nord received 17 inquiries about phenibut, 55 about gabapentin, and 126 about pregabalin over the period 2008-2022. Over the same period, the GIZ-Nord was informed of 1207 cases involving Z substances and 4324 involving benzodiazepines. In the majority of the registered intoxications, including those with phenibut, the symptoms were mild. Overdoses of phenibut (2-100 g) were reported in 15 of the 17 cases; 8 of the persons who had taken an overdose were somnolent. In such cases, observation in intensive care was recommended. Respiratory depression or coma was not encountered in any case, not even in the patient who had taken 100 g of phenibut., Conclusion: Phenibut causes symptoms resembling those of gabapentinoid and benzodiazepine use. There have been reports of phenibut use in combination with other psychotropic drugs; in particular, its use together with opiates could increase the risk of coma and respiratory depression. No deaths due to phenibut intoxication have been published in Germany or elsewhere in Western Europe, although such cases may have been overlooked, as this drug is still largely unknown to Western medicine.
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- 2024
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10. Monitoring the use of novel psychoactive substances in Australia by wastewater-based epidemiology.
- Author
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Jaunay EL, Bade R, Paxton KR, Nadarajan D, Barry DC, Zhai Y, Tscharke BJ, O'Brien JW, Mueller J, White JM, Simpson BS, and Gerber C
- Subjects
- Australia, Wastewater, Psychotropic Drugs analysis, Wastewater-Based Epidemiological Monitoring, Illicit Drugs analysis, Amphetamines, gamma-Aminobutyric Acid analogs & derivatives
- Abstract
Users of novel psychoactive substances (NPS) are at risk, due to limited information about the toxicity and unpredictable effects of these compounds. Wastewater-based epidemiology (WBE) has been used as a tool to provide insight into NPS use at the population level. To understand the preferences and trends of NPS use in Australia, this study involved liquid chromatography mass spectrometry analysis of wastewater collected from Australian states and territories from February 2022 to February 2023. In total, 59 different NPS were included across two complementary analytical methods and covered up to 57 wastewater catchments over the study. The NPS detected in wastewater were 25-B-NBOMe, buphedrone, 1-benzylpiperazine (BZP), 3-chloromethcathinone, N,N-dimethylpentylone (N,N-DMP), N-ethylheptedrone, N-ethylpentylone, eutylone, 4F-phenibut, 2-fluoro deschloroketamine, hydroxetamine, mephedrone, methoxetamine, methylone, mitragynine, pentylone, phenibut, para-methoxyamphetamine (PMA), alpha-pyrrolidinovalerophenone (α-PVP) and valeryl fentanyl. The detection frequency for these NPS ranged from 3 % to 100 % of the sites analysed. A noticeable decreasing trend in eutylone detection frequency and mass loads was observed whilst simultaneously N,N-DMP and pentylone increased over the study period. The emergence of some NPS in wastewater pre-dates other sources of monitoring and provides further evidence that WBE can be used as an additional early warning system for alerting potential NPS use., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Cobus Gerber reports financial support was provided by Drug and Alcohol Services South Australia. Cobus Gerber reports financial support was provided by Australian Criminal Intelligence Commission., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2024
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11. Potential Mechanisms of Casein Hexapeptide YPVEPF on Stress-Induced Anxiety and Insomnia Mice and Its Molecular Effects and Key Active Structure.
- Author
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Qian J, Zheng L, Huang M, and Zhao M
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- Rats, Mice, Animals, Caseins metabolism, Receptors, GABA-A metabolism, Serotonin, Anxiety, Sleep Initiation and Maintenance Disorders, Anti-Anxiety Agents pharmacology, gamma-Aminobutyric Acid analogs & derivatives
- Abstract
The hexapeptide YPVEPF with strong sleep-enhancing effects could be detected in rat brain after a single oral administration as we previously proved. In this study, the mechanism and molecular effects of YPVEPF in the targeted stress-induced anxiety mice were first investigated, and its key active structure was further explored. The results showed that YPVEPF could significantly prolong sleep duration and improve the anxiety indexes, including prolonging the time spent in the open arms and in the center. Meanwhile, YPVEPF showed strong sleep-enhancing effects by significantly increasing the level of the GABA/Glu ratio, 5-HT, and dopamine in brain and serum and regulating the anabolism of multiple targets, but the effects could be blocked by bicuculline and WAY100135. Moreover, the molecular simulation results showed that YPVEPF could stably bind to the vital GABA
A and 5-HT1A receptors due to the vital structure of Tyr-Pro-Xaa-Xaa-Pro-, and the electrostatic and van der Waals energy played dominant roles in stabilizing the conformation. Therefore, YPVEPF displayed sleep-enhancing and anxiolytic effects by regulating the GABA-Glu metabolic pathway and serotoninergic system depending on distinctive self-folding structures with Tyr and two Pro repeats.- Published
- 2024
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12. Phenibut screening and quantification with liquid chromatography-tandem mass spectrometry and its application to driving cases.
- Author
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Dziadosz M, Rosenberger W, Bolte K, Klintschar M, and Teske J
- Subjects
- Humans, Chromatography, Liquid methods, Chromatography, High Pressure Liquid methods, Tandem Mass Spectrometry methods, Methanol, gamma-Aminobutyric Acid analogs & derivatives
- Abstract
An analytical strategy for identification by an LC-MS/MS multitarget screening method and a suitable LC-MS/MS based quantification were developed for the psychotropic drug phenibut. The samples analyzed were collected during traffic control and were associated with driving under the influence of drugs. A positive sample for phenibut was identified in a single case of driving under the influence. The quantification revealed a drug concentration of 1.9 μg/mL. An interaction with blood alcohol (BAC = 0.10%) was discussed as the explanation of the way of driving and deficit manifestations observed (swaying, nystagmus, quivering of the eyelid, and reddened eyes). According to the available information, the quantified phenibut concentration could be explained by an intake of four tablets (self-reported) during the day containing 250 mg of the drug. Chromatography was performed with a Luna 5 μm C18 (2) 100 A, 150 mm × 2 mm analytical column, and a buffer system consisted of 10 mM ammonium acetate and 0.1% acetic acid (v/v) included in mobile phases marked as A (H
2 O/methanol = 95/5, v/v) and B (H2 O/methanol = 3/97, v/v). An effective limit of detection (LOD = 0.002 μg/mL) could be achieved for the multitarget screening method. The quantification of phenibut was performed on a second LC-MS/MS system with LOD/LOQ values of 0.22/0.40 μg/mL. Since phenibut quantification data are rare, the presented information can be used with caution for evaluation of positive cases in the future., (© 2023 The Authors. Journal of Forensic Sciences published by Wiley Periodicals LLC on behalf of American Academy of Forensic Sciences.)- Published
- 2024
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13. [Clinical and neurophysiological manifestations of sluggish cognitive tempo in children].
- Author
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Chutko LS, Yakovenko EA, Surushkina SY, Anisimova TI, Cherednichenko DV, Didur MD, and Chekalova SA
- Subjects
- Humans, Child, Male, Female, Cognition, Attention drug effects, Memory, Short-Term drug effects, gamma-Aminobutyric Acid analogs & derivatives, Attention Deficit Disorder with Hyperactivity drug therapy, Attention Deficit Disorder with Hyperactivity physiopathology, Attention Deficit Disorder with Hyperactivity diagnosis, Electroencephalography, Pantothenic Acid analogs & derivatives, Pantothenic Acid therapeutic use
- Abstract
Objective: To study the clinical and neurophysiological features of children with low cognitive tempo (NCT), as well as the effectiveness of the drug Pantogam in the treatment of this pathology., Material and Methods: A total of 90 children aged 8 to 10 years were examined. Of these, the main study group consisted of 30 children with NCT, the comparison group consisted of 30 children with a combined type of attention deficit hyperactivity disorder ADHD (ADHD-K), the control group consisted of 30 children without neuropsychiatric disorders. The study used clinical, neurophysiological (electroencephalography (EEG)) and parametric methods. The CMAS scale of apparent anxiety (The Children's Form of Manifest Anxiety Scale), the SNAP-IY scale (assessment of the degree of inattention, hyperactivity and impulsivity), the TOVA computer test (the Test of Variables of Attention), the scale «SCT» (Sluggish Cognitive Tempo) for assessing manifestations of low cognitive tempo, the «RAM» technique for quantifying working memory. Pantogam was used to treat patients at a dose of 750 mg per day for 8 weeks., Results: Patients with NCT are characterized by more pronounced attention disorders compared with healthy peers and with children with ADHD-K, and they have a decrease in mainly not selective attention, but the overall level of functional activity. Also, the group of children with NCT has an increased level of anxiety compared to the group of children with ADHD. A comparative analysis of the level of impulsivity showed that children with NCT are less characterized by a deficit in inhibition processes. According to the quantitative analysis of the EEG, specific changes in functional activity in the frontal and central regions of the cerebral cortex were revealed (a statistically significant increase in the ratio of absolute theta rhythm to beta1 rhythm, compared with other groups), reflecting insufficient cortical arousal and less focused neural states. When re-evaluating the condition of children with NCT after a course of therapy with Pantogam, an improvement in the form of a decrease in the degree of inattention, the severity of memory impairment and a decrease in reaction time was recorded in 60% of cases. According to quantitative EEG analysis, there was a significant decrease in the ratio of absolute theta rhythm to beta1 rhythm in the central leads of both hemispheres and in the parietal-temporal leads of the left hemisphere, indicating an increase in the level of overall activation of the cerebral cortex after a course of treatment., Conclusion: Clinical and neurophysiological differences were revealed in patients with NCT and with combined ADHD. It has been shown that the use of Pantogam for the treatment of children with NCT leads not only to a decrease in the main manifestations of this disorder, but also to an improvement in the functional state of the brain.
