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Objective: To determine whether erenumab is effective and safe in refractory chronic migraine with medication overuse headache. Methods: In this prospective, multicentric, real-life study, chronic migraine with medication overuse headache patients who received erenumab were recruited. Study inclusion was limited to patients who previously failed onabotulinumtoxinA in addition to at least three other pharmacological commonly used migraine preventive medication classes. Results: Of 396 patients who received erenumab, 38% (n = 149) met inclusion criteria. After 3 months, 51% (n = 76) and 20% (n = 30) patients achieved ≥ 50% and ≥ 75% reduction in monthly headache days, respectively. Monthly pain medications intake decreased from 46.1 ± 35.3 to 16.8 ± 13.9 (p < 0.001), while monthly headache days decreased from 25.4 ± 5.4 to 14.1 ± 8.6 (p < 0.001). Increasing efficacy of erenumab over the study period was observed. Allodynia was a negative predictive factor of erenumab response (odds ratio = 0.47; p = 0.03). Clinical conversion to episodic migraine with no medication overuse was observed in 64% (n = 96) patients. No serious adverse events were observed. Conclusions: Erenumab reduced significantly migraine frequency and pain medication intake in refractory chronic migraine with MOH patients. [ABSTRACT FROM AUTHOR]

Head and neck cancer (HNC) is the 6th most common cancer across the world, with a particular increase in HNC associated with human papilloma virus (HPV) among younger populations. Historically, the standard treatment for this disease consisted of combined surgery and radiotherapy or curative platinum-based concurrent chemoradiotherapy, with associated long term and late toxicities. However, HPV-positive HNC is recognized as a unique cancer subtype, typically with improved clinical outcomes. As such, treatment de-escalation strategies have been widely researched to mitigate the adverse effects associated with the current standard of care without compromising efficacy. These strategies include treatment de-escalation, such as novel surgical techniques, alternative radiation technologies, radiation dose and volume reduction, as well as neoadjuvant chemotherapies, immunotherapies, and combined therapies. Although these therapies show great promise, many of them are still under investigation due to hesitation surrounding their widespread implementation. The objective of this review is to summarize the most recent progress in de-escalation strategies and neoadjuvant therapies designed for HPV-positive HNC. While specific treatments may require additional research before being widely adopted, encouraging results from recent studies have highlighted the advantages of neoadjuvant chemotherapy and immunotherapy, as well as radiation and surgical de-escalation approaches in managing HPV-positive HNC. [Display omitted] • HPV+HNC is rising in incidence, but patients have better prognoses, warranting the investigation of de-escalation strategies to mitigate toxicities. • Reduced-dose radiotherapy and transoral surgery have been shown to limit adverse effects without compromising survival. • Taxane chemotherapies and immunomodulatory agents show promising anti-tumor activity in HPV+HNC when used in adjuvant and neoadjuvant settings. [ABSTRACT FROM AUTHOR]

[3H]Genipin was synthesized in a single step by Ir(I) catalyzed hydrogen isotope exchange. Conditions for selective exchange of the sp2 CH bond ortho to the methyl ester functionality were developed through deuterium modeling studies through a catalyst screen. Optimized conditions so obtained were then utilized with tritium gas to generate [3H]genipin at a specific activity of 18.5 Ci/mmol. Racemic [14C]genipin was prepared in eight steps in overall 5.4% radiochemical yield from potassium [14C]cyanide. [ABSTRACT FROM AUTHOR]

Extra-intestinal E. coli are emerging as a global threat due to their diffusion as opportunistic pathogens and, above all, to their wide set of antibiotic resistance determinants. There are still many gaps in our knowledge of their origin and spread pathways, although food animals have been adjudicated vehicles for passing mult-drug resistant bacteria to humans. This study analyzed 46 samples of meat purchased from retail stores in Palermo in order to obtain quinolone-resistant E. coli isolates. Strains were screened for their phylogenetic groups, ST131-associated single nucleotide polymorphisms (SNPs), and then typed by ERIC-PCR. Their set of virulence factors, namely, kpsMII, papA, sfaS, focG, iutA, papC, hlyD, and afa genes, were investigated and their fluoroquinolone-resistance determinants evaluated. The data obtained show a dramatically high prevalence of multidrug resistance patterns in the Palermo area, with 28% of the isolates having virulence factor genes typical of ExPEC strains. No B2 group or ST131 strains were detected. Moreover, 20% of our isolates showed positivity to all the plasmid-mediated quinolone resistance (PMQR) determinants, showing a potential to transfer these genes among other bacteria. Therefore, these data underline the possibility that food animals and, specifically, poultry in particular may be a significant source of resistant bacterial strains, posing a potential zoonotic risk. [ABSTRACT FROM AUTHOR]

