Neurohormetic phytochemicals in the pathogenesis of neurodegenerative diseases.

The world population is progressively ageing, assuming an enormous social and health challenge. As the world ages, neurodegenerative diseases are on the rise. Regarding the progressive nature of these diseases, none of the neurodegenerative diseases are curable at date, and the existing treatments can only help relieve the symptoms or slow the progression. Recently, hormesis has increased attention in the treatment of age-related neurodegenerative diseases. The concept of hormesis refers to a biphasic dose-response phenomenon, where low levels of the drug or stress exert protective of beneficial effects and high doses deleterious or toxic effects. Neurohormesis, as the adaptive aspect of hormetic dose responses in neurons, has been shown to slow the onset of neurodegenerative diseases and reduce the damages caused by aging, stroke, and traumatic brain injury. Hormesis was also observed to modulate anxiety, stress, pain, and the severity of seizure. Thus, neurohormesis can be considered as a potentially innovative approach in the treatment of neurodegenerative and other neurologic disorders. Herbal medicinal products and supplements are often considered health resources with many applications. The hormesis phenomenon in medicinal plants is valuable and several studies have shown that hormetic mechanisms of bioactive compounds can prevent or ameliorate the neurodegenerative pathogenesis in animal models of Alzheimer's and Parkinson's diseases. Moreover, the hormesis activity of phytochemicals has been evaluated in other neurological disorders such as Autism and Huntington's disease. In this review, the neurohormetic dose-response concept and the possible underlying neuroprotection mechanisms are discussed. Different neurohormetic phytochemicals used for the better management of neurodegenerative diseases, the rationale for using them, and the key findings of their studies are also reviewed.

Evaluation of family planning methods in married women with epilepsy.

BACKGROUND: Epilepsy is one of the most common neurologic unit diseases that have different prevalence in different parts of the world. Antiepileptic drugs (AEDs) are associated with major fertility risks for women of childbearing age. Due to the fact that studies on family planning methods in married women with epilepsy (WWE) have not been conducted in Iran, the aim of this study was to evaluate the family planning methods in married WWE in Birjand, Iran. METHODS: An analytical-descriptive study was performed on 126 married WWE hospitalized in the neurology ward or referred to Vali-e-Asr specialized and sub-specialized clinic in Birjand. Demographic information of patients as well as data on the type of used AED, and various methods of family planning were collected in a questionnaire. Data analysis was performed using Chi-square and Fisher tests. All of the above analyses were considered at a significance level of less than 5% by SPSS v.19 software. RESULTS: The mean age of the patients was 33.41 ±â€¯9.15 years. The mean age of experiencing the first seizure and the onset of menstruation were 24.82 and 13.79 years, respectively. Fifty (35.5%), 38 (27%), 15 (10.6%), 14 (9.9%), and 14 (9.9%) patients used sodium valproate, carbamazepine, phenytoin, levetiracetam, and lamotrigine, respectively. The results showed that 72 sexually active patients (70.6%) used family planning methods, of which 43 patients (59.7%) used withdrawal method, 20 patients (27.8%) used condoms, and 6 patients (8.3%) used oral contraceptive pills (OCP). Eight patients (9.6%) had a history of unintended pregnancy and 3 patients (3.6%) had a history of abortion. CONCLUSION: It is recommended to apply effective family planning methods in married WWE to prevent unintended pregnancies and the subsequent adverse effects in the fetus, considering the fact that a significant percentage of WWE did not use effective family planning methods and 8 cases of unintended pregnancies were reported. Because of high consumption of valproate in women of childbearing age in our study and concerning issue about its fetal malformation, it is recommended to reduce the administration of valproate in this population. Moreover, regarding the low consumption of folic acid, especially for women of childbearing age and pregnant WWE who are taking AED, the necessary recommendations should be made by our physicians.

Two trade names of deferasirox (Osveral® and Exjade®) in reduction of iron overload parameters in major beta-thalassemia patients: A randomized open labeled clinical trial.