- Published
- 2024
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14. Picamilon, a γ-aminobutyric acid (GABA) analogue and marketed nootropic, is inactive against 50 biological targets.
- Author
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Santillo MF and Sprando RL
- Subjects
- Receptors, GABA-A metabolism, gamma-Aminobutyric Acid analogs & derivatives, gamma-Aminobutyric Acid pharmacology, Nootropic Agents
- Abstract
Picamilon is an analogue of the neurotransmitter γ-aminobutyric acid (GABA), which is marketed as a nootropic claiming to enhance cognition. There is a lack of in silico, in vitro and in vivo data on the safety of picamilon. Therefore, to ascertain potential physiological effects of picamilon, it was screened against 50 safety-related biological targets (receptors, ion channels, enzymes and transporters) by in silico and in vitro methods. Using two in silico tools, picamilon was not predicted to bind to the targets. Similarly, picamilon exhibited weak or no binding to the targets when measured in vitro at 10 μM. Overall, this data shows that picamilon, although structurally similar to other GABA analogues, has a different biological target binding profile. Picamilon's lack of binding to the 50 targets fills important data gaps among GABA analogues, a group of structurally related substances found in drugs and other consumer products., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA.)
- Published
- 2023
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15. A Withdrawal Syndrome After a Switch of Phenibut to Another γ-Aminobutyric Acid Agonist.
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Pain S, Bouquet E, Coulon M, Fauconneau B, and Perault-Pochat MC
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- Humans, gamma-Aminobutyric Acid adverse effects, gamma-Aminobutyric Acid analogs & derivatives, GABA Agonists, Substance Withdrawal Syndrome etiology
- Published
- 2022
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16. A Case of Phenibut Directed Detoxification Leading to Toxicity During the COVID-19 Pandemic.
- Author
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Peterkin AF, Abraham R, and Harris MTH
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- Adult, Analgesics, Opioid adverse effects, Benzodiazepines adverse effects, Female, Fentanyl adverse effects, Humans, Pandemics, COVID-19 epidemiology, Self Medication adverse effects, Substance Withdrawal Syndrome drug therapy, Substance Withdrawal Syndrome epidemiology, gamma-Aminobutyric Acid analogs & derivatives, gamma-Aminobutyric Acid toxicity
- Abstract
Background: Phenibut is a non-Food and Drug Administration-approved gamma-aminobutyric acid analog marketed in the United States as an anxiolytic, cognitive enhancer, and alcohol withdrawal treatment through online supplement vendors. In this case report, we describe a woman's self-directed detoxification with phenibut used to manage withdrawal symptoms from fentanyl and benzodiazepines in March 2020 during the height of the COVID-19 pandemic., Case: A 38-year-old woman with severe opioid, benzodiazepine, gabapentin, stimulant use disorders developed altered mental status after oral phenibut ingestion intended to help self-manage opioid and benzodiazepine withdrawal. She chose self-directed detoxification as she feared COVID-19 exposure in detoxification facilities. Her altered mental status drove her to jump out a third-story window causing multiple spinal fractures. After a long hospitalization, she self-directed her discharge home due to concerns about COVID-19. Her premature discharge disrupted opioid and benzodiazepine use disorder treatment plans., Conclusion: This case highlights the risks of phenibut use for selfdirected detoxification. With COVID-19 related changes in the drug supply, people may be more likely to use online pharmaceuticals, therefore, substance use assessments should inquire about the online acquisition of new psychoactive drugs. Public health messaging regarding the risks of infectious disease transmission in addiction care settings is needed to guide addiction treatment choices among people who use substances., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 American Society of Addiction Medicine.)
- Published
- 2022
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17. Phenibut and Bromazolam Use Disorders Requiring Hospitalization for Medically Supervised Withdrawal.
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McDermott S, Johnson BE, and Balasanova AA
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- Hospitalization, Humans, Opiate Substitution Treatment, Substance Withdrawal Syndrome drug therapy, gamma-Aminobutyric Acid analogs & derivatives
- Published
- 2022
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18. Interindividual Variability in the Bioavailability of Gabapentin Enacarbil Extended Release in Healthy Adults: An Analysis of Data From 6 Phase I Studies.
- Author
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Lal R, Ellenbogen A, and Gidal B
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- Administration, Oral, Adult, Area Under Curve, Biological Availability, Cross-Over Studies, Gabapentin, Humans, Carbamates, gamma-Aminobutyric Acid analogs & derivatives
- Abstract
Background: The absorption and bioavailability of oral gabapentin are associated with a high degree of interindividual variability. Gabapentin enacarbil, a prodrug of gabapentin, is well absorbed and provides sustained, dose-proportional exposure to gabapentin. The aim of this analysis was to describe the interindividual variability in the bioavailability of gabapentin after gabapentin enacarbil administration in healthy subjects., Methods: Gabapentin pharmacokinetic (PK) parameters after an oral dose of gabapentin enacarbil 1200 mg (2 600-mg tablets) were compared across 6 phase I studies in healthy adults (n = 12 per study). The distribution of bioavailability values was assessed in all studies., Results: The mean PK parameters of gabapentin were consistent across the trials: maximum concentration range: 6.4-7.9 μg/mL, time to maximum concentration range: 5.2-8.2 hours, area under the plasma-concentration curve extrapolated from time 0 to infinity or at steady state range: 70.8-109.4 μg·h/mL, and bioavailability range: 64.8%-82.9%. Overall, the mean bioavailability was 74.1% (SD, 14.1; coefficient of variation, 19.1%). Individual bioavailability across all studies ranged from 42% to 100%., Conclusions: Gabapentin PK after gabapentin enacarbil administration was consistent across studies, with low interindividual variability in bioavailability. Gabapentin enacarbil may provide more consistent and predictable exposure to gabapentin than oral gabapentin formulations., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.)
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- 2022
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19. Use of Pregabalin in Patients with Painful Neuropathic Disorders under the Care of General Practitioners in the U.K.
- Author
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Berger, Ariel, Sadosky, Alesia, Dukes, Ellen, Edelsberg, John, and Oster, Gerry
- Subjects
- *
NEURALGIA , *PAIN , *ANALGESIA , *GABA , *PERIPHERAL nervous system - Abstract
Purpose: To examine the use of pregabalin in patients with painful neuropathic disorders under the care of general practitioners (GPs) in the U.K. Materials and Methods: Using a large U.K. database of GP encounters, we identified all persons aged ≥ 18 years with at least one GP encounter with a diagnosis of a painful neuropathic disorder (eg, postherpetic neuralgia, diabetic peripheral neuropathy) between January 1, 2004 and July 31, 2006. Among these patients, we then identified those who initiated therapy with pregabalin; the date of initial receipt of pregabalin was designated the “index date.” We then examined use of pregabalin over the 6-month period following this date (“follow-up”), as well as changes in the use of other pain-related medications (eg, opioids, tricyclic antidepressants [TCAs], other antiepileptics [AEDs]) between the 6-month period preceding the index date (“pretreatment”) and follow-up. Patients with less than 6 months of pretreatment and follow-up data were excluded, as were those without any encounters during pretreatment for a painful neuropathic disorder. Results: A total of 1,400 patients (1.4% of all identified patients with painful neuropathic disorders) initiated therapy with pregabalin and met all other entry criteria; mean age was 62 years, and 58% were women. During pretreatment, most (54%) patients received three or more different types of pain-related medications. During follow-up, patients averaged four prescriptions for pregabalin, totaling 93 therapy days. Compared with pretreatment, fewer patients received other pain-related medications during follow-up, including TCAs (37% during pretreatment vs. 27% during follow-up), opioids (64% vs. 55%), and AEDs other than pregabalin (36% vs. 16%) (all P < 0.01). Conclusions: In the U.K., many patients prescribed pregabalin by their GPs may have been refractory to other pain-related medications. Use of these medications declined following initiation of pregabalin therapy. [ABSTRACT FROM AUTHOR]
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- 2009
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20. Chronic Phenibut Use: Symptoms, Severe Withdrawal, and Recovery.
