α-Lipoic acid: physiologic mechanisms and indications for the treatment of metabolic syndrome

In animal experiments, the potent antioxidant and free radical scavenger α-lipoic acid has been shown to cause weight loss, ameliorate insulin resistance and atherogenic dyslipidemia, as well as to lower blood pressure, all of these being components of the metabolic syndrome. Recent investigations on its mechanisms of action indicate that α-lipoic acid can affect central and peripheral modulation of 5′-AMP-activated protein kinase, activate PPAR-α and PPAR-γ, modulate PPAR-regulated genes and upregulate the expression of PPAR-γ mRNA and protein in cardiac tissue and aorta smooth muscle. To a large extent, these findings can explain the observed beneficial metabolic effects of α-lipoic acid, supporting its potential application as a therapeutic agent for the treatment of the metabolic syndrome.     

Synthesis and Study of the Analgesic and Antiinflammatory Activity of α-Acetoxyphenylacetic Acid Amides

Pharmaceutical Chemistry Journal -     

Is the Measurement of Serum Formate Concentration Useful in the Diagnostics of Acute Methanol Poisoning? A Prospective Study of 38 Patients

The aim of this article was to study the role of serum formate (S‐formate) in diagnosing methanol poisoning. A prospective study was undertaken of 38 patients from the Czech methanol mass poisoning in 2012 – median age 51 [interquartile range (IQR) 37–62] years with confirmed methanol poisoning. S‐formate was measured enzymatically. The receiver operating characteristics (ROC) curve was used to examine the predictive ability of S‐formate. Asymptomatic patients had median S‐formate of 1.9 (IQR 1.5–2.4) mmol/L. The median S‐formate was 15.2 (IQR 13.9–17.6) mmol/L in symptomatic subjects with visual disturbances, 15.4 (12.1–18.0) mmol/L in subjects with dyspnoea and 15.7 (IQR 12.8–18.5) mmol/L in comatose patients. The differences in serum formate concentrations in symptomatic patients depending on clinical features were not significant (all p > 0.05). Patients with long‐term visual sequelae of poisoning had median S‐formate of 16.1 (IQR 14.3–19.9) mmol/L; with central nervous system (CNS) sequelae, patients had 15.9 (IQR 14.2–19.5) mmol/L. In lethal cases, the median S‐formate was 15.2 (IQR 13.8–15.9) mmol/L. The probability of a poor outcome (death or survival with sequelae) was higher than 90% in patients with S‐formate ≥17.5 mmol/L, S‐lactate ≥7.0 mmol/L and/or pH <6.87. The ROC analysis showed that the corresponding areas under the curve (AUC) were 0.64 (0.44–0.85 CI 95%) for S‐formate, 0.75 (0.56–0.93 CI 95%) for ‘S‐formate+S‐lactate’ and only 0.54 (0.38–0.69 CI 95%) for serum methanol, which is lower than for S‐formate (p < 0.05). The measurement of S‐formate is an important tool in the laboratory diagnostics and clinical management of acute methanol poisoning. S‐formate ≥3.7 mmol/L can lead to the first clinical signs of visual toxicity, indicating haemodialysis. S‐formate ≥11–12 mmol/L is associated with visual/CNS sequelae and a lethal outcome.     

Efficacy and Tolerability of a Low-dose of Oesclim® (25 mcg Daily) in the Management of Symptomatic Menopausal Women: A French Open-label Study

Summary

Objective: To establish the proportion of symptomatic postmenopausal women, whose HRT treatment is initiated on Oesclim® 25, who can be satisfactorily maintained on this low dose after two months. Study design and patients: This was an open-label, multicentre, non-comparative, four-month treatment study. Treatment was initiated with Oesclim® 25 (17β-oestradiol transdermal patch, 25 mcg/day). Dosage could be increased to Oesclim® 50 if required after two months, according to clinical evaluation. Sequential treatment with an oral progestagen was also given for ≥12 days/month in all non-hysterectomised women. A total of 1465 women were included in the study.

Results: 82.3% (CI: 80.1–84.4) of patients remained on Oesclim® 25 across the whole study. The mean number of hot flushes was reduced similarly by 93% and 94% at month 4 in the Oesclim® 25 group and Oesclim® 50 group, respectively. However, at month 2 the decrease in hot flushes and other menopausal symptoms was less marked until the dose was adjusted, in patients switching to Oesclim® 50. In a global evaluation, 97.5% of the investigators and 95.7% of the patients rated the overall efficacy of the treatment as good/very good. Overall, treatment initiated at a low dose was well tolerated throughout the study, with a trend showing Oesclim® 25 as being better tolerated than Oesclim® 50.

