Unexpected Discoveries Should Be Reconsidered in Science-A Look to the Past?

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.

Medical Devices; Clinical Chemistry and Clinical Toxicology Devices; Classification of the Meprobamate Test System. Final order.

The Food and Drug Administration (FDA or we) is classifying the meprobamate test system into class II (special controls). The special controls that apply to the device type are identified in this order and will be part of the codified language for the meprobamate test system's classification. We are taking this action because we have determined that classifying the device into class II (special controls) will provide a reasonable assurance of safety and effectiveness of the device. We believe this action will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens.

[What happened after meprobamate's withdrawal? Survey in two nursing homes]. / Enquête dans deux Ehpad sur le retrait du méprobamate.

We have conducted in two nursing homes a survey to study the impact of meprobamate's withdrawal, at the beginning of 2012, in terms of extent of prescribing to others psychotropic drugs and occurrence of adverse events. After meprobamate's withdrawal, 65 % of residents did not receive alternative medication and within three months after meprobamate stopping, adverse events (drowsiness, falls and hospitalization) decreased while agitation did not increase.

Using bone marrow matrix to analyze meprobamate for forensic toxicological purposes.

Bone marrow (BM) analysis is of forensic interest for postmortem toxicological investigations where blood samples are unavailable or unusable. Due to the lack of studies, it remains difficult to interpret concentrations of xenobiotics measured in this matrix. Based on a statistical approach published previously to interpret meprobamate concentrations in bile and vitreous humor, we propose here a diagnostic test for interpretation of BM meprobamate concentrations from analysis of 99 sets of autopsy data. The mean age was 48 years (range 18-80 years, one unknown) for males and 50 years (range 19-80 years, one unknown) for females, with a male/female ratio at 0.768. A BM concentration threshold of 11.3 µg/g was found to be statistically equivalent to that of a blood meprobamate concentration threshold of 50 µg/ml in distinguishing overdose from therapeutic use. The intrinsic qualities of this diagnostic test were good with sensitivity of 0.82 and specificity of 0.92. Compared to previous tests published with the same objective on vitreous humor and bile, this study shows that BM is a useful alternative matrix to reveal meprobamate overdose when blood, vitreous humor, and bile are not available or unusable.

CYP2C19 genetics in fatal carisoprodol intoxications.

INTRODUCTION: Carisoprodol, a frequently used muscle relaxant, can cause potentially fatal intoxications. Conversion to its active metabolite meprobamate is almost solely mediated by cytochrome P450 2C19 (CYP2C19), and mutations in this enzyme could have significant effects on serum concentrations. The objective of this study was to investigate the role of CYP2C19 genetics in mortalities due to carisoprodol intoxication. METHODS: The frequencies of CYP2C19 variant alleles were compared between the study group (n = 75) and two control groups, i.e. (1) deaths where carisoprodol was detected in the blood of the deceased, but intoxication was not the cause of death (control group A, n = 38), and (2) a healthy population not using carisoprodol (control group B, n = 185). In the study group and control A, the concentrations of carisoprodol and meprobamate were compared between the different genotype subgroups. RESULTS: The variant allele frequencies of CYP2C19 did not differ significantly between the study group and control groups. Moreover, no statistically significant difference in the concentrations of carisoprodol and meprobamate between the different genotype subgroups was found. CONCLUSIONS: This study finds no evidence for an important association between CYP2C19 genetics and mortality risk of carisoprodol. Other factors, such as co-administration with other drugs, likely play a more important role.

Acute hand ischemia after intra-arterial injection of meprobamate powder.

BACKGROUND: Meprobamate tablets contain microcrystalline cellulose, a potent embolic agent that has been shown to cause gangrene in animal studies. Microvascular embolization caused by microcrystalline cellulose can contribute to the ischemic process. OBJECTIVE: We report a case of acute hand ischemia after accidental intra-arterial injection of crushed meprobamate powder in a 23-year-old male drug abuser. CASE REPORT: The distal tips of the patient's right thumb, index finger, ring finger, and little finger continued to develop gangrene despite medical therapy with heparinization, low molecular-weight dextran infusion, corticosteroid administration, and hyperbaric oxygen therapy. CONCLUSION: We believe this is the first case of acute limb ischemia caused by intra-arterial injection of meprobamate powder documented in humans. Emergency physicians should be aware that accidental intra-arterial injection of crushed oral drug formulations is potentially limb threatening and prompt recognition of similar clinical scenarios is of vital importance.