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VanDreese B, Holland A, and Murray A
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- Adult, Humans, Male, gamma-Aminobutyric Acid analogs & derivatives, gamma-Aminobutyric Acid therapeutic use, Baclofen therapeutic use, Substance Withdrawal Syndrome drug therapy
- Abstract
Introduction: Phenibut is a psychoactive drug with GABA
B agonism. It remains unregulated and easily attainable in the United States, where it has become a novel drug of abuse., Case Presentation: We present the case of a 34-year-old man who used phenibut consistently for 3 years. After 6 months of use, he developed signs of dependence and failed outpatient detoxification. While taking high doses, he experienced parasomnia-like symptoms and periods of dysexecutive function. After abrupt cessation, he developed severe withdrawal symptoms, was hospitalized, and required intubation. His condition improved after 1 week of treatment. After recovery and discharge, he remains stable utilizing an extended taper of acamprosate and baclofen., Discussion: Phenibut is not detected on urine drug screen and withdrawal symptoms are nonspecific. Optimal treatment of withdrawal remains unknown. Baclofen and phenobarbital have been successful for treatment of dependence., Conclusion: Clinicians should be aware of phenibut abuse and the potential for dependence and withdrawal., (Copyright© Board of Regents of the University of Wisconsin System and The Medical College of Wisconsin, Inc.)- Published
- 2022
21. Quantity of phenibut in dietary supplements before and after FDA warnings.
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Cohen PA, Ellison RR, Travis JC, Gaufberg SV, and Gerona R
- Subjects
- Dietary Supplements adverse effects, Dietary Supplements analysis, Humans, United States, United States Food and Drug Administration, gamma-Aminobutyric Acid analogs & derivatives, Alcoholism, Substance Withdrawal Syndrome
- Abstract
Introduction: Phenibut is used to treat anxiety, insomnia, alcohol withdrawal and other conditions in Russia. The drug, however, has abuse potential and may cause lethargy, delirium, psychosis and coma. In the United States (US), the US Food and Drug Administration (FDA) has never approved the use of phenibut as a prescription medication, but the drug is available over-the-counter in dietary supplements. More than 80 cases of coma and death have been associated with phenibut consumption and withdrawal, and the FDA recently warned that the drug is not permitted in over-the-counter supplements. We designed our study to determine the presence and quantity of phenibut in over-the-counter supplements before and after the FDA warnings., Methods: Phenibut products were included if they (a) listed phenibut or a synonym as an ingredient on the label, (b) were labeled as a dietary supplement, and (c) were available for sale both before and after the FDA warning. Supplements were analyzed by liquid chromatography time-of-flight mass spectrometry; quantification was performed by isotope dilution method., Results: Four brands of dietary supplements labeled as containing phenibut met the inclusion criteria. Prior to the FDA warnings, two of the four brands contained phenibut, at dosages of 484 mg and 487 mg per serving. After the FDA warning, all four products contained phenibut, ranging in dosages from 21 mg to 1,164 mg per serving. Phenibut was first detected only after the FDA warnings in two brands, and the quantity of phenibut increased in three of four products after the FDA warnings. Quantities detected per dose were as much as 450% greater than a typical 250 mg pharmaceutical tablet manufactured in Russia., Conclusion: Following FDA issuing an advisory that phenibut is not permitted in dietary supplements, the quantity of phenibut increased in 3 of 4 brands of over-the-counter phenibut supplements.
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- 2022
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22. Effects of Gabapentin Enacarbil on Postoperative Pain After Hip and Knee Arthroplasty: A Placebo-controlled Randomized Trial.
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Ayad SS, Makarova N, Niazi AK, Khoshknabi DS, Stang T, Raza S, and Kim DD
- Subjects
- Adult, Analgesics, Analgesics, Opioid therapeutic use, Carbamates, Double-Blind Method, Humans, Morphine therapeutic use, Pain Measurement, Pain, Postoperative drug therapy, Pain, Postoperative etiology, gamma-Aminobutyric Acid analogs & derivatives, Arthroplasty, Replacement, Hip adverse effects, Arthroplasty, Replacement, Knee adverse effects
- Abstract
Objectives: Total joint arthroplasties are among the most common elective procedures performed in the United States, and they are associated with postoperative pain. Gabapentin enacarbil is a prodrug with an extended-release formulation that has been proposed for multimodal postoperative analgesia, but the drug's efficacy for major arthroplasties remains unclear., Materials and Methods: We enrolled 60 adult patients scheduled for primary knee or hip arthroplasty expected to remain hospitalized for at least 3 days. Eligible patients were randomly assigned to placebo or gabapentin enacarbil 600 mg twice daily starting the day before surgery continuing for 3 days thereafter.The primary outcome was analyzed using a joint hypothesis framework of pain (0 to 10 verbal response scores) and cumulative opioid consumption (mg of morphine equivalent) within the first 72 hours. Secondary outcomes were nausea and vomiting, pain persisting 90 days after surgery, duration of hospitalization, and early postoperative health status using quality of recovery score (QoR-15)., Results: Twenty-eight patient in gabapentin enacarbil group and 32 in placebo group were analyzed. Since pain scores did not differ significantly (difference of means: -0.2 in pain scores; 95% confidence interval: -1.1, 0.7), nor did opioid consumption, conditions for joint hypothesis testing were not met. Moreover, there were no significant differences between groups for secondary outcomes., Discussion: We did not identify statistically significant or clinically meaningful differences in our primary and secondary outcomes related to perioperative use of gabapentin enacarbil in patients having primary hip or knee arthroplasties., Competing Interests: This trial was funded by Arbor Pharmaceuticals, LLC, Atlanta, GA. The sponsor had no role in study conduct, data acquisition, analysis, or manuscript preparation. The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2022
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23. [Treatment of patients with chronic cerebral ischemia: experience of using the combined neuroprotective drug Picamilon Ginkgo].
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Zakharov VV, Borodulina IV, and Vakhnina NV
- Subjects
- Ginkgo biloba, Humans, Phytotherapy, Plant Extracts therapeutic use, Quality of Life, gamma-Aminobutyric Acid analogs & derivatives, Brain Ischemia complications, Brain Ischemia drug therapy, Neuroprotective Agents therapeutic use
- Abstract
Objective: To compare the clinical efficacy and safety of Picamilon Ginkgo and ginkgo biloba in patients with cognitive impairment in vascular diseases of the brain (chronic cerebral ischemia)., Material and Methods: An open multicenter randomized comparative study involved 278 patients over 45 years of age with a diagnosis of chronic cerebral ischemia and cognitive impairment. 139 of them received Picamilon Ginkgo and 139 received monotherapy with ginkgo biloba extract for 90 days. Dynamics were compared on the MoCA, MMSE, Hamilton scale for assessing depression and the quality of life of EQ-5D, and the subjective effectiveness of therapy by patients and doctors was evaluated., Results: Combination therapy resulted in significantly greater regression of cognitive impairment compared to monotherapy. At the end of the study, the differences between the groups were significant both on the MMSE scale ( p =0.007) and on the MoCA scale ( p =00003). At the same time, significant differences between the groups in the magnitude of cognitive improvement on the MoCA scale were noted already from the 30th day of treatment. Combination therapy also contributed to a more significant improvement in the patient's quality of life: dynamics on the EQ-5D scale significantly ( p< 0.05) differed in the groups, also starting from the 30th day of therapy. There were no significant differences in the dynamics of the Hamilton scale for assessing depression between the compared groups. Both Picamilon Ginkgo and monotherapy with ginkgo biloba extract were safe and were not accompanied by significant adverse events., Conclusion: The combination of standardized ginkgo biloba extract with Picamilon has an advantage over monotherapy with ginkgo biloba extract in patients with chronic cerebral ischemia, as it contributes to a more significant regression of cognitive impairment and improvement of quality of life.
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- 2022
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24. [Effects of Skin Environmental Changes by Steam Towel, Ethanol, l-Menthol and Carpronium on the Drug Behavior in the Minoxidil Nanoparticles-applied Mice].
- Author
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Goto R, Oaku Y, Sasaki F, Kubota C, Deguchi S, Kadowaki R, Abe A, Nagahama T, and Nagai N
- Subjects
- Animals, Ethanol, Menthol, Mice, Steam, gamma-Aminobutyric Acid analogs & derivatives, Minoxidil pharmacology, Nanoparticles
- Abstract
We previously designed the formulation containing minoxidil (MXD) nanoparticles (MXD-NPs), and found that the MXD-NPs can mainly deliver MXD into hair bulbs via hair follicles pathway, and that the therapeutic efficiency for hair growth is higher in comparison with the formulation containing dissolved MXD. In this study, we investigated whether the skin environmental changes by the treatment of steam towel, ethanol, l-menthol and commercially available (CA) carpronium affect the drug behavior in the MXD-NPs-applied mice. The steam towel, ethanol, l-menthol and CA-carpronium were pre-treated 3 min before MXD-NPs application, and the MXD content in the hair bulge, bulb, skin tissue and blood of mice were measured 4 h after MXD-NPs application. No significant difference of MXD levels in the blood was observed by the pre-treatment of steam towel, ethanol, l-menthol and CA-carpronium. On the other hand, the pre-treatment of steam towel and l-menthol enhanced the MXD levels in hair bulge and/or bulb. Although, the MXD levels in hair bulge and bulb were not changed by the pre-treatment of ethanol, the MXD levels in skin tissue was higher than that of saline-pre-treated group (control). The MXD levels in hair bulge, bulb and skin tissue of mice pre-treated with CA-carpronium were remarkably higher in comparison with control. In conclusion, we showed that the changes in skin environment by the steam towel, ethanol, l-menthol and CA-carpronium affected the absorption of MXD-NPs, and these increased MXD levels in the hair bulb and blood by the combination may enhance the therapeutic efficiency without side effects.
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- 2022
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25. Cholinergic crisis caused by ingesting topical carpronium chloride solution: A case report.