Conclusion: Oesclim® low dose (25 mcg) can effectively reduce symptoms in most postmenopausal women with a very satisfactory level of tolerability. The risk/benefit ratio observed is probably one key reason for good patient compliance.     

Investigation of the Drug–Drug Interaction Between α-Lipoic Acid and Valproate via Mitochondrial β-oxidation

Purpose  To investigate the potential drug–drug interaction (DDI) between lipoic acid (LA) and valproate (VA) via the mitochondrial β-oxidation pathway in rats. Methods   In vitro mitochondrial assays were performed to compare the biotransformation of VA to valproyl-CoA (VA-CoA), in the absence and presence of LA. In vitro microsomal and protein binding assays were performed to elucidate their potential DDI at the microsomal metabolism and distribution levels. A pharmacokinetic study was conducted in Lister Hooded rats to ascertain the in vivo DDI between LA and VA. Results  LA was shown to decrease significantly (p < 0.05) the in vitro formation of VA-CoA in a concentration-dependent manner. Our in vitro assay results confirmed that there was minimal interaction between LA and VA in microsomal metabolism and protein binding. Based on the pharmacokinetic data, the absolute bioavailability of VA was determined to be 1.3 in the presence of LA. Conclusions  Our study demonstrated for the first time that there is a potential DDI between LA and VA at the mitochondrial β-oxidation level. While further clinical study is essential, our preliminary finding suggested that medical practitioners need to be prudent when managing epileptic patients who are co-administered with both VA and LA.     

“Trip-Sitting” in the Black Hole: A Netnographic Study of Dissociation and Indigenous Harm Reduction

An array of dissociative novel psychoactive substances, including “methoxetamine,” “3-MeO-PCP,” and “methoxphenidine,” have emerged as substitutes for the illicit substance “ketamine.” A netographic research methodology aimed to describe online, dissociative novel psychoactive substance users’ perceptions of risk, informed knowledge around use, and indigenous harm-reduction practices as advocated within online drug fora, so as to provide credible information which can be used to inform public online health education and drug prevention. Systematic Internet searches were performed using the terms “synthetic dissociative,” “methoxetamine,” “methoxphenidine,” “diphenidine,” “3-MeO-PCP,” “4-MeO-PCP,” “2-MDP,” and “dissociative research chemical” in combination with “forum.” Following screening of 3,476 forum threads with removal of duplicates and exclusion criteria, 90 user trip reports and 115 fora threads from seven drug fora websites were analyzed by conducting content analysis. Five themes emerged with 43 categories. The findings illustrated how forum activity within the cyber drug user community disseminated and exchanged “communal folk pharmacology” relating to the use of dissociative novel psychoactive substances. Further research and consistent monitoring of Internet drug fora are advised to explore variations in harm-reduction tactics throughout dissociative NPS populations, and to consider how existing harm-reduction initiatives are influencing these hard-to-reach groups.     

β-Blockers and the Risk of Depression: A Matched Case–Control Study

Drug Safety - Depression is a commonly cited adverse effect of β-blockers but the evidence for a causal relationship is limited. We aimed to explore whether β-blockers are associated with...     

“A Different Atmosphere of Love”: A Qualitative Study of the Experiences of Participants in Evangelical Substance User Rehabilitation Programs in the Russian Federation

This article explores the lived experiences of individuals who have participated in faith-based substance user rehabilitation programs in the Russian Federation. The Russian Federation has high rates of alcohol and opioid dependence and a dearth of professional treatment options. In the post-Soviet period, Evangelical Christian groups have developed substance user rehabilitation programs to attempt to address substance use and its related problems. Data were collected during 2010 via focus group interviews with participants in three Evangelical rehabilitation programs in the Volga region of the Russian Federation. Themes emerging from the qualitative data analysis process were classified into three broad categories: Typical Day, Personal Background/Decision to Enter Rehabilitation, and Helpful Aspects of Rehabilitation Process.     

