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International Journal of Molecular... Aug 2019From the past, we know how much "serendipity" has played a pivotal role in scientific discoveries. The definition of serendipity implies the finding of one thing while...
From the past, we know how much "serendipity" has played a pivotal role in scientific discoveries. The definition of serendipity implies the finding of one thing while looking for something else. The most known example of this is the discovery of penicillin. Fleming was studying "Staphylococcus influenzae" when one of his culture plates became contaminated and developed a mold that created a bacteria-free circle. Then he found within the mold, a substance that proved to be very active against the vast majority of bacteria infecting human beings. Serendipity had a key role in the discovery of a wide panel of psychotropic drugs as well, including aniline purple, lysergic acid diethylamide, meprobamate, chlorpromazine, and imipramine. Actually, many recent studies support a step back in current strategies that could lead to new discoveries in science. This change should seriously consider the idea that to further focus research project milestones that are already too focused could be a mistake. How can you observe something that others did not realize before you? Probably, one pivotal requirement is that you pay a high level of attention on what is occurring all around you. But this is not entirely enough, since, specifically talking about scientific discoveries, you should have your mind sufficiently unbiased from mainstream infrastructures, which normally make you extremely focused on a particular endpoint without paying attention to potential "unexpected discoveries". Research in medicine should probably come back to the age of innocence and avoid the age of mainstream reports that do not contribute to real advances in the curing of human diseases. Max Planck said "Science progresses not because scientists change their minds, but rather because scientists attached to erroneous views die, and are replaced", and Otto Warburg used the same words when he realized the lack of acceptance of his ideas. This editorial proposes a series of examples showing, in a practical way, how unfocused research may contribute to very important discoveries in science.
Topics: Chlorpromazine; Humans; Imipramine; Lysergic Acid Diethylamide; Meprobamate; Psychotropic Drugs
PubMed: 31443232
DOI: 10.3390/ijms20163973 -
Epilepsia Mar 2021Since 1955, several alkyl-carbamates have been developed for the treatment of anxiety and epilepsy, including meprobamate, flupirtine, felbamate, retigabine,... (Comparative Study)
Comparative Study Review
Since 1955, several alkyl-carbamates have been developed for the treatment of anxiety and epilepsy, including meprobamate, flupirtine, felbamate, retigabine, carisbamate, and cenobamate. They have each enjoyed varying levels of success as antiseizure drugs; however, they have all been plagued by the emergence of serious and sometimes life-threatening adverse events. In this review, we compare and contrast their predominant molecular mechanisms of action, their antiseizure profile, and where possible, their clinical efficacy. The preclinical, clinical, and mechanistic profile of the prototypical γ-aminobutyric acidergic (GABAergic) modulator phenobarbital is included for comparison. Like phenobarbital, all of the clinically approved alkyl-carbamates share an ability to enhance inhibitory neurotransmission through modulation of the GABA receptor, although the specific mechanism of interaction differs among the different drugs discussed. In addition, several alkyl-carbamates have been shown to interact with voltage-gated ion channels. Flupirtine and retigabine share an ability to activate K currents mediated by KCNQ (Kv7) K channels, and felbamate, carisbamate, and cenobamate have been shown to block Na channels. In contrast to other alkyl-carbamates, cenobamate seems to be unique in its ability to preferentially attenuate the persistent rather than transient Na current. Results from recent randomized controlled clinical trials with cenobamate suggest that this newest antiseizure alkyl-carbamate possesses a degree of efficacy not witnessed since felbamate was approved in 1993. Given that ceno-bamate's mechanistic profile is unique among the alkyl-carbamates, it is not clear whether this impressive efficacy reflects an as yet undescribed mechanism of action or whether it possesses a unique synergy between its actions at the GABA receptor and on persistent Na currents. The high efficacy of cenobamate is, however, tempered by the risk of serious rash and low tolerability at higher doses, meaning that further safety studies and clinical experience are needed to determine the true clinical value of cenobamate.