- Author
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Endo T, Amagasa S, Kashiura M, Kubota Y, and Moriya T
- Subjects
- Aged, 80 and over, Consciousness Disorders chemically induced, Eating, Female, Flushing chemically induced, Humans, Salivation drug effects, Suicide, Attempted, Sweating drug effects, gamma-Aminobutyric Acid poisoning, Cholinesterase Inhibitors poisoning, gamma-Aminobutyric Acid analogs & derivatives
- Abstract
A cholinergic crisiss is a state characterized by excess acetylcholine owing to the ingestion of cholinesterase inhibitors or cholinergic agonists. We report the first case of a cholinergic crisis after the ingestion of a carpronium chloride solution, a topical solution used to treat alopecia, seborrhea sicca, and vitiligo. An 81-year-old woman with no prior medical history was transported to our emergency department because the patient had disturbance of consciousness after ingesting three bottles of FUROZIN® solution (90 mL, 4500 mg as carpronium chloride). A family member who found the patient called for emergency medical services (EMS) personnel, who contacted the patient ten minutes after ingestion. The patient's Glasgow Coma Scale score was 12 (E4V3M5), and vital signs were as follows: blood pressure, 80/40 mmHg; heart rate, 40 beats/min. The patient vomited repeatedly in the ambulance. On arrival to the ED, the patient's systolic blood pressure and heart rate temporarily decreased to 80 mmHg and 40 beats/min, respectively. Seventy-eight minutes after ingestion, gastric lavage was performed. The patient's symptoms, which included excess salivation, sweating, and hot flush, improved 24 h after ingestion, and the patient's vital signs stabilized without atropine or vasopressors. On the second day of admission, the patient was examined by a psychiatrist and discharged without suicidal ideation. Carpronium chloride has a chemical structure similar to that of acetylcholine; therefore, it exhibits both cholinergic and local vasodilatory activities. There is limited information on the pharmacokinetics of ingested carpronium chloride; therefore, physicians should be made aware that ingesting a carpronium chloride solution may cause a cholinergic crisis., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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26. The Coenzyme A Level Modulator Hopantenate (HoPan) Inhibits Phosphopantotenoylcysteine Synthetase Activity.
- Author
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Mostert KJ, Sharma N, van der Zwaag M, Staats R, Koekemoer L, Anand R, Sibon OCM, and Strauss E
- Subjects
- Amino Acid Sequence, Amino Acid Substitution, Animals, Cells, Cultured, Crystallization, Drosophila melanogaster, Kinetics, Molecular Conformation, Pantothenic Acid pharmacology, Peptide Synthases metabolism, Substrate Specificity, gamma-Aminobutyric Acid pharmacology, Coenzyme A metabolism, Enzyme Inhibitors pharmacology, Pantothenic Acid analogs & derivatives, Peptide Synthases antagonists & inhibitors, gamma-Aminobutyric Acid analogs & derivatives
- Abstract
The pantothenate analogue hopantenate (HoPan) is widely used as a modulator of coenzyme A (CoA) levels in cell biology and disease models─especially for pantothenate kinase associated neurodegeneration (PKAN), a genetic disease rooted in impaired CoA metabolism. This use of HoPan was based on reports that it inhibits pantothenate kinase (PanK), the first enzyme of CoA biosynthesis. Using a combination of in vitro enzyme kinetic studies, crystal structure analysis, and experiments in a typical PKAN cell biology model, we demonstrate that instead of inhibiting PanK, HoPan relies on it for metabolic activation. Once phosphorylated, HoPan inhibits the next enzyme in the CoA pathway─phosphopantothenoylcysteine synthetase (PPCS)─through formation of a nonproductive substrate complex. Moreover, the obtained structure of the human PPCS in complex with the inhibitor and activating nucleotide analogue provides new insights into the catalytic mechanism of PPCS enzymes─including the elusive binding mode for cysteine─and reveals the functional implications of mutations in the human PPCS that have been linked to severe dilated cardiomyopathy. Taken together, this study demonstrates that the molecular mechanism of action of HoPan is more complex than previously thought, suggesting that the results of studies in which it is used as a tool compound must be interpreted with care. Moreover, our findings provide a clear framework for evaluating the various factors that contribute to the potency of CoA-directed inhibitors, one that will prove useful in the future rational development of potential therapies of both human genetic and infectious diseases.
- Published
- 2021
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27. [Influence of pantogam and atomoxetine on attention stability and distribution of dopamine D2 and GABAB receptors in the attention deficit mouse model].
- Author
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Kovalev GI, Sukhorukova NA, Vasileva EV, Kondrakhin EA, and Salimov RM
- Subjects
- Animals, Atomoxetine Hydrochloride pharmacology, Dopamine, Mice, Pantothenic Acid analogs & derivatives, gamma-Aminobutyric Acid analogs & derivatives, Attention Deficit Disorder with Hyperactivity drug therapy
- Abstract
The closed enriched cross maze test was employed as a new experimental model of the attention deficit disorder (ADD) for evaluation of the behavioral and neurochemical effects of the nootropic drug pantogam (100 mg/kg, intraperitoneally) and atomoxetine hydrochloride (3 mg/kg, intraperitoneally) administered subchronically to CD-1 outbred mice. Two subpopulations of rodents differed spontaneously in attention to enriched compartments (ED-Low and ED-High), were estimated on the basis of time spent by the mice in the empty or enriched compartments. The ED-Low and ED-High mice insignificantly differed in parameters associated with anxiety, exploratory efficacy and motor activity. Subchronic administration of both drugs in selected doses produced corrective effect on animal behavior seen as a selective increase in the ED-ratio values in the ED-Low subpopulation. Differences in the distribution of dopamine D2 and GABAB receptors (Bmax) between placebo-treated ED-Low and ED-High mice were found in the prefrontal cortex using the radioligand binding method. The neuroreceptor effects of atomoxetine were seen in prefrontal cortex of ED-Low mice as decrease in the Bmax values of D2 receptors by 14%. Pantogam in the prefrontal cortex of ED-Low subpopulation showed a decrease in the Bmax values of D2 receptors by 22% and an increase for GABAB receptors by 44%. Therefore, subchronic administration of pantogam had a positive corrective effect on the behavior parameters and the density of the studied receptor subtypes in animals with severe attention deficit.
- Published
- 2021
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28. Difference in background factors between responders to gabapentin enacarbil treatment and responders to placebo: pooled analyses of two randomized, double-blind, placebo-controlled studies in Japanese patients with restless legs syndrome.
- Author
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Inoue Y, Hirata K, Hoshino Y, and Yamaguchi Y
- Subjects
- Carbamates therapeutic use, Double-Blind Method, Humans, Japan, Treatment Outcome, gamma-Aminobutyric Acid analogs & derivatives, Restless Legs Syndrome drug therapy
- Abstract
Objective: Restless legs syndrome (RLS) is a sensorimotor disorder that is characterized by uncomfortable and unpleasant sensations mainly in the legs. Two placebo-controlled studies (Phase II/III and post-marketing) in Japanese patients with RLS failed to demonstrate the efficacy of gabapentin enacarbil (GE) 600 mg in the change from baseline in International Restless Legs Syndrome Rating Scale (IRLS) score at the end of the treatment period. The high response to placebo is thought to be a possible reason why the post-marketing study failed. The objectives of these post hoc analyses were to determine potential predictive factors associated with improvement in IRLS score with GE treatment and to identify subgroups with higher placebo responses., Methods: We combined data from the two Japanese studies and analyzed change from baseline in IRLS score in the pooled population and subgroups defined by several patient characteristics. Moreover, we calculated the variable importance of each factor and performed predictive enrichment analysis to identify an enrichable subpopulation with greater improvement by GE treatment., Results: The post hoc analyses suggested that higher baseline IRLS score (≥21) and higher body mass index (≥25 kg/m
2 ) were associated with higher placebo responses. On the other hand, positive family history of RLS, prior use of dopaminergic receptor agonists, and higher baseline ferritin level (≥50 ng/mL) were associated with higher responses to GE., Conclusions: Our results suggest that patients with typical idiopathic RLS characteristics, including positive family history and no low ferritin level, would be expected to derive the greatest benefits from GE treatment., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2021
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29. Sedative-Hypnotic Agents That Impact Gamma-Aminobutyric Acid Receptors: Focus on Flunitrazepam, Gamma-Hydroxybutyric Acid, Phenibut, and Selank.