BACKGROUND: Beta-thalassemia major patients typically require chronic transfusion and iron-chelating agents to reduce serum iron overload. Osveral® is an available Iranian brand name of deferasirox used by majority of thalassemic patients. The aim of this study was to compare the efficacy of Osveral® vs. Exjade® in major beta- thalassemia patients. METHODS: In this randomized clinical trial, all patients received a single daily dose of 30 mg/kg either of Osveral® or Exjade® for 6 months. Primary outcome was the mean of bimonthly changes in serum ferritin concentration and secondary outcomes included mean changes of heart and liver MRI T2* after a year. RESULTS: Finally, 80 patients completed the study. The mean serum ferritin level at the end of sixth month significantly decreased in Osveral® and Exjade® groups (p<0.01). After a year, means cardiac MRI T2* in Osveral® group were changed from 25.9±9.6 ms to 25.4±9.7 ms and in Exjade® group from 24.8±9.2 ms to 26.9±5.9 ms, with no significant difference (P=0.43). Mean liver MRI T2* for Osveral® and Exjade® groups were 8.6±6.4 ms (baseline 6.3±4.7) and 6.3±4 ms (baseline 4.9±3.5), respectively and there was no significant difference between two study arms (P=0.1). CONCLUSION: Osveral® decreased significantly the serum ferritin level and improved heart and liver iron overload as efficient as Exjade®. It can be a suitable cost-effective alternative agent in beta-thalassemia major patients.

L-carnitine: Searching for New Therapeutic Strategy for Sepsis Management.

In this review, we discussed the biological targets of carnitine, its effects on immune function, and how L-carnitine supplementation may help critically ill patients. L-carnitine is a potent antioxidant. L-carnitine depletion has been observed in prolonged intensive care unit (ICU) stays, while L-carnitine supplementation has beneficial effects in health promotion and regulation of immunity. It is essential for the uptake of fatty acids into mitochondria. By inhibiting the ubiquitin-proteasome system, down-regulating the apelin receptor in cardiac tissue, and reducing ß-oxidation of fatty acid, carnitine may decrease vasopressor requirement in septic shock and improve clinical outcomes of this group of patients. We also reviewed animal and clinical studies that have been recruited for evaluating the beneficial effects of L-carnitine in the management of sepsis/ septic shock. Additional clinical data are required to evaluate the optimal daily dose and duration of L-carnitine supplementation.

Update on Statin Treatment in Patients with Neuropsychiatric Disorders.

Statins are widely accepted as first-choice agents for the prevention of lipid-related cardiovascular diseases. These drugs have both anti-inflammatory and anti-oxidant properties, which may also make them effective as potential treatment marked by perturbations in these pathways, such as some neuropsychiatric disorders. In this narrative review, we have investigated the effects of statin therapy in individuals suffering from major depressive disorder (MDD), schizophrenia, anxiety, obsessive-compulsive disorder (OCD), bipolar disorder (BD), delirium, and autism spectrum disorders using a broad online search of electronic databases. We also explored the adverse effects of these drugs to obtain insights into the benefits and risks associated with their use in the treatment of these disorders. Lipophilic statins (including simvastatin) because of better brain penetrance may have greater protective effects against MDD and schizophrenia. The significant positive effects of statins in the treatment of anxiety disorders without any serious adverse side effects were shown in numerous studies. In OCD, BD, and delirium, limitations, and contradictions in the available data make it difficult to draw conclusions on any positive effect of statins. The positive effects of simvastatin in autism disorders have been evaluated in only a small number of clinical trials. Although some studies showed positive effect of statins in some neuropsychiatric disorders, further prospective studies are needed to confirm this and define the most effective doses and treatment durations.

Malus domestica reduces chemotherapy-induced nausea and vomiting: A randomized double-blind placebo-controlled clinical trial.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) is considered as the most common complications of chemotherapy which has a detrimental influence on the quality of life of patients with cancer. We assessed the efficacy of Apple (Malus domestica) syrup for reducing CINV. MATERIALS AND METHODS: This study was a randomized, double-blind, placebo-controlled trial carried out in a Hematooncology Clinic affiliated to Mazandaran University of Medical Sciences, Sari, Iran (from October 2017 to August 2018). Subjects were randomly allocated to receive apple syrup or placebo along with their previous antiemetic treatment and chemotherapy regimen, three times a day. Thirty-four patients received apple syrup (n = 16) or placebo (n = 18). Statistical analysis was conducted using SPSS software Version 21® (SPSS Inc., Chicago, IL, USA). A P < 0.05 indicated statistical significance. RESULTS: Both acute and delayed nausea grades were significantly lower in M. domestica syrup in comparison to placebo syrup (P = 0.001 and 0.001, respectively). The duration of nausea (P = 0.04) was lower in intervention group compared to placebo group. CONCLUSION: These findings demonstrated that M. domestica syrup can reduce the severity and duration of nausea in cancer patients who received chemotherapy.

Therapeutic Effects of Punica granatum (Pomegranate): An Updated Review of Clinical Trials.