Topics: Anticonvulsants; Carbamates; Chlorophenols; Epilepsy; Humans; Tetrazoles; Treatment Outcome
PubMed: 33580520
DOI: 10.1111/epi.16832 -
Acta Poloniae Pharmaceutica 2014The aim of this study was to discuss the therapeutic substances used to treat nicotine addiction, not registered in Poland. This paper presents the results of the latest... (Review)
Review
The aim of this study was to discuss the therapeutic substances used to treat nicotine addiction, not registered in Poland. This paper presents the results of the latest clinical trials and the possibility of their use in the treatment of nicotine addiction. The first two discussed drugs clonidine and nortriptyline are recommended by clinical practice guidelines AHRQ (Agency for Healthcare Research and Quality) as the substance of the second line in the fight against addiction. Nortriptyline belongs to tricyclic antidepressants. Its mechanism of action is the inhibition of the reuptake of norepinephrine. It is suggested as the antagonist of activity of nicotinic receptors. The results confirm its efficacy in the treatment of nicotine addiction, but many side effects limit its use. Clonidine acts presumably by inhibition of sympathetic hyperactivity characteristic of symptoms associated with nicotine rehab. The remaining compounds under discussion, such as: venlafaxine, fluoxetine, moclobemide and rimonabant, are not registered in any country with an indication to use in the treatment of nicotine addiction, however, due to the mechanism in which they act, the possibility of their use in the treatment of this disease is considered. The possibility of using anxiolytics such as: buspirone, diazepam, meprobamate and beta-blockers: metoprolol and oxprenolol is also considered in order to treat the anxiety appearing as one of the symptoms of abstinence. An interesting proposal to combat nicotine addiction are vaccines--NicVAX, CYT002-NicQb and TA-NIC. Currently, they are in clinical phase I and II of their development. Their operation would be based on the induction of specific antibodies that bind nicotine in the plasma, thus prevent it reaching the nicotinic receptors. Preliminary results confirm the possible positive effects in the prevention and treatment of nicotine addiction.
Topics: Aryl Hydrocarbon Hydroxylases; Cannabinoid Receptor Antagonists; Clinical Trials as Topic; Clonidine; Cytochrome P-450 CYP2A6; Humans; Nortriptyline; Tobacco Use Disorder; Vaccines
PubMed: 25272878
DOI: No ID Found -
Journal of Clinical Medicine Feb 2022Carisoprodol was authorised in 1959 without a full pharmacokinetic-pharmacodynamic (PK-PD) characterisation. We designed a crossover, double-blind, placebo-controlled,...
Single and Multiple Dose PK-PD Characterization for Carisoprodol. Part I: Pharmacokinetics, Metabolites, and 2C19 Phenotype Influence. Double-Blind, Placebo-Controlled Clinical Trial in Healthy Volunteers.
Carisoprodol was authorised in 1959 without a full pharmacokinetic-pharmacodynamic (PK-PD) characterisation. We designed a crossover, double-blind, placebo-controlled, randomized clinical trial to characterize the PKs of carisoprodol and its main active metabolite, meprobamate, after single (350 mg), multiple (350 mg/8 h, 14 days), and double (700 mg) doses of carisoprodol. Thirteen healthy volunteers were enrolled. After a single (350 mg) dose, the main carisoprodol parameters were (mean ± SD) Cmax: 2580 ± 1214 ng/mL, AUC: 8072 ± 6303 h·ng/mL, and half-life (T): 2 ± 0.8 h. For meprobamate, the parameters were Cmax: 2181 ± 605 ng/mL and 34,529 ± 7747 h·ng/mL y 9 ± 1.9 h. Different profiles were found for extensive and poor 2C19 metabolizers. After 14 days of treatment (350 mg/8 h) the results for carisoprodol were (mean ± SD) Cmax: 2504 ± 730 ng/mL, AUC: 7451 ± 3615 h·ng/mL, and T: 2 ± 0.7 h. For meprobamate (a steady state was reached), the parameters were Cmax: 5758 ± 1255 ng/mL and 79,699 ± 17,978 h·ng/mL y 8.7 ± 1.4 h. The study allowed for the full characterization of the pharmacokinetic profile of carisoprodol and meprobamate. Accumulation of meprobamate but not of carisoprodol was evident after 14 days of treatment.
PubMed: 35160309
DOI: 10.3390/jcm11030858 -
Journal of Mass Spectrometry : JMS Oct 2016We report the evaluation of several mass spectrometry-based methods for the determination of carisoprodol and meprobamate in samples obtained from the rat brain by in...
We report the evaluation of several mass spectrometry-based methods for the determination of carisoprodol and meprobamate in samples obtained from the rat brain by in vivo intracranial microdialyis. Among the techniques that aspire to perform analyses without chromatographic separation and thereby increase throughput, chip-based nanoelectrospray ionization and the use of an atmospheric pressure solids analysis probe fell short of requirements because of insufficient detection sensitivity and hard ionization, respectively. Although direct analysis in real time provided the required soft ionization, shortcomings of a tandem mass spectrometry-based assay also included inadequate detection sensitivity and, in addition, poor quantitative reproducibility. Therefore, liquid chromatography coupled with atmospheric pressure chemical ionization tandem mass spectrometry was developed to determine carisoprodol and meprobamate from artificial cerebrospinal fluid as the medium. No desalting and/or extraction of the samples was necessary. The assay, combined with in vivo sampling via intracranial microdialyis, afforded time-resolved concentration profiles for the drug and its major metabolite from the nucleus accumbens region of the brain in rats after systemic administration of carisoprodol. Copyright © 2016 John Wiley & Sons, Ltd.
Topics: Animals; Brain; Carisoprodol; Chromatography, High Pressure Liquid; Humans; Male; Meprobamate; Microdialysis; Rats, Sprague-Dawley; Reproducibility of Results; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry
PubMed: 27747995
DOI: 10.1002/jms.3799