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Molecules (Basel, Switzerland) Oct 2021Glyceryl trinitrate (GTN) is one of the earliest known treatments for angina with a fascinating history that bridges three centuries. However, despite its central role... (Review)
Review
Glyceryl trinitrate (GTN) is one of the earliest known treatments for angina with a fascinating history that bridges three centuries. However, despite its central role in the nitric oxide (NO) story as a NO-donating compound, establishing the precise mechanism of how GTN exerts its medicinal benefit has proven to be far more difficult. This review brings together the explosive and vasodilatory nature of this three-carbon molecule while providing an update on the likely in vivo pathways through which GTN, and the rest of the organic nitrate family, release NO, nitrite, or a combination of both, while also trying to explain nitrate tolerance. Over the last 20 years the alcohol detoxification enzyme, aldehyde dehydrogenase (ALDH), has undoubtedly emerged as the front runner to explaining GTN's bioactivation. This is best illustrated by reduced GTN efficacy in subjects carrying the single point mutation (Glu504Lys) in ALDH, which is also responsible for alcohol intolerance, as characterized by flushing. While these findings are significant for anyone following the GTN story, they appear particularly relevant for healthcare professionals, and especially so, if administering GTN to patients as an emergency treatment. In short, although the GTN puzzle has not been fully solved, clinical study data continue to cement the importance of ALDH, as uncovered in 2002, as a key GTN activator.
Topics: Alcohol Drinking; Alcoholism; Aldehyde Dehydrogenase; Animals; Humans; Nitroglycerin; Vasodilator Agents
PubMed: 34770988
DOI: 10.3390/molecules26216581 -
Northern Clinics of Istanbul 2020The use of food additives in food production is inevitable in this modern world. Although only a safe amount of food additives is approved, their safety has always been... (Review)
Review
The use of food additives in food production is inevitable in this modern world. Although only a safe amount of food additives is approved, their safety has always been questioned. To our knowledge, the effects of food additives on microbiota have not been investigated in a detailed manner in the literature so far. In this review, the effects of artificial sweeteners, sugar alcohols, emulsifiers, food colorants, flavor enhancers, thickeners, anticaking agents, and preservatives on microbiota were reviewed. Even though most of the results illustrated negative outcomes, few of them showed positive effects of food additives on the microbiota. Although it is difficult to obtain exact results due to differences in experimental animals and models, said the findings suggest that nonnutritive synthetic sweeteners may lead to glucose intolerance by affecting microbiota and a part of sugar alcohols show similar effects like probiotics.
PubMed: 32259044
DOI: 10.14744/nci.2019.92499 -
American Journal of Lifestyle Medicine 2016Glucose intolerance is a global health concern that encompasses glucose metabolism abnormalities such as impaired fasting glucose (IFG), impaired glucose tolerance... (Review)
Review
Glucose intolerance is a global health concern that encompasses glucose metabolism abnormalities such as impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes (T2D). There is an urgent need to focus on the prediabetes (ie, IGT and IFG) stage before the disease actually occurs. The progression from IGT to T2D can be prevented or delayed by modifying the lifestyles in high-risk individuals, and these health benefits are well documented in various ethnicities with prediabetes across the world. Specifically, consuming a healthy diet (high in polyunsaturated fatty acids, monounsaturated fatty acids, fiber, and whole grains), losing weight, quitting smoking, consuming alcohol in moderation, and increasing physical activity can improve glucose tolerance and reduce the risk of T2D. Also, pharmacological agents and botanicals can be used to manage glucose intolerance if the implementation of lifestyle changes is challenging. Pharmacological treatments have been successful in managing glucose intolerance; however, they have adverse effects. Also, more research on botanicals is warranted before a definitive recommendation can be made for their use in managing glucose intolerance. To make progress on this worldwide problem, efforts are needed to improve the awareness of prediabetes, increase promotion of healthy behaviors, and improve the availability of evidence-based lifestyle intervention programs to the community.
