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•Acute neuropathic pain after SCI can be present at- and below-level.•Multiple sources of pain challenge the diagnosis in the acute phase after injury.•Distinct neuropathic pain phenotypes develop as a function of time since injury.

Homozygous familial hypercholesterolemia is caused by mutations in the low-density lipoprotein receptor gene. It is diagnosed in children or youth who present with extensive tendinous and cutaneous xanthomas and extreme elevation of low-density lipoprotein cholesterol. Untreated, premature coronary artery disease develops in the teenage years or earlier and survival to ages older than 30 years is rare. Herein we describe the clinical course of a patient with homozygous familial hypercholesterolemia treated according to the standards of care and experimental approaches. Despite aggressive therapies, atherosclerosis in all vascular beds progressed, leading to the patient’s demise at age 59 years, highlighting the importance of early diagnosis and appropriate follow-up.

Patients with homozygous and heterozygous familial hypercholesterolemia (HeFH) develop severe aortic calcifications in an age- and gene dosage-dependent manner. The purpose of this study was to determine the rate of progression of aortic calcification in patients with HeFH.

Study Design:Validation study.Objectives:To describe the development and validation of a computerized application of the international standards for neurological classification of spinal cord injury (ISNCSCI).Setting:Data from acute and rehabilitation care.Methods:The Rick Hansen Institute-ISNCSCI Algorithm (RHI-ISNCSCI Algorithm) was developed based on the 2011 version of the ISNCSCI and the 2013 version of the worksheet. International experts developed the design and logic with a focus on usability and features to standardize the correct classification of challenging cases. A five-phased process was used to develop and validate the algorithm. Discrepancies between the clinician-derived and algorithm-calculated results were reconciled.Results:Phase one of the validation used 48 cases to develop the logic. Phase three used these and 15 additional cases for further logic development to classify cases with ‘Not testable’ values. For logic testing in phases two and four, 351 and 1998 cases from the Rick Hansen SCI Registry (RHSCIR), respectively, were used. Of 23 and 286 discrepant cases identified in phases two and four, 2 and 6 cases resulted in changes to the algorithm. Cross-validation of the algorithm in phase five using 108 new RHSCIR cases did not identify the need for any further changes, as all discrepancies were due to clinician errors. The web-based application and the algorithm code are freely available at www.isncscialgorithm.com.Conclusion:The RHI-ISNCSCI Algorithm provides a standardized method to accurately derive the level and severity of SCI from the raw data of the ISNCSCI examination. The web interface assists in maximizing usability while minimizing the impact of human error in classifying SCI.Sponsorship:This study is sponsored by the Rick Hansen Institute and supported by funding from Health Canada and Western Economic Diversification Canada.

Caveolin 1 expression is down-regulated in various cancer cell lines. Interestingly, in several drug-resistant cancer cells, a strong induction of caveolin 1 expression has been reported suggesting a role for caveolin 1 in the acquisition and/or the maintenance of multidrug resistance phenotype. In addition, it was reported that p-glycoprotein localized to caveolin-rich membrane domains in these cells. In this study, we progressively exposed A549 lung adenocarcinoma cells to increasing doses of etoposide. Both R1 and R2 cell lines had greatly increased levels of p-glycoprotein expression while mrp expression levels were moderately increased but only R2 cells had raised caveolin levels compared to control A549 cells. Both caveolin-1 and p-glycoprotein co-localize in Triton-insoluble membrane domains in all our cell lines but only caveolins-1 was solubilized by the addition of octylglucoside at 4C suggesting that these two proteins are located in different membrane domains. Using an anti-caveolin-1 antibody, we did not succeed to immunoprecipitate p-glycoprotein. Interestingly, total cellular cholesterol (the major lipid component of caveolae and triton-insoluble domains) was greatly increased in both R1 and R2 cell lines compared to naïve A549 cells.

Phentermine (Ib), N-hydroxymephentermine (Ic) and N-hydroxyphentermine (Id) were identified as metabolic products after in vitroincubation of mephentermine (Ia) with rabbit liver microsomal fractions. Compounds Ia, Ib and Ic were also identified as excretion products in the urine of a human subject given a single dose of mephentermine (Ia) sulphate. Derivatization with acetic anhydride, trifluoroacetic anhydride and the trimethylsilyl donor reagent N,O-bis-(trimethylsilyl)-trifluoroacetamide (BSTFA) or hexamethyldisilazane (HMDS) were used for qualitative identification of the metabolic products Ib–Id by g.l.c.-mass spectrometry and for quantitative determination of Ia–Id after extraction from rabbit hepatic homogenates. The synthesis of N-hydroxymephentermine (Ic) and the properties of the metabolic products are reported.