- Author
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Doyno CR and White CM
- Subjects
- Drug Overdose physiopathology, Flunitrazepam pharmacology, Humans, Oligopeptides pharmacology, Receptors, GABA metabolism, Receptors, Metabotropic Glutamate drug effects, Receptors, Metabotropic Glutamate metabolism, Substance Withdrawal Syndrome physiopathology, Substance-Related Disorders epidemiology, gamma-Aminobutyric Acid analogs & derivatives, gamma-Aminobutyric Acid pharmacology, Hypnotics and Sedatives pharmacology, Receptors, GABA drug effects, Substance-Related Disorders physiopathology
- Abstract
There are many nonopioid central nervous system depressant substances that share a gamma-aminobutyric acid (GABA) receptor-related mechanism of action. These sedatives-hypnotics can be indicated to treat anxiety, seizures, depression, and insomnia but are also used as substances of abuse and used to facilitate sexual assault. Barbiturates, methaqualone, and glutethimide were among the first type A GABA receptor-mediated sedative-hypnotics. Their clinical use was limited for most indications by serious adverse events and strong abuse potential but continue to be used illicitly around the world. The benzodiazepines supplanted barbiturates for most indications because they were less likely to cause severe adverse events in monotherapy. Flunitrazepam is a newer benzodiazepine that is preferentially used recreationally and to facilitate sexual assault. Flunitrazepam has greater potency and higher affinity for the type A GABA receptor than most benzodiazepines. Gamma-hydroxybutyric acid is sought illicitly for its hypnotic, euphoric and anabolic effects as well as to facilitate sexual assault. When any of these GABAergic drugs are used in high doses or with other sedative hypnotic agents, respiratory depression, coma, and death have occurred. Chronic use of these GABAergic drugs can lead to significant withdrawal syndromes. Phenibut and selank are poorly studied Russian drugs with GABAergic mechanisms that are inexplicably sold to US consumers as dietary supplements. Poison control center calls regarding phenibut have increased substantially over the past 5 years. Desired euphoriant effects account for the recreational and illicit use of many GABA-modulating agents. However, illicit use can lead to significant toxicities related to abuse, dependence, and subsequent withdrawal syndromes. Significant evaluation of developing agents with GABA properties should be conducted to determine abuse potential before public access ensues., (© 2021, The American College of Clinical Pharmacology.)
- Published
- 2021
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30. Inhibition of Fatty Acid Metabolism Increases EPA and DHA Levels and Protects against Myocardial Ischaemia-Reperfusion Injury in Zucker Rats.
- Author
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Kuka J, Makrecka-Kuka M, Vilks K, Korzh S, Cirule H, Sevostjanovs E, Grinberga S, Dambrova M, and Liepinsh E
- Subjects
- Animals, Male, Metabolome, Myocardial Reperfusion Injury etiology, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury pathology, Rats, Rats, Zucker, gamma-Aminobutyric Acid pharmacology, Docosahexaenoic Acids metabolism, Eicosapentaenoic Acid metabolism, Insulin Resistance, Lipid Metabolism drug effects, Myocardial Reperfusion Injury prevention & control, Quaternary Ammonium Compounds pharmacology, gamma-Aminobutyric Acid analogs & derivatives
- Abstract
Long-chain ω -3 polyunsaturated fatty acids (PUFAs) are known to induce cardiometabolic benefits, but the metabolic pathways of their biosynthesis ensuring sufficient bioavailability require further investigation. Here, we show that a pharmacological decrease in overall fatty acid utilization promotes an increase in the levels of PUFAs and attenuates cardiometabolic disturbances in a Zucker rat metabolic syndrome model. Metabolome analysis showed that inhibition of fatty acid utilization by methyl-GBB increased the concentration of PUFAs but not the total fatty acid levels in plasma. Insulin sensitivity was improved, and the plasma insulin concentration was decreased. Overall, pharmacological modulation of fatty acid handling preserved cardiac glucose and pyruvate oxidation, protected mitochondrial functionality by decreasing long-chain acylcarnitine levels, and decreased myocardial infarct size twofold. Our work shows that partial pharmacological inhibition of fatty acid oxidation is a novel approach to selectively increase the levels of PUFAs and modulate lipid handling to prevent cardiometabolic disturbances., Competing Interests: JK, MMK, HC, SG, MD, and EL are listed as inventors in several international patent applications regarding the use of methyl-GBB for the treatment of cardiovascular and cardiometabolic diseases. None of the authors currently own any of these patents., (Copyright © 2021 Janis Kuka et al.)
- Published
- 2021
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31. The effects of flavonoids, green tea polyphenols and coffee on DMBA induced LINE-1 DNA hypomethylation.
- Author
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Szabo L, Molnar R, Tomesz A, Deutsch A, Darago R, Nowrasteh G, Varjas T, Nemeth B, Budan F, and Kiss I
- Subjects
- Animals, Anticarcinogenic Agents pharmacology, Camellia sinensis drug effects, Carcinogens pharmacology, Catechin pharmacology, Coffee chemistry, DNA metabolism, Female, Flavonoids pharmacology, Glutathione pharmacology, Kidney drug effects, Liver drug effects, Long Interspersed Nucleotide Elements genetics, Mice, Mice, Inbred CBA, Myrica chemistry, Phenols pharmacology, Polyphenols pharmacology, Spleen drug effects, Tea chemistry, gamma-Aminobutyric Acid analogs & derivatives, DNA Methylation drug effects, Long Interspersed Nucleotide Elements drug effects, Plant Extracts pharmacology
- Abstract
The intake of carcinogenic and chemopreventive compounds are important nutritional factors related to the development of malignant tumorous diseases. Repetitive long interspersed element-1 (LINE-1) DNA methylation pattern plays a key role in both carcinogenesis and chemoprevention. In our present in vivo animal model, we examined LINE-1 DNA methylation pattern as potential biomarker in the liver, spleen and kidney of mice consuming green tea (Camellia sinensis) extract (catechins 80%), a chinese bayberry (Morella rubra) extract (myricetin 80%), a flavonoid extract (with added resveratrol) and coffee (Coffee arabica) extract. In the organs examined, carcinogen 7,12-dimethylbenz(a)anthracene (DMBA)-induced hypomethylation was prevented by all test materials except chinese bayberry extract in the kidneys. Moreover, the flavonoid extract caused significant hypermethylation in the liver compared to untreated controls and to other test materials. The tested chemopreventive substances have antioxidant, anti-inflammatory properties and regulate molecular biological signaling pathways. They increase glutathione levels, induce antioxidant enzymes, which decrease free radical damage caused by DMBA, and ultimately, they are able to increase the activity of DNA methyltransferase enzymes. Furthermore, flavonoids in the liver may inhibit the procarcinogen to carcinogen activation of DMBA through the inhibition of CYP1A1 enzyme. At the same time, paradoxically, myricetin can act as a prooxidant as a result of free radical damage, which can explain that it did not prevent hypomethylation in the kidneys. Our results demonstrated that LINE-1 DNA methylation pattern is a useful potential biomarker for detecting and monitoring carcinogenic and chemopreventive effects of dietary compounds., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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32. Phenibut Use in a Patient Prescribed Gabapentinoids.
- Author
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Tamarelli C and Hosanagar A
- Subjects
- Humans, gamma-Aminobutyric Acid analogs & derivatives
- Published
- 2021
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33. Phenibut Dependence and Withdrawal.
- Author
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Sethi R, Ravishankar DA, and Nagireddy R
- Subjects
- Humans, Substance Withdrawal Syndrome diagnosis, gamma-Aminobutyric Acid analogs & derivatives
- Published
- 2021
- Full Text
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34. Mitochondrial-Protective Effects of R-Phenibut after Experimental Traumatic Brain Injury.
- Author
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Kupats E, Stelfa G, Zvejniece B, Grinberga S, Vavers E, Makrecka-Kuka M, Svalbe B, Zvejniece L, and Dambrova M
- Subjects
- Animals, Male, Mice, Mice, Inbred ICR, gamma-Aminobutyric Acid pharmacology, Brain Injuries, Traumatic drug therapy, Brain Injuries, Traumatic metabolism, Brain Injuries, Traumatic pathology, Hydrogen Peroxide metabolism, Mitochondria metabolism, Mitochondria pathology, Neocortex metabolism, Neocortex pathology, Neurons metabolism, Neurons pathology, gamma-Aminobutyric Acid analogs & derivatives
- Abstract
Altered neuronal Ca
2+ homeostasis and mitochondrial dysfunction play a central role in the pathogenesis of traumatic brain injury (TBI). R-Phenibut ((3R)-phenyl-4-aminobutyric acid) is an antagonist of the α2 δ subunit of voltage-dependent calcium channels (VDCC) and an agonist of gamma-aminobutyric acid B (GABA-B) receptors. The aim of this study was to evaluate the potential therapeutic effects of R-phenibut following the lateral fluid percussion injury (latFPI) model of TBI in mice and the impact of R- and S-phenibut on mitochondrial functionality in vitro . By determining the bioavailability of R-phenibut in the mouse brain tissue and plasma, we found that R-phenibut (50 mg/kg) reached the brain tissue 15 min after intraperitoneal (i.p.) and peroral (p.o.) injections. The maximal concentration of R-phenibut in the brain tissues was 0.6 μ g/g and 0.2 μ g/g tissue after i.p. and p.o. administration, respectively. Male Swiss-Webster mice received i.p. injections of R-phenibut at doses of 10 or 50 mg/kg 2 h after TBI and then once daily for 7 days. R-Phenibut treatment at the dose of 50 mg/kg significantly ameliorated functional deficits after TBI on postinjury days 1, 4, and 7. Seven days after TBI, the number of Nissl-stained dark neurons (N-DNs) and interleukin-1beta (IL-1 β ) expression in the cerebral neocortex in the area of cortical impact were reduced. Moreover, the addition of R- and S-phenibut at a concentration of 0.5 μ g/ml inhibited calcium-induced mitochondrial swelling in the brain homogenate and prevented anoxia-reoxygenation-induced increases in mitochondrial H2 O2 production and the H2 O2 /O ratio. Taken together, these results suggest that R-phenibut could serve as a neuroprotective agent and promising drug candidate for treating TBI., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 Einars Kupats et al.)- Published
- 2020
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35. Nighttime Agitation and Restless Legs Syndrome in Persons With Alzheimer's Disease: Study Protocol for a Double-Blind, Placebo-Controlled, Randomized Trial (NightRest).