PubMed: 30202302
DOI: 10.1177/1559827614554186 -
PloS One 2023There is significant overlap between non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) with regards to risk factors and disease...
BACKGROUND AND AIMS
There is significant overlap between non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) with regards to risk factors and disease progression. However, the mechanism by which fatty liver disease arises from concomitant obesity and overconsumption of alcohol (syndrome of metabolic and alcohol-associated fatty liver disease; SMAFLD), is not fully understood.
METHODS
Male C57BL6/J mice were fed chow diet (Chow) or high-fructose, high-fat, high-cholesterol diet (FFC) for 4 weeks, then administered either saline or ethanol (EtOH, 5% in drinking water) for another 12 weeks. The EtOH treatment also consisted of a weekly 2.5 g EtOH/kg body weight gavage. Markers for lipid regulation, oxidative stress, inflammation, and fibrosis were measured by RT-qPCR, RNA-seq, Western blot, and metabolomics.
RESULTS
Combined FFC-EtOH induced more body weight gain, glucose intolerance, steatosis, and hepatomegaly compared to Chow, EtOH, or FFC. Glucose intolerance by FFC-EtOH was associated with decreased hepatic protein kinase B (AKT) protein expression and increased gluconeogenic gene expression. FFC-EtOH increased hepatic triglyceride and ceramide levels, plasma leptin levels, hepatic Perilipin 2 protein expression, and decreased lipolytic gene expression. FFC and FFC-EtOH also increased AMP-activated protein kinase (AMPK) activation. Finally, FFC-EtOH enriched the hepatic transcriptome for genes involved in immune response and lipid metabolism.
CONCLUSIONS
In our model of early SMAFLD, we observed that the combination of an obesogenic diet and alcohol caused more weight gain, promoted glucose intolerance, and contributed to steatosis by dysregulating leptin/AMPK signaling. Our model demonstrates that the combination of an obesogenic diet with a chronic-binge pattern alcohol intake is worse than either insult alone.
Topics: Mice; Animals; Male; Leptin; Diet, Western; Glucose Intolerance; AMP-Activated Protein Kinases; Ethanol; Liver; Liver Diseases, Alcoholic; Non-alcoholic Fatty Liver Disease; Obesity; Lipid Metabolism; Diet, High-Fat; Mice, Inbred C57BL
PubMed: 37134024
DOI: 10.1371/journal.pone.0281954 -
Current Opinion in Psychology Dec 2019Substances of abuse are characterized by their rewarding effects and engagement of reward pathways in the brain. However, these substances also provide rapid relief of... (Review)
Review
Substances of abuse are characterized by their rewarding effects and engagement of reward pathways in the brain. However, these substances also provide rapid relief of negative affect, and thus are highly negatively reinforcing. Accordingly, negative affectivity and other affective vulnerabilities (factors related to the experience of affect) are strongly linked to problematic substance use and substance use disorders. In this review, we provide a critical overview of the literature on affective vulnerabilities in substance use disorders. We discuss how both the experience of affect (e.g. negative affectivity, stress reactivity) and the interpretation of affect (e.g. distress intolerance, anxiety sensitivity) are pertinent to the development, maintenance, and treatment of substance use disorders.
Topics: Affect; Anxiety; Humans; Substance-Related Disorders
PubMed: 30851660
DOI: 10.1016/j.copsyc.2019.01.011 -
Journal of the European Academy of... Jun 2022Benzyl alcohol is a widely used preservative, solvent and fragrance material. According to published data, it is a rare sensitizer in humans.
BACKGROUND
Benzyl alcohol is a widely used preservative, solvent and fragrance material. According to published data, it is a rare sensitizer in humans.
OBJECTIVES
To identify characteristics and sensitization patterns of patients with positive patch test reactions to benzyl alcohol and to check the reliability of the patch test preparation benzyl alcohol 1% pet.
PATIENTS AND METHODS
Retrospective analysis of data from the Information Network of Departments of Dermatology (IVDK), 2010-2019.