The microsomal N-oxidation of phentermine (Ia) to N-hydroxyphentermine (Ib) and to α,α-dimethyl-α-nitroso-β-phenylethane (Ic) was investigated. Maximum activities were obtained with microsomal (9000 gsupernatant and microsomes) fractions of rabbit liver in the presence of an NADPH generating system. Incubation of Ia with hepatic washed microsomes from a phenobarbitone pretreated rabbit increased the formation of Ib and decreased that of Ic but the total amount of N-oxidized metabolites (i.e. Ib + Ic) was not affected. The ratio of the metabolically produced Ic to Ib but not the total amount of N-oxygenated metabolites varied greatly depending of the liver microsomal fractions used in the incubation mixtures of Ia; more Ib was produced from Ia using 9000 gsupernatant and conversely, more Ic was formed using the washed microsomes of the same liver. The nitroso compound (Ic) was metabolically reduced to Ib and Ib to Ia by the hepatic 9000 gsupernatant and soluble fraction; under the same conditions, washed microsomes had only limited reductive properties towards Ic and Ib. N-Hydroxyphentermine (Ib) was not metabolically oxidized to Ic when incubated with washed microsomes from rabbit liver. The use of known carbon-oxidation inhibitors showed that cytochrome P-450 is not involved in the incorporation of oxygen at the nitrogen centre of Ia. The metabolic characteristics and kinetic behaviour of the microsomal N-oxidation of Ia supported a recently proposed mechanism explaining the independent formation of Ib and Ic from a common precursor resulting from metabolic N-oxidation of Ia.

Resolution of mexiletine enantiomers from the racemic mixture has been achieved by fractional crystallization through the formation of diastereoisomeric p-toluoyl tartrate salts. Following three crystallization steps in methanol, R-(–)- and S-(+)-mexiletine were resolved with an optical purity > 98 % (yield ∼ 30%) and their hydrochloride salts formed. Incremental doses of mexiletine enantiomers were administered to dogs with experimentally-induced arrhythmias to investigate the stereoselective antiarrhythmic and electrophysiological effects of these compounds. Using up to three extrastimuli, programmed electrical stimulation was performed in conscious animals 7–30 days after coronary ligation. R-(–)-Mexiletine prevented ventricular tachycardia in 3/6 dogs (2 after 0·5 mg kg−1, 1 after 8 mg kg−1); two animals died after 1 and 8 mg kg−1, respectively; one remained unchanged even at the highest dosage (16 mg kg−1). S-(+)-Mexiletine prevented ventricular tachycardia in only one dog (after 1 mg kg−1); two died after 4 and 8 mg kg−1, respectively; 2/5 remained unchanged even after the administration of 16 mg kg−1. No significant changes in any electrocardiographic intervals (PR, QRS, QTc) or refractory periods were induced by mexiletine enantiomers at any doses used (0·5–16·0 mg kg−1). These results suggest that R-(–)-mexiletine possesses greater antiarrhythmic properties than the opposite enantiomer.

It was reported previously that mexiletine undergoes stereoselective disposition in humans and that formation of three of its major metabolites co-segregates with polymorphic debrisoquin 4-hydroxylase (CYP2D6) activity. In this study, the hypothesis was tested that the CYP2D6-mediated oxidation pathways of mexiletine are responsible for the stereoselective disposition of the racemate in humans. Fourteen healthy subjects (10 extensive metabolizers [EMs] and 4 poor metabolizers [PMs]) participated in this study. They received a single 200-mg oral dose of racemic mexiletine hydrochloride on two occasions: once alone and once during administration of low-dose quinidine (50 mg four times a day). Blood and urine samples were obtained over 48 hr after the administration of mexiletine and analyzed by a stereoselective high-performance liquid chromatography assay. As reported previously, RS-mexiletine disposition was altered by a genetically determined (PM) or drug-induced (quinidine) decrease in CYP2D6 activity. In contrast, R/S ratio of the apparent total and nonrenal clearances of mexiletine and the R/S ratio of the urinary recovery of both enantiomers were similar in EMs and PMs. Moreover, these ratios were unaltered by quinidine administration. Partial metabolic clearance of N-hydroxymexiletine glucuronide, a non-CYP2D6 dependent metabolite, was highly stereoselective; the R/S ratio was 11.3 +/- 3.4. This ratio was similar in subjects with either an EM or a PM phenotype and was not altered by quinidine administration. Thus, the results obtained in this study suggest that non-CYP2D6-dependent metabolic pathways are responsible for the stereoselective disposition of mexiletine in humans.