[Severe meprobamate poisoning: description of 146 cases in a French department]. / Intoxications graves au méprobamate : description d'une série de 146 cas dans le département de la Loire.

Meprobamate poisoning are serious and sometimes fatal. Faced with a potential stop of marketing, we conducted a multicenter retrospective study to assess the severity criteria presented by patients admitted to the ICU for severe meprobamate poisoning, whether with alone form or in combination with aceprometazine. One hundred fourty-six patients have been enrolled between January 2005 and June 2011: 38 had a single meprobamate poisoning, 104 to meprobamate and aceprometazine and 4 to both forms. At admission, 88% of patients exhibited coma (Glasgow ≤ 7) and half of them a systolic blood pressure ≤ 90 mmHg. Mortality rate was 3%. Our results did not find any significant between-group difference, either in regard of clinical or biological severity criteria. These data argue for a cessation of marketing of all meprobamate-based specialities.

Rapid Extraction and Qualitative Screening of 30 Drugs in Oral Fluid at Concentrations Recommended for the Investigation of DUID Cases.

A rapid, simple extraction method followed by qualitative screening using liquid chromatography-tandem mass spectrometry (LC-MS-MS) for drugs in oral fluid is presented. The decision points were selected to be at, or lower, than those recommended as Tier I compounds by the National Safety Council's Alcohol, Drugs and Impairment Division for toxicological investigation of driving under the influence of drug (DUID) cases and were also at, or lower, than those recommended by Substance Abuse and Mental Health Service Administration and the Department of Transportation for Federal workplace drug testing programs. The method included 30 drugs: delta-9-tetrahydrocannabinol, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyamphetamine, cocaine, benzoylecgonine, carisoprodol, meprobamate, zolpidem, alprazolam, clonazepam, 7-aminoclonazepam, diazepam, nordiazepam, lorazepam, oxazepam, temazepam, codeine, morphine, 6-acetylmorphine, buprenorphine, fentanyl, hydrocodone, hydromorphone, oxycodone, oxymorphone, methadone, tramadol and phencyclidine. Phencyclidine was included because it is in the Federal workplace program even though it is considered a Tier II drug for DUID cases. A liquid-liquid extraction method using isopropanol, hexane and ethyl acetate to extract drugs from the oral fluid-buffer mix collected in a Quantisal™ device, followed by LC-MS-MS screening, was developed and validated according to ANSI/ASB 2019 Standard Practices for Method Validation in Forensic Toxicology. Interference studies, limit of detection, precision at the decision point, ionization suppression/enhancement and processed sample stability were determined for each drug. The method was successfully applied to proficiency specimens and routine samples received in the laboratory.

Interpretation of drug concentrations in an alternative matrix: the case of meprobamate in vitreous humor.

The use of vitreous humor (VH) as an alternative matrix to blood in the field of forensic toxicology has been described for numerous drugs. Interpretation of drug concentrations measured in VH, as in other matrices, requires statistical analysis of a data set obtained on a significant series. In the present study, two diagnostic tests interpreting postmortem VH concentrations of meprobamate in 117 sets of autopsy data are reported. (1) A VH meprobamate concentration threshold of 28 mg/l was statistically equivalent to that of blood meprobamate concentration threshold of 50 mg/l distinguishing overdose from therapeutic use in blood. The intrinsic qualities of the test were good, with sensitivity of 0.95 and absolute specificity of 1. (2) A novel interpretation tool is proposed, allowing blood concentration range to be evaluated, with a known probability, from VH concentration.

Acute pancreatitis in the course of meprobamate poisoning.

