The Role of ERK1/2 Pathway in the Pathophysiology of Alzheimer's Disease: An Overview and Update on New Developments.

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide. Several findings suggest that correcting the dysregulated signaling pathways may offer a potential therapeutic approach in this disease. Extracellular signal-regulated kinase 1/2 (ERK1/2), a member of the mitogen-activated protein kinase family, plays a major role in regulation of cell proliferation, autophagy process, and protein synthesis. The available literature suggests dysregulated ERK1/2 in AD patients with potential implications in the multifaceted underlying pathologies of AD, including amyloid-ß plaque formation, tau phosphorylation, and neuroinflammation. In this regard, in the current review, we aim to summarize the reports on the potential roles of ERK1/2 in AD pathophysiology.

Potential drug-drug interactions in a multi-center study of death cases of COVID-19: The significance of appropriate drug choice.

OBJECTIVES: The prevalence, types, severity, risk ratings, and common pairs of involved drugs, and the most important potential drug-drug interactions (pDDIs) in coronavirus disease 2019 (-COVID-19) deceased cases were evaluated. MATERIALS AND METHODS: We reviewed the medical records of 157 confirmed COVID-19 deceased cases hospitalized in 27 province-wide hospitals. Patients' demographics and clinical data (including comorbidities, vital signs, length of in-hospital survival, electrocardiograms (ECGs), medications, and lab test results) were extracted. The online Lexi-interact database and Stockley's drug interactions reference were used to detect pDDIs retrospectively. The QTc interval and total Tisdale risk score were also calculated. Descriptive analysis, analysis of variance, Fisher exact test, and multivariate analysis were conducted for data analysis. RESULTS: Of 157 study cases, 63% were male, had a mean age of 68 years, and 55.7% had one or more underlying diseases. All patients had polypharmacy, with 69.2% having ≥ 15 drugs/day. We detected 2,416 pDDIs in patients' records, of which 658 (27.2%) were interactions with COVID drugs. Lopinavir/ritonavir among -COVID drugs and fentanyl among non-COVID drugs were commonly involved in the interactions. pDDIs was significantly higher in the polypharmacy group of ≥ 15 medications (p < 0.001). A majority (83%) had received drug(s) with the QTc prolongation effect, of whom 67% had actual QTc prolongations in their ECGs. The regression analysis showed that by increasing 6.7% in polypharmacy, one day increase in-hospital survival can be expected. Moreover, an increase of 2.3% in white blood cells or 10.5% in serum potassium level decreased in-hospital survival by 1%. CONCLUSION: The findings underscored the importance of careful drug choice, especially in the hectic search for early treatments in pandemics of novel diseases. Close monitoring of patients' drug choice is warranted for reducing pDDIs and their adverse effects in any new disease outbreak.

Potentially inappropriate medication prescribing based on 2019 Beers criteria and the impact of pharmacist intervention in elderly patients with kidney diseases: A report from Iran.

Background and Aims: A potentially inappropriate medication (PIM) is a pharmaceutical agent that poses a greater risk of harm than potential benefit to elderly patients. This study aimed to detect PIMs and their risk factors in hospitalized elderly patients with kidney disease. Methods: This cross-sectional study assessed medication orders of elderly patients (≥65 years old) with kidney diseases admitted to the hospital. In the first 6 months, we retrospectively evaluated all medications to identify PIMs according to the 2019 Beers criteria. In the second phase, a clinical pharmacist prospectively evaluated all medications and suggested modifications as needed. Data were analyzed to determine risk factors for prescribing PIMs. Results: Based on our evaluation of 258 patients, we observed that the utilization of PIMs was prevalent among the study population. Of the total patients evaluated, 273 instances of PIM use were identified, with only 23.3% of patients not having any PIMs. Notably, proton pump inhibitors and benzodiazepines were the most frequently prescribed PIMs. The risk of experiencing a PIM was significantly amplified by a higher degree of polypharmacy, with odds approximately 2.68 times higher (p < 0.01). Several factors were found to be associated with an increased likelihood of having a PIM, including being male, undergoing hemodialysis, having chronic kidney disease or other comorbidities, and having an extended hospital stay. The second phase of study, in terms of addressing these issues, physicians adhered to 67.5% of the 120 recommendations made by pharmacists regarding the discontinuation of PIM usage. Conclusion: High prevalence of PIMs was detected in our study population. Preventing medication-associated harms in the elderly can reduce the financial burden imposed on healthcare systems. Therefore, routine evaluation of medications with clinical pharmacists and/or implementation of computerized medication decision support systems is recommended to prevent PIMs use.