Efficacy and Safety of Dorocontin? versus Sustac? in the Treatment of Stable Angina Pectoris: A Randomized,Double-Blind Comparative Trial

Background: Development of generic drugs has numerous benefits in terms of cost-efficiency and availability. Slow-release nitroglycerin is a vasodilator drug commonly prescribed for patients with angina pectoris. Objective: The objective of this study was to compare the efficacy and safety of generic slow-release nitroglycerin (Dorocontin^®) with that of the innovator brand (Sustac^®) in patients with stable angina pectoris. Methods: In this randomized, double-blind comparative trial, 110 patients were allocated to Dorocontin^® (n=67) or Sustac^® (n=43) at a dose of 6.4 mg TID, for a total period of two months. Maximum endurable MET (metabolic equivalent of task), MPI (myocardial perfusion imaging), along with changes in the ECG and biomarkers of renal (serum creatinine, BUN) and hepatic (AST, ALT, and ALP) function, lipid profile (total cholesterol, LDL-C, HDL-C, VLDL-C, and triglycerides), electrolytes (Na⁺ and K⁺), CBC-diff (RBC, WBC, Plt, Hb, Hct, MCV, MCH, MCHC, and RDW), and FBS were assessed at the baseline and at the end of the trial. The frequency of adverse events during the course of the trial was also recorded. Results: Apart from a significantly greater reduction in maximum ST depression in the Sustac^® versus the Dorocontin^® group (p=0.03), none of the functional (MET, MPI, and ECG) and paraclinical (renal function, hepatic function, lipid profile, electrolytes, and FBS) parameters significantly differed between the study groups. The mean Hb (p=0.035), Hct (p=0.045), and MCH (p=0.032) were decreased by the end of the trial in the Sustac^®, but not in the Dorocontin^® group, whilst there was no change in other CBC-diff parameters. Reported adverse events were not serious and included headache, vertigo, gastrointestinal upset, and orthostatic hypotension. The frequency of these adverse events was comparable between the study groups. Conclusion: The findings of the present trial showed comparable efficacy and safety of the generic and innovator products of slow-release nitroglycerin in the management of stable angina pectoris.     

Overview of the Proton-coupled MCT (SLC16A) Family of Transporters: Characterization, Function and Role in the Transport of the Drug of Abuse γ-Hydroxybutyric Acid

The transport of monocarboxylates, such as lactate and pyruvate, is mediated by the SLC16A family of proton-linked membrane transport proteins known as monocarboxylate transporters (MCTs). Fourteen MCT-related genes have been identified in mammals and of these seven MCTs have been functionally characterized. Despite their sequence homology, only MCT1-4 have been demonstrated to be proton-dependent transporters of monocarboxylic acids. MCT6, MCT8 and MCT10 have been demonstrated to transport diuretics, thyroid hormones and aromatic amino acids, respectively. MCT1-4 vary in their regulation, tissue distribution and substrate/inhibitor specificity with MCT1 being the most extensively characterized isoform. Emerging evidence suggests that in addition to endogenous substrates, MCTs are involved in the transport of pharmaceutical agents, including gamma-hydroxybuytrate (GHB), 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins), salicylic acid, and bumetanide. MCTs are expressed in a wide range of tissues including the liver, intestine, kidney and brain, and as such they have the potential to impact a number of processes contributing to the disposition of xenobiotic substrates. GHB has been extensively studied as a pharmaceutical substrate of MCTs; the renal clearance of GHB is dose-dependent with saturation of MCT-mediated reabsorption at high doses. Concomitant administration of GHB and L: -lactate to rats results in an approximately two-fold increase in GHB renal clearance suggesting that inhibition of MCT1-mediated reabsorption of GHB may be an effective strategy for increasing renal and total GHB elimination in overdose situations. Further studies are required to more clearly define the role of MCTs on drug disposition and the potential for MCT-mediated detoxification strategies in GHB overdose.     

Can Botulinum Toxin-A Contribute to Reconstructing the Physiological Homeostasis of the Masticatory Complex in Short-Faced Patients during Occlusal Therapy? A Prospective Pilot Study

The physiological homeostasis of the masticatory complex in short-faced patients is too robust to be disintegrated and reconstructed due to the powerful masseter muscle. This study innovatively introduced the botulinum toxin-A (BTX-A) into the field of dental occlusal treatment, providing a novel and minimally invasive therapy perspective for the two major clinical problems in these patients (low treatment efficiency and high rates of complications). In total, 10 adult patients with skeletal low angle seeking occlusal treatment (age: 27.0 ± 6.1 years; 4 males and 6 females) were administered 30–50 U of BTX-A in each masseter muscle and evaluated before and 3 months after injection based on cone-beam computed tomography (CBCT). We found a significant reduction in the thickness of the masseter muscle (MMT) (p < 0.0001). With regards to occlusion, we found a significant increase in the height of the maxillary second molar (U7-PP) (p < 0.05) with significantly flattened occlusal curves (the curve of Spee [COS] (p < 0.01), and the curve of Wilson [COW] (p < 0.05)). Furthermore, the variations in the temporomandibular joint exhibited a significant reduction in the anterior joint space (AJS) (p < 0.05) and superior joint space (SJS) (p < 0.05). In addition, the correlation analysis of the masticatory complex provided the basis for the following multiple regression equation: MMT = 10.08 − 0.11 COW + 2.73 AJS. The findings from our pilot study indicate that BTX-A, as a new adjuvant treatment attempt of occlusal therapy for short-faced patients, can provide a more favorable muscular environment for subsequent occlusal therapy through the adjustment of the biting force and may contribute to the reconstruction of healthier homeostasis of the masticatory complex. However, further research is required to establish the reliability and validity of these findings.     