CONTEXT: We report a case of massive poisoning with meprobamate leading to acute pancreatitis. CASE REPORT: A 43-year-old patient with a history of schizophrenia and multiple suicide attempts was admitted to the intensive care unit for severe poisoning with meprobamate (voluntary ingestion of 60 g). On admission, the patient was deeply comatose with low blood pressure and hypothermia. Laboratory analysis revealed leukocytosis and high lipase and amylase serum levels. There was no eosinophilia. Abdominal computed tomography showed pancreatitis grade A. The patient was intubated and ventilated, and intravenous dopamine was infused. The patient regained consciousness and was extubated five days later. Improvement in pancreatic tests was noted several days later. The outcome was favorable. DISCUSSION: According to the Naranjo probability scale, meprobamate-induced acute pancreatitis was probable. Acute pancreatitis in meprobamate poisoning is exceptional. The pathogenesis of pancreatitis-induced meprobamate poisoning may be explained by two mechanisms: stimulation of pancreatic secretion secondary to cholinergic activation and pancreatic ductal hypertension. CONCLUSIONS: The signs of severe meprobamate toxicity are numerous including cardiovascular and central nervous symptoms. Acute pancreatitis should also be added as a possible manifestation of meprobamate poisoning.

Inappropriate use of promethazine and promethazine-containing products in children under the age of three years in Harare, Zimbabwe.

OBJECTIVES: To determine whether there was inappropriate use of promethazine, Stopayne or Goldgesic in children under three (3) years of age in Harare, and to measure its extent. Inappropriate referred to administering these medicines to children under the age of two (2) years for any indication or the administering of these medicines to an otherwise healthy child less than three (3) years old for sedation purposes. DESIGN: A descriptive cross-sectional study carried out between May and July 2010. SETTING: Retail pharmacies in Harare, Zimbabwe. RESULTS: The percentages of pharmacy personnel who indicated that parents request these syrups for sedation purposes in their children were: 20.8% promethazine; 18.9% Stopayne; and 9.6% Goldgesic. With respect to parents, it was found that 25% administered these syrups to children aged below 2 years. Of the parents who administered these syrups to their children about 7.7% did so for sedation purposes. CONCLUSION: There was significant inappropriate use of all 3 syrups in children under the age of 3 years (p < 0.05). Direct evidence was seen in that pharmacy personnel dispensed these medicines for use in infants and parents administered these syrups to infants.

Simultaneous Determination of Paracetamol, Propyphenazone and Caffeine in Presence of Paracetamol Impurities Using Dual-Mode Gradient HPLC and TLC Densitometry Methods.

Two chromatographic methods were validated for the determination of the widely prescribed analgesic and antipyretic drug combination of paracetamol (PC) (recently integrated into the supportive treatment of COVID-19), propyphenazone (PZ) and caffeine (CF) in the presence of two PC impurities, namely 4-aminophenol and 4-nitrophenol. A "dual-mode" gradient high-performance liquid chromatography method was developed, where the separation was achieved via "dual-mode" gradient by changing both the ternary mobile phase composition (acetonitrile: methanol: water) and the flow rate. This enables a good resolution within a relatively shorter analysis time. The analysis was realized using Zorbax Eclipse XDB column C18, 5 µm (250 × 4.6 mm) and the UV detector was set at 220 nm. The other method is a thin-layer chromatography densitometry method, where the separation was achieved using a mobile phase composed of chloroform: toluene: ethyl acetate: methanol: acetic acid (6: 6: 1: 2: 0.1, by volume). Densitometric detection was performed at 220 nm on silica gel 60 F254 plates. The developed methods were fully validated as per the ICH guidelines and proved to be accurate, robust, specific and suitable for application as purity indicating methods for routine analysis of PC in pure form or in pharmaceuticals with PZ and CF in quality control laboratories.

Human health risk assessment of pharmaceuticals in water: an uncertainty analysis for meprobamate, carbamazepine, and phenytoin.

This study presents a step-wise development of a quantitative pharmaceutical risk assessment (QPhRA, hereafter) framework, including Monte Carlo uncertainty analysis for meprobamate, carbamazepine, and phenytoin during (1) accidental exposures of stream water and fish consumption and (2) direct ingestion of finished drinking water for children and adults. Average hazard quotients of these pharmaceuticals (i.e., the ratio of values of chronic daily intake to acceptable daily intake) were found to lie between 1x10(-10) and 3x10(-5) and 99 th percentile values of hazard quotients were found to be less than 1x10(-4) for both sub-populations, indicating no potential risks of adverse effects due to pharmaceuticals exposures. In addition, pharmaceutical concentrations were also observed to be lower than their respective calculated acceptable daily intake-equivalent drinking water levels, indicating no potential human health risks. To the authors' knowledge, for the first time in QPhRA studies, this study has attempted to characterize and quantify effects of factors, such as considerations for sensitive sub-populations using subpopulation-specific toxic endpoints and use of pharmaceutical concentrations in stream and finished drinking waters on risk estimates. Acceptable daily intake was observed to be the primary contributor (>93% variance contribution) in the overall uncertainties of estimates of hazard quotients, followed by fish consumptions and pharmaceutical concentrations in water. Further research efforts are required to standardize use of acceptable daily intake values to reduce large variability in estimation of hazard quotients.