Punica granatum L. belongs to the Punicaceae family which is distributed around the world. Different parts of pomegranate like seed, peel, juice, and leaves are rich in potential bioactive compounds. These plants have found application in traditional medicine such as in treatment of gastrointestinal, cardiovascular, and endocrine diseases, among others. The present review aimed to summarize the current research on the traditional and scientific applications of P. granatum with regard to the phytochemical content and clinical applications that may be useful for future drug development. Information about P. granatum was obtained from local classic herbal literature and electronic databases, such as PubMed, Scopus, and ScienceDirect. Several phytochemical constituents including polyphenolics, flavonoids, anthocyanosides, alkaloids, lignans, and triterpenes have been reported from the plant. Randomized clinical trials have provided evidence as to the pharmacological activities of pomegranate in several diseases including diabetes, cardiovascular disease, oral cavity disorders, endocrine disorders, and cancer. The present review has provided an insight into the traditional applications of the plants, and some of them have been validated by scientific evidence, particularly their applications as treatment of cardiovascular and endocrine diseases.

Aromatic hydrocarbon receptors in mitochondrial biogenesis and function.

Mitochondria are ubiquitous membrane-bound organelles that not only play a key role in maintaining cellular energy homeostasis and metabolism but also in signaling and apoptosis. Aryl hydrocarbons receptors (AhRs) are ligand-activated transcription factors that recognize a wide variety of xenobiotics, including polyaromatic hydrocarbons and dioxins, and activate diverse detoxification pathways. These receptors are also activated by natural dietary compounds and endogenous metabolites. In addition, AhRs can modulate the expression of a diverse array of genes related to mitochondrial biogenesis and function. The aim of the present review is to analyze scientific data available on the AhR signaling pathway and its interaction with the intracellular signaling pathways involved in mitochondrial functions, especially those related to cell cycle progression and apoptosis. Various evidence have reported the crosstalk between the AhR signaling pathway and the nuclear factor κB (NF-κB), tyrosine kinase receptor signaling and mitogen-activated protein kinases (MAPKs). The AhR signaling pathway seems to promote cell cycle progression in the absence of exogenous ligands, whereas the presence of exogenous ligands induces cell cycle arrest. However, its effects on apoptosis are controversial since activation or overexpression of AhR has been observed to induce or inhibit apoptosis depending on the cell type. Regarding the mitochondria, although activation by endogenous ligands is related to mitochondrial dysfunction, the effects of endogenous ligands are not well understood but point towards antiapoptotic effects and inducers of mitochondrial biogenesis.

Iranian Salvia species: A phytochemical and pharmacological update.

Salvia is the largest genus of the Lamiaceae family, with over 900 species in the world which about 60 species are distributed in Iran, 17 of them are endemic. In Iran, Salvia species have been used to treat various diseases with a wide spectrum of pharmacological activity in vitro and in vivo. The present review summarizes the phytochemistry and pharmacology of medicinal Iranian Salvia species in order to describe their therapeutic potential for a range of diseases. . Phytochemical investigations reveal that the Iranian Salvia has a varied range of metabolites including terpenoids, flavonoids and phenolic acids. The most important pharmacological activities are antidiabetic, antioxidant, antimicrobial, cytotoxic and anti-inflammatory. Iranian Salvia traditionally used as carminatives, analgesics, digestive aids, antiseptics, sedative, anxiolytic, hypnotic, pain reduction and antidiabetic. Among the endemic species, the most interesting for human health are treating a variety of diseases.

The prophylaxis and treatment potential of supplements for COVID-19.

The global impact of the new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), infection that caused COVID-19 has been evident in the last few months from the unprecedented socioeconomic disruption to more than 600,000 deaths. The lack of vaccine and effective therapeutic agents for the disease prompted world-wide effort to test those antiviral therapeutics already in use for other diseases. Another interesting approach has been based on the pathological sequel of the disease that involve severe inflammatory reaction (or the cytokine storm) associated with pneumonia in critically ill patients. This article outlines the prophylaxis therapeutic potential of supplements vitamins and micronutrients in COVID-19. By ameliorating the inflammatory and oxidative stress associated with the disease and some direct antiviral effects, the application of these agents as adjuvants and other alternative approaches are discussed. Available clinical trials including those currently registered on these supplements are scrutinized.

Pharmacological treatments of COVID-19.