- Author
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Richards K, Morrison J, Wang YY, Rangel A, Loera A, Hanlon A, Lozano A, Kovach C, Gooneratne N, Fry L, and Allen R
- Subjects
- Aged, Double-Blind Method, Female, Humans, Male, Middle Aged, Treatment Outcome, gamma-Aminobutyric Acid therapeutic use, Alzheimer Disease complications, Anxiety therapy, Carbamates therapeutic use, Restless Legs Syndrome drug therapy, Sleep drug effects, gamma-Aminobutyric Acid analogs & derivatives
- Abstract
Nighttime agitation is a prevalent symptom in persons with Alzheimer's disease (AD). Effective treatments are absent due to our limited knowledge of its etiology. We hypothesized that restless legs syndrome (RLS), a common neurological sensorimotor disorder of uncomfortable leg sensations that appear at night and interfere with sleep, might be a cause for nighttime agitation in persons with AD. RLS is infrequently identified in persons with AD because traditional diagnosis is dependent on patients answering complex questions about their symptoms. With a validated observational tool for RLS diagnosis, the Behavioral Indicators Test-Restless Legs, we aim to diagnose RLS and determine the effect of gabapentin enacarbil (GEn) compared to placebo on nighttime agitation, sleep, antipsychotic medications, and the mechanism for these effects. We hypothesize that frequency of RLS behaviors will mediate the relationship between GEn and nighttime agitation. This study is an 8-week, double-blind, placebo-controlled, randomized pilot clinical trial, followed by an 8-week open-label trial, that is being conducted in long-term care settings and private homes. The results of this study may shift, personalize, and improve standards of care for treatment of nighttime agitation; reduce aggression and other nighttime agitation behaviors; and improve sleep., Targets: Persons with AD with nighttime agitation potentially caused by RLS., Intervention Description: Diagnose RLS and determine the effect of GEn., Mechanisms of Action: The frequency of RLS behaviors will mediate the relationship between GEn and nighttime agitation., Outcomes: Determine the effect of GEn on nighttime agitation, sleep, and antipsychotic medications., Trial Registration: ClinicalTrials.gov Identifier: NCT03082755 (Date of registration March 6, 2017). [Research in Gerontological Nursing, 13(6), 280-288.]., (Copyright 2020, SLACK Incorporated.)
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- 2020
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36. F-phenibut (β-(4-Fluorophenyl)-GABA), a potent GABA B receptor agonist, activates an outward-rectifying K + current and suppresses the generation of action potentials in mouse cerebellar Purkinje cells.
- Author
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Irie T, Yamazaki D, and Kikura-Hanajiri R
- Subjects
- Action Potentials, Animals, Baclofen pharmacology, Dose-Response Relationship, Drug, Female, GABA-B Receptor Agonists toxicity, In Vitro Techniques, Male, Mice, Inbred ICR, Purkinje Cells metabolism, Receptors, GABA-B metabolism, gamma-Aminobutyric Acid analogs & derivatives, gamma-Aminobutyric Acid toxicity, GABA-B Receptor Agonists pharmacology, Potassium metabolism, Potassium Channels metabolism, Purkinje Cells drug effects, Receptors, GABA-B drug effects, gamma-Aminobutyric Acid pharmacology
- Abstract
The GABA analog phenibut (β-Phenyl-GABA) is a GABA
B receptor agonist that has been licensed for various uses in Russia. Phenibut is also available as a dietary supplement from online vendors worldwide, and previous studies have indicated that phenibut overdose results in intoxication, withdrawal symptoms, and addiction. F-phenibut (β-(4-Fluorophenyl)-GABA), a derivative of phenibut, has not been approved for clinical use. However, it is also available as a nootropic supplement from online suppliers. F-phenibut binds to GABAB with a higher affinity than phenibut; therefore, F-phenibut may lead to more serious intoxication than phenibut. However, the mechanisms by which F-phenibut acts on GABAB receptors and influences neuronal function remain unknown. In the present study, we compared the potency of F-phenibut, phenibut, and the GABAB agonist (±)-baclofen (baclofen) using in vitro patch-clamp recordings obtained from mouse cerebellar Purkinje cells slice preparations Our findings indicate that F-phenibut acted as a potent GABAB agonist. EC50 of outward current density evoked by the three GABAB agonists decreased in the following order: phenibut (1362 μM) > F-phenibut (23.3 μM) > baclofen (6.0 μM). The outward current induced by GABAB agonists was an outward-rectifying K+ current, in contrast to the previous finding that GABAB agonists activates an inward-rectifying K+ current. The K+ current recorded in the present study was insensitive to extracellular Ba2+ , intra- or extracellular Cs+ , and intra- or extracellular tetraethylammonium-Cl. Moreover, F-phenibut suppressed action potential generation in Purkinje cells. Thus, abuse of F-phenibut may lead to severe damage by inhibiting the excitability of GABAB -expressing neurons., (Copyright © 2020 Elsevier B.V. All rights reserved.)- Published
- 2020
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37. Rethinking Opioids, Gabapentinoids, and Pain.
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Alderman C
- Subjects
- COVID-19, Coronavirus Infections, Humans, Pandemics, Pneumonia, Viral, United States, Analgesics, Opioid, Opioid Epidemic, Pain drug therapy, gamma-Aminobutyric Acid analogs & derivatives
- Abstract
Through the use of opiate analgesia, it is possible to alter perceptions of pain, but equally, these same drugs have the potential to cause other profound consequences. Long before the COVID-19 pandemic began to impact societies worldwide, many developed nations (and particularly the United States) were caught up in a struggle to contain the consequences of opioid use, which has directly contributed to numerous deaths and ongoing disability for many others.
- Published
- 2020
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38. Notes from the Field: Phenibut Exposures Reported to Poison Centers - United States, 2009-2019.
- Author
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Graves JM, Dilley J, Kubsad S, and Liebelt E
- Subjects
- Adolescent, Adult, Female, Humans, Male, Poisoning epidemiology, United States epidemiology, Young Adult, gamma-Aminobutyric Acid poisoning, Poison Control Centers statistics & numerical data, gamma-Aminobutyric Acid analogs & derivatives
- Abstract
Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.
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- 2020
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39. Safety and Tolerability of the Anxiolytic and Nootropic Drug Phenibut: A Systematic Review of Clinical Trials and Case Reports.
- Author
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Kupats E, Vrublevska J, Zvejniece B, Vavers E, Stelfa G, Zvejniece L, and Dambrova M
- Subjects
- Anti-Anxiety Agents therapeutic use, Humans, Nootropic Agents poisoning, Nootropic Agents therapeutic use, Substance-Related Disorders, gamma-Aminobutyric Acid adverse effects, gamma-Aminobutyric Acid poisoning, gamma-Aminobutyric Acid therapeutic use, Anti-Anxiety Agents adverse effects, Nootropic Agents adverse effects, gamma-Aminobutyric Acid analogs & derivatives
- Abstract
Phenibut is a nootropic drug that exerts anxiolytic and antinociceptive effects by acting on the GABA
B receptor and the α2 -δ subunit of voltage-dependent calcium channels. An increased number of reports of dependence to and intoxication by phenibut purchased online on the one hand and the wide prescription of phenibut in Eastern Europe for more than half a century on the other hand have resulted in a number of controversies regarding its use. In this review, we have summarized currently available information from case reports of phenibut dependence and intoxication and safety data from clinical trials. We included 14 dependence and intoxication case reports (16 patients) and reviewed 11 phenibut clinical trials (583 patients). The clinical symptoms in the case reports included cardiovascular effects, insomnia, anxiety and agitation, hallucinations, and depressed level of consciousness. In addition, the doses used (0.5-100 g/day) were much higher than the recommended daily dose (0.25-2 g/day). An analysis of phenibut side effects described in the clinical trials showed adverse events in only 5.66% of patients, and the most reported side effect was somnolence (1.89%). There are discrepancies in the reported side effects of phenibut in clinical trials compared to those reported in cases of online-purchased phenibut dependence and intoxication. The current systematic review provides evidence that, at therapeutic doses, phenibut is safe and well tolerated with minor adverse effects, but questions regarding the quality of phenibut obtained online and the contribution of alcohol and other drug abuse to phenibut dependence and intoxication remain open., Competing Interests: The authors declare no conflict of interest., (Thieme. All rights reserved.)- Published
- 2020
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40. Gabapentin Enacarbil Extended-Release Versus Placebo: A Likely Responder Reanalysis of a Randomized Clinical Trial.