RESULTS
Of 70 867 patients patch tested with benzyl alcohol 1% pet., 146 (0.21%) showed a positive reaction, most of them (89%) only weakly positive. The number of doubtful and irritant reactions significantly exceeded the number of positive reactions. Reproducibility of positive test reactions was low. Among benzyl alcohol-positive patients, compared to benzyl alcohol-negative patients, there were significantly more patients with leg dermatitis (17.8% vs. 8.6%), more patients aged 40 years or more (81.5% vs. 70.5%) and more patients who were tested because of a suspected intolerance reaction to topical medications (34.9% vs. 16.6%). Concomitant positive reactions were mainly seen to fragrances, preservatives and ointment bases.
CONCLUSIONS
Sensitization to benzyl alcohol occurs very rarely, mainly in patients with stasis dermatitis. In view of our results, benzyl alcohol cannot be regarded as a significant contact allergen, and therefore marking it as skin sensitizer 1B and labelling it with H 317 is not helpful.
Topics: Allergens; Benzyl Alcohol; Dermatitis, Allergic Contact; Humans; Patch Tests; Perfume; Preservatives, Pharmaceutical; Reproducibility of Results; Retrospective Studies
PubMed: 35080274
DOI: 10.1111/jdv.17968 -
The Lancet. Haematology Mar 2020Polycythaemia vera is a myeloproliferative neoplasm characterised by excessive proliferation of erythroid, myeloid, and megakaryocytic components in the bone marrow due... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Polycythaemia vera is a myeloproliferative neoplasm characterised by excessive proliferation of erythroid, myeloid, and megakaryocytic components in the bone marrow due to mutations in the Janus kinase 2 (JAK2) gene. Ruxolitinib, a JAK 1 and JAK 2 inhibitor, showed superiority over best available therapy in a phase 2 study in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea. We aimed to compare the long-term safety and efficacy of ruxolitinib with best available therapy in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea.
METHODS
We report the 5-year results for a randomised, open-label, phase 3 study (RESPONSE) that enrolled patients at 109 sites across North America, South America, Europe, and the Asia-Pacific region. Patients (18 years or older) with polycythaemia vera who were resistant to or intolerant of hydroxyurea were randomly assigned 1:1 to receive either ruxolitinib or best available therapy. Patients randomly assigned to the ruxolitinib group received the drug orally at a starting dose of 10 mg twice a day. Single-agent best available therapy comprised hydroxyurea, interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or observation without pharmacological treatment. The primary endpoint, composite response (patients who achieved both haematocrit control without phlebotomy and 35% or more reduction from baseline in spleen volume) at 32 weeeks was previously reported. Patients receiving best available therapy could cross over to ruxolitinib after week 32. We assessed the durability of primary composite response, complete haematological remission, overall clinicohaematological response, overall survival, patient-reported outcomes, and safety after 5-years of follow-up. This study is registered with ClinicalTrials.gov, NCT01243944.
FINDINGS
We enrolled patients between Oct 27, 2010, and Feb 13, 2013, and the study concluded on Feb 9, 2018. Of 342 individuals screened for eligibility, 222 patients were randomly assigned to receive ruxolitinib (n=110, 50%) or best available therapy (n=112, 50%). The median time since polycythaemia vera diagnosis was 8·2 years (IQR 3·9-12·3) in the ruxolitinib group and 9·3 years (4·9-13·8) in the best available therapy group. 98 (88%) of 112 patients initially randomly assigned to best available therapy crossed over to receive ruxolitinib and no patient remained on best available therapy after 80 weeks of study. Among 25 primary responders in the ruxolitinib group, six had progressed at the time of final analysis. At 5 years, the probability of maintaining primary composite response was 74% (95% CI 51-88). The probability of maintaining complete haematological remission was 55% (95% CI 32-73) and the probability of maintaining overall clinicohaematological responses was 67% (54-77). In the intention-to-treat analysis not accounting for crossover, the probability of survival at 5 years was 91·9% (84·4-95·9) with ruxolitinib therapy and 91·0% (82·8-95·4) with best available therapy. Anaemia was the most common adverse event in patients receiving ruxolitinib (rates per 100 patient-years of exposure were 8·9 for ruxolitinib and 8·8 for the crossover population), though most anaemia events were mild to moderate in severity (grade 1 or 2 anaemia rates per 100 patient-years of exposure were 8·0 for ruxolitinib and 8·2 for the crossover population). Non-haematological adverse events were generally lower with long-term ruxolitinib treatment than with best available therapy. Thromboembolic events were lower in the ruxolitinib group than the best available therapy group. There were two on-treatment deaths in the ruxolitinib group. One of these deaths was due to gastric adenocarcinoma, which was assessed by the investigator as related to ruxolitinib treatment.