The viral infection due to the new coronavirus or coronavirus disease 2019 (COVID-19), which was reported for the first time in December 2019, was named by the World Health Organization (WHO) as Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV2), because of the very similar genome and also its related symptoms to SARS-CoV1. The ongoing COVID-19 pandemic with significant mortality, morbidity, and socioeconomic impact is considered by the WHO as a global public health emergency. Since there is no specific treatment available for SARS-CoV2 infection, and or COVID-19, several clinical and sub-clinical studies are currently undertaken to find a gold-standard therapeutic regimen with high efficacy and low side effect. Based on the published scientific evidence published to date, we summarized herein the effects of different potential therapies and up-to-date clinical trials. The review is intended to help readers aware of potentially effective COVID-19 treatment and provide useful references for future studies.

Neutrophil elastase inhibitor (sivelestat) may be a promising therapeutic option for management of acute lung injury/acute respiratory distress syndrome or disseminated intravascular coagulation in COVID-19.

WHAT IS KNOWN AND OBJECTIVE: This article summarizes the effects of sivelestat on acute lung injury/acute respiratory distress syndrome (ALI/ARDS) or ARDS with coagulopathy, both of which are frequently seen in patients with COVID-19. COMMENT: COVID-19 patients are more susceptible to thromboembolic events, including disseminated intravascular coagulation (DIC). Various studies have emphasized the role of neutrophil elastase (NE) in the development of DIC in patients with ARDS and sepsis. It has been shown that NE inhibition by sivelestat mitigates ALI through amelioration of injuries in alveolar epithelium and vascular endothelium, as well as reversing the neutrophil-mediated increased vascular permeability. WHAT IS NEW AND CONCLUSIONS: Sivelestat, a selective NE inhibitor, has not been evaluated for its possible therapeutic effects against SARS-CoV-2 infection. Based on its promising beneficial effects in underlying complications of COVID-19, sivelestat could be considered as a promising modality for better management of COVID-19-induced ALI/ARDS or coagulopathy.

Taxane-induced peripheral neuropathy and quality of life in breast cancer patients.

PURPOSE: Taxane-induced peripheral neuropathy (TIPN) is a common and bothersome toxicity. This study aimed to determine the incidence and severity of TIPN in patients with breast cancer and to investigate the relationship between TIPN and quality of life. METHODS: A total of 82 breast cancer patients with TIPN symptoms were included in this study. The criteria of National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.03) and the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30, version 3.0) were used to evaluate grading of sensory neuropathy and quality of life, respectively. Analysis of the data was done by IBM SPSS statistics version 23. RESULTS: A total of 346 patients received taxane-based chemotherapy and 82 patients (23.7%) experience TIPN. The mean (SD) global health status/quality of life, physical functioning, role functioning, and pain subscales were 60.63 (5.26), 80.64 (9.05), 81.77 (10.41), and 43.88 (11.27), respectively. There were significant negative correlations between global health status/quality of life, physical functioning, and role functioning subscales with the grade of neuropathy (r = -0.33, -0.80, and -0.61, respectively) and positive correlation between pain subscale and the grade of neuropathy (r = 0.70). CONCLUSION: This study shows a clear association between TIPN and worsened quality of life. These findings emphasize on detecting and management of TIPN in an effort to improve the quality of life of breast cancer patients.

Comparison of the Efficacy and Safety of Pregabalin and Duloxetine in Taxane-Induced Sensory Neuropathy: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVE: Taxane-induced peripheral neuropathy (TIPN) is a main toxicity of taxanes with no effective treatment. This study aimed to compare the efficacy and safety of pregabalin (150 mg daily) and duloxetine (60 mg daily) for managing TIPN in breast cancer patients. METHODS: This randomized, double-blind, Phase II clinical trial was carried out at a chemotherapy center affiliated to Mazandaran University of Medical Sciences. Patients with breast cancer who received paclitaxel or docetaxel and had a grade 1 or more neuropathy (based on the National Cancer Institute Common Terminology Criteria for Adverse Events version (NCI-CTCAE v4.03), and who had score 4 or higher neuropathic pain severity [based on the visual analog scale (VAS)] were enrolled. Response to treatment was assessed based on improvements in the VAS, NCI-CTCAE, and Patient Neurotoxicity Questionnaire (PNQ) scores during a 6-week trial. RESULTS: Both interventions were effective in decreasing TIPN compared to baseline. At Week 6, the VAS scores were improved in 37/40 (92.5%) and 16/42 (38.1%) of the patients in the pregabalin and duloxetine groups, respectively (p < 0.001). Improvement in NCI-CTCAE sensory neuropathy was also more significant with pregabalin (37/40; 92.5%) in comparison to duloxetine (13/42; 31%) (p < 0.001). Pregabalin was also more beneficial than duloxetine in improving the PNQ scores by 36/40 (90%) and 13/42 (31%), respectively (p < 0.001). Both interventions were tolerated well with mild adverse events. CONCLUSIONS: Both pregabalin and duloxetine were well tolerated and efficacious in relieving neuropathic pain, however a 60 mg dose of duloxetine is inferior to a 150 mg dose of pregabalin.