- Author
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Laska EM, Siegel CE, Lin Z, Bogenschutz M, and Marmar CR
- Subjects
- Adult, Alcoholism psychology, Female, Humans, Machine Learning, Male, Middle Aged, Outcome Assessment, Health Care, Precision Medicine, gamma-Aminobutyric Acid therapeutic use, Alcoholism drug therapy, Carbamates therapeutic use, gamma-Aminobutyric Acid analogs & derivatives
- Abstract
Background: We reanalyzed a multisite 26-week randomized double-blind placebo-controlled clinical trial of 600 mg twice-a-day Gabapentin Enacarbil Extended-Release (GE-XR), a gabapentin prodrug, designed to evaluate safety and efficacy for treating alcohol use disorder. In the original analysis (n = 338), published in 2019, GE-XR did not differ from placebo. Our aim is to advance precision medicine by identifying likely responders to GE-XR from the trial data and to determine for likely responders if GE-XR is causally superior to placebo., Methods: The primary outcome measure in the reanalysis is the reduction from baseline of the number of heavy drinking days (ΔHDD). Baseline features including measures of alcohol use, anxiety, depression, mood states, sleep, and impulsivity were used in a random forest (RF) model to predict ΔHDD to treatment with GE-XR based on those assigned to GE-XR. The resulting RF model was used to obtain predicted outcomes for those randomized to GE-XR and counterfactually to those randomized to placebo. Likely responders to GE-XR were defined as those predicted to have a reduction of 14 days or more. Tests of causal superiority of GE-XR to placebo were obtained for likely responders and for the whole sample., Results: For likely responders, GE-XR was causally superior to placebo (p < 0.0033), while for the whole sample, there was no difference. Likely responders exhibited improved outcomes for the related outcomes of percent HDD and drinks per week. Compared with unlikely responders, at baseline likely responders had higher HDDs; lower levels of anxiety, depression, and general mood disturbances; and higher levels of cognitive and motor impulsivity., Conclusions: There are substantial causal benefits of treatment with GE-XR for a subset of patients predicted to be likely responders. The likely responder statistical paradigm is a promising approach for analyzing randomized clinical trials to advance personalized treatment., (© 2020 The Authors. Alcoholism: Clinical & Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcoholism.)
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- 2020
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41. Phenibut: A Novel Nootropic With Abuse Potential.
- Author
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Mash JE and Leo RJ
- Subjects
- Adult, Humans, Male, Substance Withdrawal Syndrome etiology, Substance-Related Disorders etiology, gamma-Aminobutyric Acid adverse effects, Nootropic Agents adverse effects, gamma-Aminobutyric Acid analogs & derivatives
- Published
- 2020
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42. Prescription analgesia and adjuvant use by pain severity at admission among nursing home residents with non-malignant pain.
- Author
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Lapane KL, Hume AL, Morrison RA, and Jesdale BM
- Subjects
- Aged, Aged, 80 and over, Analgesia, Anticonvulsants therapeutic use, Antidepressive Agents therapeutic use, Female, Glucocorticoids therapeutic use, Humans, Male, Middle Aged, Neuromuscular Agents therapeutic use, Severity of Illness Index, gamma-Aminobutyric Acid analogs & derivatives, gamma-Aminobutyric Acid therapeutic use, Analgesics therapeutic use, Chemotherapy, Adjuvant, Nursing Homes statistics & numerical data, Pain drug therapy
- Abstract
Objective: We estimated the use of prescribed analgesics and adjuvants among nursing home residents without cancer who reported pain at their admission assessment, in relation to resident-reported pain severity., Methods: Medicare Part D claims were used to define 3 classes of analgesics and 7 classes of potential adjuvants on the 21st day after nursing home admission (or the day of discharge for residents discharged before that date) among 180,780 residents with complete information admitted between January 1, 2011 and December 9, 2016, with no cancer diagnosis., Results: Of these residents, 27.9% reported mild pain, 46.6% moderate pain, and 25.6% reported severe pain. The prevalence of residents in pain without Part D claims for prescribed analgesic and/or adjuvant medications was 47.3% among those reporting mild pain, 35.7% among those with moderate pain, and 24.8% among those in severe pain. Among residents reporting severe pain, 33% of those ≥ 85 years of age and 35% of those moderately cognitively impaired received no prescription analgesics/adjuvants. Use of all classes of prescribed analgesics and adjuvants increased with resident-reported pain severity, and the concomitant use of medications from multiple classes was common., Conclusion: Among nursing home residents with recognized pain, opportunities to improve the pharmacologic management of pain, especially among older residents, and those living with cognitive impairments exist.
- Published
- 2020
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43. Synthesis, Properties, and Biodegradation of Sequential Poly(Ester Amide)s Containing γ-Aminobutyric Acid.
- Author
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Nakayama Y, Watanabe K, Tanaka R, Shiono T, Kawasaki N, Yamano N, and Nakayama A
- Subjects
- Nylons chemistry, Polyesters chemistry, Seawater, Biodegradable Plastics chemical synthesis, gamma-Aminobutyric Acid analogs & derivatives
- Abstract
Poly(ester amide)s are attracting attention because they potentially have excellent thermal and mechanical properties as well as biodegradability. In this study, we synthesized a series of novel poly(ester amide)s by introducing γ-aminobutyric acid (GABA) regularly into polyesters, and investigated their properties and biodegradabilities. GABA is the monomer unit of biodegradable polyamide 4 (PA4). The new poly(ester amide)s were synthesized from the reaction of ammonium tosylate derivatives of alkylene bis(γ-aminobutylate) and p -nitrophenyl esters of dicarboxylic acids. All the obtained polymers showed relatively high melting temperatures ( T
m ). Their thermal decomposition temperatures were improved in comparison with that of PA4 and higher enough than their Tm . The poly(ester amide)s exhibited higher biodegradability in seawater than the corresponding homopolyesters. Their biodegradabilities in activated sludge were also studied.- Published
- 2020
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44. Post-mortem tissue analyses in a patient with succinic semialdehyde dehydrogenase deficiency (SSADHD). I. Metabolomic outcomes.
- Author
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Kirby T, Walters DC, Brown M, Jansen E, Salomons GS, Turgeon C, Rinaldo P, Arning E, Ashcraft P, Bottiglieri T, Roullet JB, and Gibson KM
- Subjects
- Adult, Amino Acid Metabolism, Inborn Errors pathology, Brain pathology, Carnitine metabolism, Developmental Disabilities pathology, Glycine metabolism, Humans, Male, Metabolomics, Succinate-Semialdehyde Dehydrogenase metabolism, gamma-Aminobutyric Acid metabolism, Amino Acid Metabolism, Inborn Errors metabolism, Amino Acids metabolism, Brain metabolism, Carnitine analogs & derivatives, Creatine metabolism, Creatinine metabolism, Developmental Disabilities metabolism, Glycine analogs & derivatives, Succinate-Semialdehyde Dehydrogenase deficiency, gamma-Aminobutyric Acid analogs & derivatives
- Abstract
Metabolomic characterization of post-mortem tissues (frontal and parietal cortices, pons, cerebellum, hippocampus, cerebral cortex, liver and kidney) derived from a 37 y.o. male patient with succinic semialdehyde dehydrogenase deficiency (SSADHD) was performed in conjunction with four parallel series of control tissues. Amino acids, acylcarnitines, guanidino- species (guanidinoacetic acid, creatine, creatinine) and GABA-related intermediates were quantified using UPLC and mass spectrometric methods that included isotopically labeled internal standards. Amino acid analyses revealed significant elevation of aspartic acid and depletion of glutamine in patient tissues. Evidence for disruption of short-chain fatty acid metabolism, manifest as altered C4OH, C5, C5:1, C5DC (dicarboxylic) and C12OH carnitines, was observed. Creatine and guanidinoacetic acids were decreased and elevated, respectively. GABA-associated metabolites (total GABA, γ-hydroxybutyric acid, succinic semialdehyde, 4-guanidinobutyrate, 4,5-dihydroxyhexanoic acid and homocarnosine) were significantly increased in patient tissues, including liver and kidney. The data support disruption of fat, creatine and amino acid metabolism as a component of the pathophysiology of SSADHD, and underscore the observation that metabolites measured in patient physiological fluids provide an unreliable reflection of brain metabolism.
- Published
- 2020
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45. A Remarkable Difference That One Fluorine Atom Confers on the Mechanisms of Inactivation of Human Ornithine Aminotransferase by Two Cyclohexene Analogues of γ-Aminobutyric Acid.
- Author
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Zhu W, Doubleday PF, Catlin DS, Weerawarna PM, Butrin A, Shen S, Wawrzak Z, Kelleher NL, Liu D, and Silverman RB
- Subjects
- Cyclohexanecarboxylic Acids chemical synthesis, Cyclohexanecarboxylic Acids metabolism, Cyclohexylamines chemical synthesis, Cyclohexylamines metabolism, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors metabolism, Humans, Hydrocarbons, Fluorinated chemical synthesis, Hydrocarbons, Fluorinated metabolism, Models, Chemical, Molecular Docking Simulation, Molecular Dynamics Simulation, Molecular Structure, Ornithine-Oxo-Acid Transaminase chemistry, Ornithine-Oxo-Acid Transaminase metabolism, Protein Binding, Pyridoxal Phosphate chemistry, gamma-Aminobutyric Acid analogs & derivatives, Cyclohexanecarboxylic Acids chemistry, Cyclohexylamines chemistry, Enzyme Inhibitors chemistry, Hydrocarbons, Fluorinated chemistry, Ornithine-Oxo-Acid Transaminase antagonists & inhibitors
- Abstract
Human ornithine aminotransferase ( h OAT), a pyridoxal 5'-phosphate-dependent enzyme, plays a critical role in the progression of hepatocellular carcinoma (HCC). Pharmacological selective inhibition of h OAT has been shown to be a potential therapeutic approach for HCC. Inspired by the discovery of the nonselective aminotransferase inactivator (1 R ,3 S ,4 S )-3-amino-4-fluoro cyclopentane-1-carboxylic acid ( 1 ), in this work, we rationally designed, synthesized, and evaluated a novel series of fluorine-substituted cyclohexene analogues, thereby identifying 8 and 9 as novel selective h OAT time-dependent inhibitors. Intact protein mass spectrometry and protein crystallography demonstrated 8 and 9 as covalent inhibitors of h OAT, which exhibit two distinct inactivation mechanisms resulting from the difference of a single fluorine atom. Interestingly, they share a similar turnover mechanism, according to the mass spectrometry-based analysis of metabolites and fluoride ion release experiments. Molecular dynamics (MD) simulations and electrostatic potential (ESP) charge calculations were conducted, which elucidated the significant influence of the one-fluorine difference on the corresponding intermediates, leading to two totally different inactivation pathways. The novel addition-aromatization inactivation mechanism for 9 contributes to its significantly enhanced potency, along with excellent selectivity over other aminotransferases.