Comparison between the effect of Empagliflozin and Pioglitazone added to metformin in patients with type 2 diabetes and nonalcoholic fatty liver disease.

BACKGROUND/AIMS: Non-alcoholic fatty liver disease (NAFLD), defined as the accumulation of >5% fat in the liver, is the most frequently co-exist disease with diabetics up to 70%. Current study was conducted to compare efficacy of combination therapy of empagliflozin (EMPA) or pioglitazone (PGZ) with metformin (MET) in patients with T2DM and NAFLD. METHODS: In this open label, prospective clinical trial, sixty patients were randomly assigned to receive EMPA 10 mg/day or PGZ 30 mg/day in combination Metformin (at least 1500 mg) for six months. NAFLD grade and liver stiffness were defined and measured at the beginning and after 6 months. As the secondary outcomes, anthropometric characteristics, lipid profile, plasma glucose test, and liver enzymes test were measured at the baseline and endpoint. RESULTS: The results showed that both combination therapy with EMPA+ MET or PGZ+MET significantly reversed fibrosis stage of NAFLD (P<0.05). Significant reduction in lipid profile test, and liver enzymes test were seen in both groups (P<0.05). However, the greater reduction in waist circumference was observed in EMPA groups compared to PGZ (-4.4 ± 2.39 vs -2.05±1.28, p<0.001), meanwhile weight and BMI decreased significantly only in the patients receiving EMPA (-5.78 ± 3.6 kg vs 0.93 ± 0.33 kg and -2.01± 3.19 kg/m2 vs 0.33 ± 0.12 kg/m2, respectively, P<0.001). CONCLUSION: combination of EMPA or PGZ with metformin equally improved liver fibrosis stage and stiffness in T2DM patients with NAFLD. The improvements of laboratory tests were observed in the both groups, while, regarding weight reduction, only the regimen containing EMPA was effective.

Role of Bmal1 and Gut Microbiota in Alzheimer's Disease and Parkinson's Disease Pathophysiology: The Probable Effect of Melatonin on Their Association.

In recent years, the role of new factors in the pathophysiology of neurodegenerative diseases has been investigated. Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases worldwide. Although pathological changes such as the accumulation of aggregated proteins in the brain and inflammatory responses are known as the main factors involved in the development of these diseases, new studies show the role of gut microbiota and circadian rhythm in the occurrence of these changes. However, the association between circadian rhythm and gut microbiota in AD and PD has not yet been investigated. Recent results propose that alterations in circadian rhythm regulators, mainly Bmal1, may regulate the abundance of gut microbiota. This correlation has been linked to the regulation of the expression of immune-related genes and Bmal-1 mediated oscillation of IgA and hydrogen peroxide production. These data seem to provide new insight into the molecular mechanism of melatonin inhibiting the progression of AD and PD. Therefore, this manuscript aims to review the role of the gut microbiota and circadian rhythm in health and AD and PD and also presents a hypothesis on the effect of melatonin on their communication.

Platelet Activation and Alzheimer's Disease: The Probable Role of PI3K/AKT Pathway.

In recent years, the association between the activity of platelets and risk of Alzheimer's disease (AD) risk has been noticed in numerous studies. However, there in no investigations on the role of specific intracellular pathways to explain this connection. The phosphatidylinositol 3 kinase (PI3K)/AKT pathway is one of the main regulators of cell survival which regulates cellular responses to environmental changes. This pathway also regulates the activity of platelets, and its aberrant activity has been linked to platelet dysfunction in different pathologies. On the other hand, the PI3K/AKT pathway regulates amyloid-ß (Aß) production through regulation of amyloid-ß protein precursor (AßPP), BACE-1, ADAMs, and γ-secretase. In addition, alterations in the activity of all of these factors in platelets has been shown in AD-related pathologies. Therefore, this paper aims to introduce the PI3K/AKT pathway as a molecular inducer of platelet dysfunction during aging and AD progression.