Expression of ERα, its ERαΔ3 Splice Variant and γ-SYNUCLEIN in Ovarian Cancer: A Pilot Study

AIMS: Ovarian cancer has the highest mortality of any gynaecological malignancy; this is due to rapid peritoneal spread of tumour cells and neovascularization. Understanding the mechanisms underlying this is critical to developing early diagnostic or treatment strategies. We devised a pilot study to examine the role of γ-SYNUCLEIN (γ-SYN), oestrogen receptor (ER)α, and the splice variant ERαΔ3. METHODOLOGY: With ethical approval, ovarian tissue was collected from patients (n=24) undergoing oopherectomy for non-ovarian pathology or primary surgery for suspected ovarian cancer. Quantitative gene expression analysis was employed for γ-SYN, ERα, and ERαΔ3. To identify the in situ localization, immunofluorescence for γ-syn was carried out. RESULTS: Ovarian tumour tissue exhibited an elevated expression of γ-SYN and high-grade tumours had an elevated ERαΔ3:ERα ratio compared with benign tissue. The majority of previous studies point to the γ-syn protein being present in epithelial cells of high-grade disease. Our study supports this, but additionally we conclusively identify its presence in the endothelial cells of vasculature surrounding low-grade disease; immunofluorescence was strongest in the apical cells surrounding the lumen. CONCLUSION: Our results demonstrate for the first time that there are readily-expressed levels of γ-SYN and ERαΔ3 in normal ovarian tissue and ovarian tumours. In high-grade disease, γ-syn and an elevated ERαΔ3:ERα ratio might confer metastatic potential to the tumourigenic cells and promote neoangiogenesis. Future in vitro studies might be necessary to delineate such a mechanism, which could potentially be the basis of early intervention.     

α-Lipoic acid inhibits liver fibrosis through the attenuation of ROS-triggered signaling in hepatic stellate cells activated by PDGF and TGF-β

Reactive oxygen species (ROS) have been implicated in hepatic stellate cell activation and liver fibrosis. We previously reported that α-lipoic acid (LA) and its reduced form dihydrolipoic acid (DHLA) inhibited toxicant-induced inflammation and ROS generation. In the present study, we further examined the effects of LA/DHLA on thioacetamide (TAA)-induced liver fibrosis in rats and the possible underlying mechanisms in hepatic stellate cells in vitro. We found that co-administration of LA to rats chronically treated with TAA inhibited the development of liver cirrhosis, as indicated by reductions in cirrhosis incidence, hepatic fibrosis, and AST/ALT activities. We also found that DHLA inhibited TGF-β/PDGF-stimulated HSC-T6 activation and ROS generation. These effects could be mediated by the MAPK and PI3K/Akt pathways. According to our current results, LA may have a beneficial role in the treatment of chronic liver diseases caused by ongoing hepatic damage.     

Structure – Activity Relationship and Therapeutic Benefits of Flavonoids in the Management of Diabetes and Associated Disorders

Pharmaceutical Chemistry Journal - Commonly flavonoids are the natural components found in vegetables, spices and colored fruits. Flavonoids include a large group of polyphenolic compounds, namely...     

Do Spirituality and Religiosity Help in the Management of Cravings in Substance Abuse Treatment?