INTERPRETATION
We showed that ruxolitinib is a safe and effective long-term treatment option for patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea. Taken together, ruxolitinib treatment offers the first widely approved therapeutic alternative for this post-hydroxyurea patient population.
FUNDING
Novartis Pharmaceuticals Corporation.
Topics: Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Drug Therapy, Combination; Fibrinolytic Agents; Follow-Up Studies; Humans; Hydroxyurea; Interferon alpha-2; Interferon-alpha; Nitriles; Pipobroman; Polycythemia Vera; Polyethylene Glycols; Prognosis; Pyrazoles; Pyrimidines; Quinazolines; Recombinant Proteins; Survival Rate; Time Factors
PubMed: 31982039
DOI: 10.1016/S2352-3026(19)30207-8 -
Journal of Atherosclerosis and... Sep 2021Primary chylomicronemia (PCM) is a rare and intractable disease characterized by marked accumulation of chylomicrons in plasma. The levels of plasma triglycerides (TGs)... (Review)
Review
Primary chylomicronemia (PCM) is a rare and intractable disease characterized by marked accumulation of chylomicrons in plasma. The levels of plasma triglycerides (TGs) typically range from 1,000 - 15,000 mg/dL or higher.PCM is caused by defects in the lipoprotein lipase (LPL) pathway due to genetic mutations, autoantibodies, or unidentified causes. The monogenic type is typically inherited as an autosomal recessive trait with loss-of-function mutations in LPL pathway genes (LPL, LMF1, GPIHBP1, APOC2, and APOA5). Secondary/environmental factors (diabetes, alcohol intake, pregnancy, etc.) often exacerbate hypertriglyceridemia (HTG). The signs, symptoms, and complications of chylomicronemia include eruptive xanthomas, lipemia retinalis, hepatosplenomegaly, and acute pancreatitis with onset as early as in infancy. Acute pancreatitis can be fatal and recurrent episodes of abdominal pain may lead to dietary fat intolerance and failure to thrive.The main goal of treatment is to prevent acute pancreatitis by reducing plasma TG levels to at least less than 500-1,000 mg/dL. However, current TG-lowering medications are generally ineffective for PCM. The only other treatment options are modulation of secondary/environmental factors. Most patients need strict dietary fat restriction, which is often difficult to maintain and likely affects their quality of life.Timely diagnosis is critical for the best prognosis with currently available management, but PCM is often misdiagnosed and undertreated. The aim of this review is firstly to summarize the pathogenesis, signs, symptoms, diagnosis, and management of PCM, and secondly to propose simple diagnostic criteria that can be readily translated into general clinical practice to improve the diagnostic rate of PCM. In fact, these criteria are currently used to define eligibility to receive social support from the Japanese government for PCM as a rare and intractable disease.Nevertheless, further research to unravel the molecular pathogenesis and develop effective therapeutic modalities is warranted. Nationwide registry research on PCM is currently ongoing in Japan with the aim of better understanding the disease burden as well as the unmet needs of this life-threatening disease with poor therapeutic options.
Topics: Abdominal Pain; Animals; Disease Management; Humans; Hyperlipoproteinemia Type I; Pancreatitis; Prognosis; Triglycerides
PubMed: 33980761
DOI: 10.5551/jat.RV17054