Clinical evaluation of nebulized verapamil in out-patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is associated with many health complications, including pulmonary hypertension (PH). Although oral calcium channel blockers have shown promising results in managing COPD-induced PH, significant systemic side effects may limit their use in this population. Administering verapamil through nebulization can be an alternative approach. We aim to assess the possible therapeutic effects of verapamil inhalation in out-patients with pulmonary hypertension (PH) secondary to COPD. METHODS: A double-blind, randomized placebo-controlled clinical trial was conducted. Patients with PH were randomly assigned to two groups of 15 participants. The intervention group received a short-term single dose of 10 mg nebulized verapamil (4 ampoules of 2.5 mg/ml verapamil solutions). The control group received nebulized distilled water as a placebo in addition to their standard treatment throughout the study. RESULTS: Systolic pulmonary artery pressure (sPAP) did not improve as a primary outcome significantly in patients receiving nebulized verapamil compared with those on placebo (p = 0.89). Spirometry results showed a significant improvement in FVC in the intervention group from 1.72 ± 0.63 to 1.85 ± 0.58 L (p = 0.00), and FEV1/FVC ratio decreased significantly after verapamil administration (p = 0.027). CONCLUSION: Verapamil did not improve any of the pulmonary artery or RV parameters in patients with COPD-associated, but it did improve SpO2 and increase FVC, which revealed us possibility of verapamil in treating V/Q mismatch. The improved gas exchange may have been due to improvements in FVC as reflected in the improved spirometry. Higher doses of verapamil may be more efficacious and can be the subject of future trials.

Melatonin effect on platelet count in patients with liver disease.

AIM: A positive effect of melatonin on platelet count in patients with chronic liver disease is reported in the current study. BACKGROUND: Thrombocytopenia occurs when the severity of liver disease is exacerbated. Reduction in the secretion of thrombopoetin, as an intrinsic hormone produced mainly by the liver, plays an important role in this complication induced by liver disease. METHODS: This research was a double-blind, cross-over, placebo-controlled pilot study. Patients with liver disease were given two 5-mg pearls of melatonin or a placebo for two weeks, and after a 2-week washout period, their groups were switched. Liver function tests and platelet counts were assessed once at the beginning and once at the end of each phase of the study. RESULTS: In the current study, 40 patients meeting the eligibility criteria were included. The average platelet count was significantly increased by melatonin in comparison with the placebo (from 175.67±92.84 to 191.10±98.82 vs. from 185.22±98.39 to 176.45±91.45) (p-value <0.001). Melatonin also significantly reduced ALT, AST, total bilirubin, and direct and MELD scores in patients with liver disease (p-value <0.05). CONCLUSION: Melatonin may increase platelet count and inhibit thrombocytopenia in patients with liver disease; however, more investigations are needed to confirm the current results.

Evaluation of Antipruritic Effect of Melatonin on Hemodialysis Patients with Uremic Pruritus, A Double-Blind, Randomized, Crossover Trial.

INTRODUCTION: Uremic pruritus (UP) is one of the major complaints in hemodialysis patients without specific treatment. Considering the antipruritic effect of melatonin in atopic dermatitis (AD) and similarities in mechanism between pruritus in AD and UP, this randomized clinical trial designed to evaluate the antipruritic effect of melatonin on hemodialysis patients with UP. METHODS: This multicenter double-blind randomized clinical trial was conducted among the hemodialysis patients with UP. Adult patients were randomly assigned to receive two capsules of melatonin 5 mg /d for a 2 weeks period, undergoing a 1 week washout period, and then two capsules of placebo for another 2 weeks period, or the reverse sequence. Visual Analogue Scale (VAS), % affected Body Surface Area (%BSA) and 12-Pruritus Severity Scale questionnaire (12-PSS) were measured before and after each of the three periods. A crossover analysis of variance adjusted by treatment, period and carryover effect was performed by STATA 14. RESULTS: Thirty-nine patients under hemodialysis (mean age of 55.08 ± 12.34 years) completed the study. Mean changes in VAS, 12-PSS, and %BSA after the interventions (melatonin vs. placebo, mean ± SD) were as follows, respectively: -3.21 ± 3.33 vs. -1.38 ± 2.23, -4.59 ± 5.22 vs. -2.08 ± 4.35, and -19.10 ± 30.31 vs. 4.64 ± 29.11 (P < .05). However, the statistical significance of the treatment effect from melatonin was observed, carryover and period effects were not significant (P > .05) for any of the main variables. CONCLUSION: Based on to the preliminary results of this study, melatonin can be introduced as an effective drug for management of pruritus in uremic patients.