- Published
- 2020
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46. Severe phenibut poisoning: An adolescent case cluster.
- Author
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Isoardi KZ, Kulawickrama S, and Isbister GK
- Subjects
- Adolescent, Humans, Poisoning, gamma-Aminobutyric Acid analogs & derivatives
- Published
- 2020
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47. Effects of Gaba Derivatives on Anxious and Compulsive Behavior in Offspring of Rats with Experimental Preeclampsia.
- Author
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Muzyko EA, Tkacheva GA, Perfilova VN, Matvienko LS, Naumenko LV, Vasil'eva OS, and Tyurenkov IN
- Subjects
- Animals, Animals, Outbred Strains, Anti-Anxiety Agents pharmacology, Anxiety chemically induced, Anxiety metabolism, Anxiety physiopathology, Behavior, Animal drug effects, Female, Male, Obsessive-Compulsive Disorder chemically induced, Obsessive-Compulsive Disorder metabolism, Obsessive-Compulsive Disorder physiopathology, Pantothenic Acid analogs & derivatives, Pantothenic Acid pharmacology, Pre-Eclampsia chemically induced, Pre-Eclampsia metabolism, Pre-Eclampsia physiopathology, Pregnancy, Prenatal Exposure Delayed Effects chemically induced, Prenatal Exposure Delayed Effects metabolism, Prenatal Exposure Delayed Effects physiopathology, Rats, Sodium Chloride administration & dosage, Tranquilizing Agents pharmacology, gamma-Aminobutyric Acid pharmacology, Anxiety drug therapy, GABA Agonists pharmacology, Obsessive-Compulsive Disorder drug therapy, Pre-Eclampsia drug therapy, Prenatal Exposure Delayed Effects drug therapy, gamma-Aminobutyric Acid analogs & derivatives
- Abstract
We studied the effects of GABA derivatives on anxious and compulsive behavior of progeny of rats with experimental preeclampsia provoked by replacement of drinking water for 1.8% NaCl solution from the first day of pregnancy to delivery. In comparison with progeny of health rats, the offspring of dams with complicated pregnancy demonstrated high level of anxiety and the development of obsessive-compulsive disorder both at the early (40 and 70 days) and late (6 and 12 months) stages of ontogeny. GABA derivatives succicard, salifen, and phenibut reduced symptoms of experimental preeclampsia in offspring of various age by decreasing the level of anxiety and reducing compulsive behavior. The efficacy of the examined derivatives was similar to that of the reference drug Pantogam.
- Published
- 2020
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48. M-Channel Activation Contributes to the Anticonvulsant Action of the Ketone Body β -Hydroxybutyrate.
- Author
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Manville RW, Papanikolaou M, and Abbott GW
- Subjects
- 3-Hydroxybutyric Acid metabolism, Animals, Anticonvulsants metabolism, Binding Sites, Drug Therapy, Combination, Electrophysiology, Humans, Ketosis metabolism, Mice, Models, Animal, Molecular Docking Simulation, Patch-Clamp Techniques, Pentylenetetrazole pharmacology, Protein Binding, Protein Conformation, Signal Transduction, Tryptophan metabolism, Xenopus laevis, gamma-Aminobutyric Acid analogs & derivatives, gamma-Aminobutyric Acid pharmacology, 3-Hydroxybutyric Acid pharmacology, Anticonvulsants pharmacology, KCNQ2 Potassium Channel metabolism, KCNQ3 Potassium Channel metabolism
- Abstract
Ketogenic diets are effective therapies for refractory epilepsy, yet the underlying mechanisms are incompletely understood. The anticonvulsant efficacy of ketogenic diets correlates positively to the serum concentration of β -hydroxybutyrate (BHB), the primary ketone body generated by ketosis. Voltage-gated potassium channels generated by KCNQ2-5 subunits, especially KCNQ2/3 heteromers, generate the M-current, a therapeutic target for synthetic anticonvulsants. Here, we report that BHB directly activates KCNQ2/3 channels (EC
50 = 0.7 µ M), via a highly conserved S5 tryptophan (W265) on KCNQ3. BHB was also acutely effective as an anticonvulsant in the pentylene tetrazole (PTZ) seizure assay in mice. Strikingly, coadministration of γ -amino- β -hydroxybutyric acid, a high-affinity KCNQ2/3 partial agonist that also acts via KCNQ3-W265, similarly reduced the efficacy of BHB in KCNQ2/3 channel activation in vitro and in the PTZ seizure assay in vivo. Our results uncover a novel, unexpected molecular basis for anticonvulsant effects of the major ketone body induced by ketosis. SIGNIFICANCE STATEMENT: Ketogenic diets are used to treat refractory epilepsy but the therapeutic mechanism is not fully understood. Here, we show that clinically relevant concentrations of β -hydroxybutyrate, the primary ketone body generated during ketogenesis, activates KCNQ2/3 potassium channels by binding to a specific site on KCNQ3, an effect known to reduce neuronal excitability. We provide evidence using a mouse chemoconvulsant model that KCNQ2/3 activation contributes to the antiepileptic action of β -hydroxybutyrate., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)- Published
- 2020
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49. [Phenibut: harmless dietary supplement or dangerous drug?]
- Author
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Evenepoel J and Titeca K
- Subjects
- Adult, Dietary Supplements, Humans, Male, Psychotropic Drugs adverse effects, Young Adult, Pharmaceutical Preparations, gamma-Aminobutyric Acid analogs & derivatives
- Abstract
In clinical practice, more and more alarming signals are picked up concerning addiction and withdrawal after the use of Phenibut. Phenibut is a psychotropic agent that acts on gaba receptors. Phenibut is freely available online as a dietary supplement, but appears to have potent and potentially harmful psychotropic effects. We describe the case of a 19-year-old man with social anxiety who self-medicated by using Phenibut, which he subsequently got addicted to. We outline the dangers linked to the use of Phenibut and offer suggestions for treatment.
- Published
- 2020
50. Drug Repositioning: Antimalarial Activities of GABA Analogs in Mice Infected with Plasmodium berghei .
- Author
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Ayankunle AA, Wakeel OK, Kolawole OT, Oyekale AO, Ojurongbe O, and Adeyeba OA
- Subjects
- Animals, Antimalarials pharmacology, Female, Gabapentin pharmacology, Gabapentin therapeutic use, Malaria physiopathology, Male, Mice, Plasmodium berghei physiology, Pregabalin pharmacology, Pregabalin therapeutic use, gamma-Aminobutyric Acid pharmacology, Antimalarials therapeutic use, Drug Repositioning methods, Malaria drug therapy, Plasmodium berghei drug effects, gamma-Aminobutyric Acid analogs & derivatives, gamma-Aminobutyric Acid therapeutic use
- Abstract
Background: Drug repositioning is becoming popular due to the development of resistance to almost all the recommended antimalarials. Pregabalin and gabapentin are chemical analogs of gamma- aminobutyric acid (GABA) approved for the treatment of epilepsy and neuropathic pain., Objective: This study investigates acute toxicities and antimalarial activities of pregabalin and gabapentin in the murine malarial model., Methods: Acute toxicities were assessed using the method of Lorke, while curative activities were assessed by the administration of serial doses of pregabalin and gabapentin to Plasmodium berghei infected mice. Pregabalin was further investigated for its prophylactic activity, and curative potential when combined with either artesunate or amodiaquine. All drugs were freshly prepared and administered orally. Thin films were collected, stained, and observed under the microscope for the estimation of parasitemia and calculation of percentage chemoinhibition or chemoprevention. In pregabalin -artesunate or -amodiaquine combination aspect of this study, survival day post-infection (SDPI) was recorded, while parasitemia was re-estimated for animals that survived till day 28., Results: The oral LD50 of gabapentin, as well as pregabalin, was >5,000 mg/kg. Gabapentin at 100 and 200 mg/Kg demonstrated 35.64% and -12.78% chemoinhibition, respectively, while pregabalin demonstrated 75.60% and 100.00% chemoinhibition at doses of 12.5 and 25 mg/Kg, respectively. Moreover, pregabalin at individual doses of 25, 50 mg/Kg, and in combination with either artesunate or amodiaquine demonstrated 100.00% chemoinhibition. In its prophylactic study, pregabalin was found to be 100% chemopreventive at individual doses of 12.5 and 25 mg/Kg., Conclusion: Both GABA analogs have antimalarial properties, but pregabalin proved to be more efficacious., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2020
- Full Text
- View/download PDF
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