Endocrine disruptors and pharmaceuticals: implications for water sustainability.

The presence of pharmaceuticals and endocrine disrupting compounds (EDCs) in the environment raises many questions about risk to the environment and risk to human health. Researchers have attributed adverse ecological effect effects to the presence of these compounds, particularly EDCs, though there is no consensus on what risk, if any, these compounds pose to human health. The scientific community is in the process of developing a better understanding of the occurrence, fate, and transport of pharmaceuticals and EDCs in the environment, including a better characterization of human exposure via drinking water. This paper provides a brief review of pharmaceuticals and EDCs in drinking water, as well as uses examples from Lake Mead, Nevada, USA, to highlight the issues associated with their fate and transport. Lastly, the effects of natural or anthropogenically driven processes, like natural seasonal flow or climate-change/prolonged drought are discussed as they are factors which can drastically alter environmental concentrations of these compounds. Without question, the propensity for the contamination of fresh water will rise as (1) human population continues to grow or (2) patterns of natural surface water slow and wastewater becomes a larger fraction of flow further highlighting the need for a more comprehensive understanding of their environmental behavior.

Serendipity and psychopharmacology.

This article describes several examples where the development of drugs and devices for use in psychiatry followed from initial serendipitous observations. The potential psychotropic properties of chlorpromazine (Thorazine(®)) were first noted in surgical patients when the drug was being investigated as a potentiator of anesthesia. Similar findings were noted with iproniazid (Marsilid(®)), developed for the treatment of tuberculosis, and the drug was later released for clinical use as an antidepressant agent. The development of meprobamate (Miltown(®)), an approved treatment for anxiety, evolved from initial efforts to find a chemical that would inhibit the enzymatic destruction of the antibiotic drug penicillin. The psychiatric uses of lamotrigine (Lamictal(®)) and vagus nerve stimulation were prompted by initial observations that epilepsy patients receiving these treatments had positive mood effects. Nurses should be familiar with the concept of serendipity, as they often are in the best position to observe, record, and report on unexpected clinical effects in patients taking any kind of prescription or nonprescription medication.

Carisoprodol pharmacokinetics and distribution in the nucleus accumbens correlates with behavioral effects in rats independent from its metabolism to meprobamate.

Carisoprodol (Soma®) is a centrally-acting skeletal-muscle relaxant frequently prescribed for treatment of acute musculoskeletal conditions. Carisoprodol's mechanism of action is unclear and is often ascribed to that of its active metabolite, meprobamate. The purpose of this study was to ascertain whether carisoprodol directly produces behavioral effects, or whether metabolism to meprobamate via cytochrome P450 (CYP450) enzymatic reaction is necessary. Rats were trained to discriminate carisoprodol (100 mg/kg) to assess time course and whether a CYP450 inhibitor (cimetidine) administered for 4 days would alter the discriminative effects of carisoprodol. Additionally, pharmacokinetics of carisoprodol and meprobamate with and without co-administration of cimetidine were assessed via in vivo microdialysis combined with liquid-chromatography-tandem mass spectrometry from blood and nucleus accumbens (NAc). The time course of the discriminative-stimulus effects of carisoprodol closely matched the time course of the levels of carisoprodol in blood and NAc, but did not match the time course of meprobamate. Administration of cimetidine increased levels of carisoprodol and decreased levels of meprobamate consistent with its interfering with metabolism of carisoprodol to meprobamate. However, cimetidine failed to alter the discriminative-stimulus effects of carisoprodol. Carisoprodol penetrated into brain tissue and directly produced behavioral effects without being metabolized to meprobamate. These findings indicate that understanding the mechanism of action of carisoprodol independently of meprobamate will be necessary to determine the validity of its clinical uses.

Carisoprodol-mediated modulation of GABAA receptors: in vitro and in vivo studies.