A Pilot Randomized, Clinical Trial of the Anti-pruritus Effect of Melatonin in Patients with Chronic Liver Disease.

Pruritus is one of the disturbing complications induced by chronic liver disease (CLD), bearing a negative impact on patient quality of life and potentially resulting in early liver transplants. Given the main role of the autotaxin enzyme in pruritus induced by CLD and the suppressive effects of melatonin on the expression of the autotaxin gene, this study was designed to evaluate the antipruritic effect of melatonin in patients with CLD. A double-blind, cross-over, randomized, placebo-controlled pilot trial was conducted on patients with CLD -induced pruritis. Patients were randomly assigned to two groups where they received melatonin 10-mg at night or placebo for 2 weeks. After a 2-week washout period, patients were then crossed over to the other group. The Visual Analog Scale (VAS) and the 12-Item Pruritus Severity Score (12-PSS) were used to assess patient response to therapy as the co-primary outcomes, while liver function tests were assayed too. Forty patients completed the study. The VAS score showed alleviation of 3.21 ± 2.24 (in pruritus) with melatonin (p-value <0.05). The study goal (a reduction of at least 20% in VAS) was achieved in 33 (82%) of study participants. In patients who received melatonin, the 12-PSS and Body Surface Area (BSA) affected by pruritus decreased on average 46.57% and 51.71%, respectively, with mood, sleep pattern and daily activity levels also demonstrating significant improvement (p-value < 0.05). Melatonin was found to be effective for managing pruritus in patients with CLD.

Validity and Reliability of Persian Version of 12-Item Pruritus Severity Score Questionnaire in Patients with Chronic Liver Disease and Pruritus.

BACKGROUND Currently, there is no published questionnaire translated in the Persian language for pruritus evaluation in patients with chronic liver disease. Therefore, it would be well worth having a valid and reliable Persian questionnaire for assessing pruritus with its different aspects. This study was designed to evaluate the validity and reliability of the translated version of the 12-Item Pruritus Severity Score (12-PSS) METHODS The patients with pruritus due to chronic liver disease, who referred to the liver clinic affiliated to Tehran University of Medical Sciences, were enrolled in this cross-sectional study. Following the forward-backward translation of 12-PSS into Persian, the content validity index (CVI) and its reliability were assessed. The patients were asked to respond to the visual analog scale (VAS) along with 12-PSS on their visits to evaluate the correlation between them. RESULTS 160 eligible patients were entered in the present study. The mean age was 46.03 (±13.05) years. The Cronbach's alpha for all domains of 12-PSS was 0.81-0.92 (average 0.89), which showed a strong consistency. The mean VAS and 12-PSS were 5.47±2.55 and 11.71 ± 5.25, respectively, and the correlation of VAS and 12-PSS was strong (p < 0.05, r = 0.89). CONCLUSION The Persian version of 12-PSS is a valid questionnaire for assessing pruritus and follow up response to treatment for patients with chronic liver disease.

Is melatonin effective for pruritus caused by liver disease?

There is still no definitive treatment to relieve pruritus associated with liver disease, because the precise mechanism of itching has not yet been determined. Different mechanisms have been proposed. One recent explanation is thought to be the rise in serum levels of lysophosphatidic acid which is a metabolite of lysophosphatidyl choline conversion by autotaxin enzyme in liver disease is. Over expression of autotaxin which occurs in atopic dermatitis has been shown to be involved in itching pathology. Importantly, gene amplification of autotaxin also occurs in cholestasis. Melatonin has pleiotropic properties such as suppressive effects on serum level of autotaxin which relieves itching of atopic dermatitis. Due to some similarities in mechanism of itching, it is hypothesized that melatonin may improve itching of liver diseases.