The purpose of this study was to examine the relationship of spirituality, religiosity and self-efficacy with drug and/or alcohol cravings. A cross-sectional survey was completed by 77 male participants at an Australian Salvation Army residential rehabilitation service in 2007. The survey included questions relating to the participants' drug and/or alcohol use and also measures for spirituality, religiosity, cravings, and self-efficacy. The sample included participants aged between 19 and 74 years, with more than 57% reporting a diagnosis for a mental disorder and 78% reporting polysubstance misuse with alcohol most frequently endorsed as the primary drug of concern (71%). Seventy-five percent of the clients reported that spirituality and religious faith were useful components of the treatment program. A multivariate multiple regression analysis identified that spirituality and self-efficacy have significant relationships with cravings. Self-efficacy mediated the relationship between spirituality and drug and/or alcohol cravings. The limitations of this study included its cross-sectional design and a sample that was drawn from a faith-based program. Future research would benefit from the longitudinal examination of the relationship between spirituality, self-efficacy, and cravings; the exploration of a broader range of client-specific and interpersonal variables; and the inclusion of a control group from a secular treatment facility.     

Stereospecific Inversion of l-α-Methylfluorene-2-acetic Acid to its d-Enantiomer in the Dog

1. After administration of dl-α-methylfluorene-2-acetic acid to dogs, the optical rotation of the drug in blood increased with time. Of the total drug in blood, the d-enantiomer increased from 61 to 80% between 3 and 24 h after administration; by 384 h it was 100%.

2. Both l- and d-enantiomers had plasma half-lives and excretion characteristics similar to those of the dl-racemic mixture, indicating that the increase in the proportion of the d-enantiomer was not due to more rapid excretion of the l-enantiomer.

3. Studies of optical rotation and circular dichroism demonstrated that the l-enantiomer was converted to the d-enantiomer in the blood of the dog, but the d-enantiomer remained unchanged. After administration of the l-enantiomer, the d-enantiomer increased from 26 to 71% of the total drug in blood between 0.3 and 2 days after administration; 14 days after dosing, almost all of the drug was present as the d-enantiomer.

4. Isomerization of l-α-methylfluorene-2-acetic acid to its d-enantiomer also occurs in rat. monkev and man.     

Rationale and Methods of the Substance Use and Psychological Injury Combat Study (SUPIC): A Longitudinal Study of Army Service Members Returning From Deployment in FY2008–2011

The Substance Use and Psychological Injury Combat Study (SUPIC) will examine whether early detection and intervention for post-deployment problems among Army Active Duty and National Guard/Reservists returning from Iraq or Afghanistan are associated with improved long-term substance use and psychological outcomes. This paper describes the rationale and significance of SUPIC, and presents demographic and deployment characteristics of the study sample (N = 643,205), and self-reported alcohol use and health problems from the subsample with matched post-deployment health assessments (N = 487,600). This longitudinal study aims to provide new insight into the long-term post-deployment outcomes of Army members by combining service member data from the Military Health System and Veterans Health Administration.     

β-adrenoceptor blockers and pulmonary function in the general population: the Rotterdam Study

Aim

β-adrenoceptor blockers have been used with caution in patients with obstructive lung diseases such as asthma or chronic obstructive pulmonary disease (COPD), due to the potentially increased airway reactivity and risk of bronchial obstruction. Cardioselective β-adrenoceptor blockers have a more beneficial profile than non-cardioselective β-adrenoceptor blockers and can be safely prescribed to patients with both cardiovascular disease and COPD. We hypothesized that cardioselective β-adrenoceptor blockers also affect pulmonary function.

Methods

This study was performed within the Rotterdam Study, a prospective population-based cohort study. Effects of cardioselective and non-cardioselective β-adrenoceptor blockers on pulmonary function were analysed using regression techniques with multivariable adjustment for potential confounders.

Results

Current use of non-cardioselective β-adrenoceptor blockers was significantly associated with a lower forced expiratory volume in 1 s (FEV₁) of −198 ml (95% CI −301, −96), with a lower forced vital capacity (FVC) of −223 ml (95% CI −367, −79) and with a decreased FEV₁ : FVC of −1.38% (95% CI −2.74, −0.13%). Current use of cardioselective β-adrenoceptor blockers was significantly associated with a lower FEV₁ of −118 ml (95% CI −157, −78) and with a lower FVC of −167 ml (95% CI −222, −111), but did not affect FEV₁ : FVC. After exclusion of patients with COPD, asthma and heart failure the effects of cardioselective β-adrenoceptor blockers remained significant for FEV₁ (−142 ml [95% CI −189, −96]) and for FVC (−176 ml [95% CI −236, −117]).

Conclusion

In our study both non-cardioselective and cardioselective β-adrenoceptor blockers had a clinically relevant effect on both FEV₁ and FVC. In contrast to cardioselective β-adrenoceptor blockers, use of non-cardioselective β-adrenoceptor blockers was associated with a significantly lower FEV₁ : FVC.