In order to determine the effect of inflammation on the kinetics and dynamics of tolbutamide, two groups of seven and nine New Zealand rabbits received 50 mg/kg tolbutamide before and 48 hr after the production of an inflammatory reaction generated by the s.c. administration of turpentine in both hind legs. Tolbutamide in plasma and its two major metabolites (hydroxytolbutamide) and carboxytolbutamide in urine were assayed by high-performance liquid chromatography. The influence of inflammation on hepatic cytochrome P-450 was assessed by 1) determining the hepatic concentration in cytochrome P-450 and b5, 2) characterizing the activity of tolbutamide hydroxylase, 3) isolating hepatic microsomal protein bands by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and 4) measuring the concentrations of hepatic cytochrome P-450 isozymes LM-2 and LM-3c. The inflammatory reaction induced a marked decrease in tolbutamide total body clearance, secondary to a reduction in its metabolic clearance. Concerning the metabolites, hydroxytolbutamide metabolic rate constant and the fraction of the dose recovered in urine as carboxytolbutamide were diminished. Tolbutamide hypoglycemic response was not significantly affected by the inflammatory process. The Vmax of tolbutamide hydroxylase was reduced from 14.6 +/- 2.3 to 5.6 +/- 1.4 nmol/mg/60 min (P less than .05), and the Km remained unchanged. The concentration of hepatic cytochrome P-450 was reduced in turpentine-treated rabbits, whereas the cytochrome b5 concentration remained the same in both groups. The systemic inflammation also reduced the content in the 48, 52, 54 and 60 kDa protein bands from hepatic microsomes and the concentration of the LM-3c form.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study was designed to determine whether biological rhythm variations could be detected in the hypotensive action of prostaglandin E2 (PGE2) and arachidonic acid (AA) in normal rats. Doses of 1.0 μg kg-1 of PGE2 or 0.5 mg kg-1 of AA were administered to pentobarbital-anesthetized rats at 6 times of the day. Maximal reduction of systolic and diastolic blood pressures was obtained when PGE2 or AA were administered to rats between 0930 and 1200. The lowest falls in blood pressure were found when the same doses of the two substances were injected between 0300 and 0500. Mechanisms to explain these circadian variations are suggested.

Mexiletine is a low clearance drug which undergoes extensive metabolism in man. In vitro studies with human liver microsomes have suggested that major oxidation pathways of mexiletine are predominantly catalyzed by the genetically determined debrisoquine 4-hydroxylase (cytochrome P450IID6) activity. In this study, we investigated the role of debrisoquine polymorphism and the effects of low dose quinidine, a selective inhibitor of cytochrome P450IID6, on the disposition of mexiletine. Fourteen healthy volunteers, 10 with the extensive metabolizer (EM) and 4 with the poor metabolizer (PM) phenotype, received a single 200-mg dose of mexiletine hydrochloride orally on two occasions (1 week apart), once alone and once under steady-state conditions for quinidine (50 mg QID). During the phase mexiletine alone, total clearance, nonrenal clearance and partial metabolic clearance of mexiletine to hydroxymethylmexiletine, to m-hydroxymexiletine and to p-hydroxymexiletine were decreased in PM compared to EM (all P less than .05). In EM, quinidine decreased mexiletine total clearance from 621 +/- 298 to 471 +/- 214 ml/min (mean +/- S.D.; P less than .05) and mexiletine nonrenal clearance from 583 +/- 292 to 404 +/- 188 ml/min (P less than .05). Moreover, quinidine increased mexiletine elimination half-life in EM from 9 +/- 1 to 11 +/- 2 h (P less than .05). In these subjects, partial metabolic clearance to hydroxymethylmexiletine, m-hydroxymexiletine and p-hydroxymexiletine were decreased by quinidine coadministration 5-, 4- and 7-fold, respectively, whereas partial metabolic clearance to N-hydroxymexiletine was unaffected. Changes induced by quinidine in EM were correlated to their debrisoquine metabolic ratio. Thus, genetically determined or pharmacologically induced modulation of cytochrome P450IID6 activity represents a major determinant of mexiletine disposition.

As the coronavirus disease 2019 (COVID-19) pandemic second wave is emerging, it is of the upmost importance to screen the population immunity in order to keep track of infected individuals. Consequently, immunoassays for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with high specificity and positive predictive values are needed to obtain an accurate epidemiological picture.

The electron impact induced fragmentation of seven derivatives of trans-2-phenylcyclopropane substituted at position one with functional groups like amino (tranylcypromine), trifluoroacetamido, cyano, carboxylic acid, carboxylic acid chloride, carboxamide and carboxylate methyl ester was investigated. Mechanisms are proposed for the formation of the major ions of each compound. The nature of the substituent determined the relative abundances of [M]+?, [M-1]+, [M-R]+, [M-RH]+?, [M-C6H5]+and m/z115 ions. A molecular ion was present in all spectra except that of carboxylic acid chloride substituted compound. In most cases, metastable peaks are involved in the decomposition of the most abundant ions. An interesting elimination mechanism involving the opening of the cyclopropane ring to yield a 4-membered cyclic ion at m/z56 was obtained in the spectrum of trans-1-amino-2-phenylcyclopropane. All the above compounds gave mass spectra containing diagnostic fragment ions which are of great value for identification purposes.