Introduction: Metabolomics analysis depends on the identification and validation of specific metabolites. This task is significantly hampered by the absence of well-characterized reference standards. The one-carbon carrier 10-formyltetrahydrofolate acts as a donor of formyl groups in anabolism, where it is a substrate in formyltransferase reactions in purine biosynthesis. It has been reported as an unstable substance and is currently unavailable as a reference standard for metabolomics analysis. Objectives: The current study was undertaken to provide the metabolomics community thoroughly characterized 10-formyltetrahydrofolate along with analytical methodology and guidelines for its storage and handling. Methods: Anaerobic base treatment of 5,10-methenyltetrahydrofolate chloride in the presence of antioxidant was utilized to prepare 10-formyltetrahydrofolate. Results: Pure 10-formyltetrahydrofolate has been prepared and physicochemically characterized. Conditions toward maintaining the stability of a solution of the dipotassium salt of 10-formyltetrahydrofolate have been determined. Conclusion: This study describes the facile preparation of pure (>90%) 10-formyltetrahydrofolate, its qualitative physicochemical characterization, as well as conditions to enable its use as a reference standard in physiologic samples. [ABSTRACT FROM AUTHOR]

In order to gain additional information concerning the active conformation of the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (1) class of opioid receptor antagonists, procedures were developed for the synthesis of structurally rigid N-substituted-6-(3-hydroxyphenyl)3-azabicyclo[3.1.0]hexane and 3-methyl-4-(3-hydroxyphenyl)-4-azabicyclo[4.1.0]heptanes. Evaluation of the conformationally constrained series in a [35S]GTPγS assay showed that structural rigid compounds having the 3-hydroxyphenyl group locked in the piperidine equatorial orientation had potencies equal to or better than similar compounds having more flexible structures similar to 1. The studies of the rigid compounds also suggested that the 3-methyl group present in compound 1 type antagonists may not be necessary for their pure opioid antagonist properties. [ABSTRACT FROM AUTHOR]

The potent and selective KOR antagonist JDTic was derived from the N -substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of pure opioid antagonists. In previous studies we reported that compounds that did not have a hydroxyl on the 3-hydroxyphenyl group and did not have methyl groups at the 3- and 4-position of the piperidine ring were still potent and selective KOR antagonists. In this study we report JDTic analogs 2 , 3a – b , 4a – b , and 5 , where the 3-hydroxyphenyl ring has been replaced by a 2-, 3-, or 4-pyridyl or 3-thienyl group and do not have the 3-methyl or 3,4-dimethyl groups, remain potent and selective KOR antagonists. Of these, (3 R )-7-hydroxy- N -(1 S )-2-methyl-[4-methyl-4-pyridine-3-yl-carboxamide ( 3b ) had the best overall binding potency and selectivity in a [ 35 S]GTPγS functional assay, with a K e = 0.18 nM at the KOR and 273- and 16,700-fold selectivity for the KOR relative to the MOR and DOR, respectively. Calculated physiochemical properties for 3b suggest that it will cross the blood–brain barrier. [ABSTRACT FROM AUTHOR]

The design and discovery of JDTic as a potent and selective kappa opioid receptor antagonist used the N -substituted trans -3,4-dimethyl-4-(3-hydroxyphenyl)piperidine pharmacophore as the lead structure. In order to determine if the 3-methyl or 4-methyl groups were necessary in JDTic and JDTic analogs for antagonistic activity, compounds 4a – c , and 4d – f which have either the 3-methyl or both the 3- and 4-methyl groups removed, respectively, from JDTic and analogs were synthesized and evaluated for their in vitro opioid receptor antagonist activities using a [ 35 S]GTPγS binding assay. Other ADME properties were also assessed for selected compounds. These studies demonstrated that neither the 3-methyl or 3,4-dimethyl groups present in JDTic and analogs are required to produce potent and selective κ opioid receptor antagonists. [ABSTRACT FROM AUTHOR]

Over the last several years we have synthesized and studied the in vitro and in vivo nAChR pharmacological properties of epibatidine ( 4 ) analogs. In this study we report the synthesis, nAChR in vitro and in vivo pharmacological properties of 3′-(substituted pyridinyl)-deschloroepibatidine analogs ( 5a – e and 6a – e ). All of the analogs had high binding affinity for α4β2 ∗ -nAChRs. Several of the analogs were potent antagonists of α4β2-nAChRs in in vitro efficacy tests and were potent antagonists of nicotine-induced antinociception in the mouse tail-flick test. Compound 6b had a K i = 0.13 nM in the binding assay, 25- and 46-fold selectivity for the α4β2 ∗ -nAChR relative to the α3β4- and α7-nAChR, respectively, in the in vitro efficacy test and an AD 50 = 0.13 μg/kg in the tail-flick test. Combined with favorable calculated physiochemical properties compared to varenicline, our findings suggest that 6b should be considered for development as a potential pharmacotherapy for treating nicotine addiction and other CNS disorders. [ABSTRACT FROM AUTHOR]