Carisoprodol is a frequently prescribed muscle relaxant. In recent years, this drug has been increasingly abused. The effects of carisoprodol have been attributed to its metabolite, meprobamate, a controlled substance that produces sedation via GABA(A) receptors (GABA(A)Rs). Given the structural similarities between carisoprodol and meprobamate, we used electrophysiological and behavioral approaches to investigate whether carisoprodol directly affects GABA(A)R function. In whole-cell patch-clamp studies, carisoprodol allosterically modulated and directly activated human alpha1beta2gamma2 GABA(A)R function in a barbiturate-like manner. At millimolar concentrations, inhibitory effects were apparent. Similar allosteric effects were not observed for homomeric rho1 GABA or glycine alpha1 receptors. In the absence of GABA, carisoprodol produced picrotoxin-sensitive, inward currents that were significantly larger than those produced by meprobamate, suggesting carisoprodol may directly produce GABAergic effects in vivo. When administered to mice via intraperitoneal or oral routes, carisoprodol elicited locomotor depression within 8 to 12 min after injection. Intraperitoneal administration of meprobamate depressed locomotor activity in the same time frame. In drug discrimination studies with carisoprodol-trained rats, the GABAergic ligands pentobarbital, chlordiazepoxide, and meprobamate each substituted for carisoprodol in a dose-dependent manner. In accordance with findings in vitro, the discriminative stimulus effects of carisoprodol were antagonized by a barbiturate antagonist, bemegride, but not by the benzodiazepine site antagonist, flumazenil. The results of our studies in vivo and in vitro collectively suggest the barbiturate-like effects of carisoprodol may not be due solely to its metabolite, meprobamate. Furthermore, the functional traits we have identified probably contribute to the abuse potential of carisoprodol.

Meprobamate reduces accuracy of physiological detection of deception.

Normal male subjects attempted to deceive an experimenter recording electrodermal, respiratory, an cardiovascular activity. Those who had ingested a placebo or nothing were detected with statistically significant frequency on the basis of their phasic electrodermal responses, which clearly distinguished them from truthful suspects. That was not the case with deceptive subjects who had ingested 400 milligrams of meprobamate, nor did the examiner detect which subjects had received the drug.

Interpretation of drug concentrations in an alternative matrix: the case of meprobamate in bile.

Investigating toxicological causes of death may require alternative matrices when the usual ones are lacking. Whereas forensic toxicology uses bile almost only for xenobiotic screening, a diagnostic test interpreting postmortem bile concentrations of meprobamate is reported. Based on 128 sets of autopsy data, its intrinsic qualities were good, with 0.95 sensitivity and 0.93 specificity. In a French forensic population, the positive and negative predictive factors were 0.90 and 0.97, respectively. It is a useful means of revealing overdoses where blood samples are not available or of confirming blood tests when postmortem redistribution is suspected.

Quantitative analysis of carisoprodol and meprobamate in whole blood using benzylcarbamate and deuterated meprobamate as internal standards.

Carisoprodol and meprobamate are frequently encountered drugs in impaired driving casework. Deuterated internal standards, although preferred, were not available until recently. Earlier published studies report the use of a variety of non-deuterated internal standards, many of which lack the chemical and physical similarities that are desired for quantitative analysis. Carisoprodol and meprobamate were determined in whole blood using solid-phase extraction and gas chromatography-mass spectrometry with benzylcarbamate and meprobamate-d(7) as internal standards. When benzylcarbamate was used as internal standard, the linear ranges for carisoprodol and meprobamate were 0-20 mg/L and 0-40 mg/L, respectively. The linear range increased to 100 mg/L when meprobamate-d(7) was used. Limits of detection for carisoprodol and meprobamate were 0.2 and 0.4 mg/L, respectively, regardless of the internal standard selection. The limit of quantitation for both drugs using either internal standard was 0.4 mg/L. Accuracies using benzylcarbamate and meprobamate-d(7) were 100-106% and 91-100%, respectively. Corresponding values for precision indicated intra-assay coefficients of variation of 2.6-4.3% for benzylcarbamate and 1.0-2.3% for meprobamate-d(7). No carryover was evident at 100 mg/L, the highest concentration tested, and no interferences were observed. Results indicated that either benzylcarbamate or meprobamate-d(7) is a suitable internal standard for quantitative determination of carisoprodol or meprobamate from whole blood.