The solubility and configurational composition (Z/ E) of SL 327, the only systemically administered MEK inhibitor, in physiologically relevant media has been determined using 1H NMR as well as reversed phase HPLC, thereby enabling dosing using clear solutions of known configurational composition. [Display omitted] • SL 327 (1.5 mg/mL) in not soluble in aqueous (85%) DMSO (15%). • SL 327 has minimal (~9%) solubility in aqueous medium containing 40% (and less) DMSO. • Crystalline SL 327 has the E -configuration. • The solvent determines the configurational composition of solid SL 327 obtained. • The configurational composition of SL 327 in solution mimics that of the solid. • The equilibrium configurational composition of SL 327 (0.14 mg/mL) is 70% -80% Z. • Equilibrium is reached after 2-3 hours in 100% DMSO and 15% DMSO/85% water. • Equilibrium is reached after 6-7 hours in methanol. • Dose formulations may result in different configurational compositions of SL 327. • Contradictory results reported for SL 327 in EtOH-CPP may be due to formulation. Inconsistent results have been reported for the effects of the mitogen-activating extracellular kinase (MEK) inhibitor α-[amino(4-aminophenyl)thio]methylene-2-(trifluoromethyl)benzeneacetonitrile (SL 327) on ethanol-induced conditioned place preference (EtOH-CPP). Since such inconsistencies may be due to the configurational composition of administered SL 327, the interconvertibility of the geometric isomers of this class of compounds has been investigated. This study provides conditions for determination of configurational composition of this class of compounds by HPLC and by 1H NMR and reports details of configurational equilibria as a function of medium and time in solution along with solubility data for SL 327 in aqueous DMSO. The results suggest that the apparently inconsistent results reported for CPP-EtOH may be due to the administration of suspension v s. solutions, as well as to different configurational compositions of SL 327. [ABSTRACT FROM AUTHOR]

In 38.6% of 88 patients without anamnesis of alcoholism and/or chronic exposure to hepatotoxic drugs, selected among 120 cirrhotic subjects subsequently observed, the illness was HBV related. Markers indicating active viral replication (anti-HBc, HBsAg, HBeAg or anti-HBe) were detected in 48% of patients with active cirrhosis, and in 26% with inactive cirrhosis. It is suggested that high titers of CF antibodies anti-HSV and anti-CMV observed in several patients, indicate either reactivation of latent infections or over-infections. The absence of alcoholism and/or chronic exposure to hepatotoxic drugs, and the absence of viral markers, suggest in 61% of the 88 cirrhotic subjects either a nonA-nonB viruses etiology of the illness, or other etiological factors that escape available diagnostic and prophylactic procedures.

Anti-HBc prevalence in alcoholics, chronic hepatotoxic drugs users, exposed to both these factors, and not exposed to alcohol and drugs cirrhotic patients was compared. Anti-HBc prevalence was significantly higher both in alcoholics and in hepatotoxic drugs users cirrhotic patients, and no statistically significant difference was found between the prevalence of anti-HBc in these two groups. In male cirrhotic patients the risk of HBV infection was 4.4 times higher in chronic hepatotoxic drugs users, 4.7 times higher in alcoholics, and 6.9 times higher in patients exposed both to alcohol and drugs. These results support the hypothesis that also chronic consumption of hepatotoxic drugs may be associated with a greater prevalence of HBV infection.

The case of a patient who developed hepatitis during treatment with clofibrate is reported. The first attack of hepatitis, which resolved after the drug was suspended, was followed by another at rechallenge with a similar drug, fenofibrate.

Early diagnosis of PHC development in cirrhosis is sometimes difficult through common tests excluding invasive diagnostic procedures; liver biopsy as a routine periodical control during the course of the disease is not advisable and AFP monitoring as a diagnostic test is preferable. The present study shows the results of a screening for AFP levels in a series of 113 cirrhotic patients aged over 50. 11.5% of them presented increased levels of serum AFP, indicating development of PHC. AFP elevated values resulted in 76.5% of cases associated with a previous HBV infection, and the risk of PHC development resulted sixfold greater in anti-HBc positive male cirrhotic patients. In patients with elevated AFP levels the prevalence of complications of cirrhosis resulted up to tenfold greater than in AFP negative patients.