Comparison the Incidence and Severity of Side Effects Profile Of FOLFOX and DCF Regimens in Gastric Cancer Patients.

Gastric cancer is the fourth common cancer and the second leading cause of cancer death worldwide. Due to lack of adequate information on the side effects of chemotherapy regimens in treatment of gastric cancer, this study was aimed to determine the side effects of two common chemotherapy regimens of gastric cancer. This prospective study was conducted in Emam Khomeini Educational Hospital and Touba Polyclinic; both are affiliated to Mazandaran University of Medical Sciences. The frequency and severity of side effects of chemotherapy were recorded based on the National Cancer Institution (NCI) Toxicity Criteria (version 2). DCF (Docetaxel, Cisplatin, 5FU) and FOLFOX (Folinic acid, 5FU, Oxaliplatin) adverse reactions were compared using SPSS 16 software. One hundred twenty five chemotherapy cycles administered to seventy four patients were assessed. The most common used regimens were DCF (70%) and FOLFOX (16%). The incidence of vomiting was higher with DCF compared to FOLFOX (P = 0.049). In more than 50% of cycles, DCF regimen caused diarrhea, while in FOLFOX regimen it was less than 9% (P = 0.002). Stomatitis, visual changes, nausea, skin reactions, and constipation were not significantly different between the two regimens. It seems that the adverse drug reactions of FOLFOX regimen were more favorable than DCF regimen. The results of this study may help clinicians choosing a more favorable chemotherapy regimen especially in patients with a low performance status who have difficulties in tolerating a chemotherapy regimen with a more severe adverse effect profile.

The effect of pregabalin and duloxetine treatment on quality of life of breast cancer patients with taxane-induced sensory neuropathy: A randomized clinical trial.

BACKGROUND: The primary side effect of adjuvant chemotherapy with taxanes is the taxane-induced peripheral neuropathy (TIPN), which may have substantial negative impacts on patients' quality of life (QOL). We investigated the effect of pregabalin and duloxetine on QOL of breast cancer patients who experienced TIPN. MATERIALS AND METHODS: This was a randomized, double-blind clinical trial conducted at a chemotherapy center of Mazandaran University of Medical Sciences, Sari, Iran. Breast cancer patients 18 or more years old were included if they received paclitaxel or docetaxel and experienced neuropathy grade one or higher; and neuropathic pain score of four or more. Patients were treated with pregabalin or duloxetine until 6 weeks. Assessment of sensory neuropathy and QOL was performed at baseline, and 6 weeks after the initiation of the treatment. RESULTS: At baseline, the mean score of global health status/QOL scale for pregabalin and duloxetine groups were 61 (standard deviation [SD]; 5.11) and 60.28 (SD; 5.44), respectively (P = 0.54). After 6 weeks, both interventions were associated with improvement of global QOL compared to baseline. The global health status/QOL score was not different between two groups after 6 weeks. While the emotional functioning was improved more favorably with duloxetine (P < 0.001); pregabalin was associated with more improvement in insomnia and pain scores (P = 0.05 and P < 0.001, respectively). CONCLUSION: Pregabalin as well as duloxetine improve the global QOL of breast cancer patients with TIPN. Different effects of treatments on subscale of QLQ-C30 could help clinicians to select the appropriate agent individually.

Pharmacokinetic Parameters and Over-Responsiveness of Iranian Population to Propranolol.

Purpose: Propranolol is the most widely used treatment for cardiovascular diseases. Dosage range in our patients is usually less than the amount mentioned in references. The aim of the present study was to clarify whether pharmacokinetic differences are able to justify the need for the fewer doses in our patients or not. Methods: Twenty healthy volunteers (10 male) at heart center of Mazandaran University of Medical Sciences were studied. Samples of blood were collected before a single oral dose (40 mg) of Propranolol. Blood samples were taken up to 9 hours after dose. Total plasma concentration of Propranolol was measured by HPLC. Population Pharmacokinetic analysis was performed using population pharmacokinetics modeling software P-Pharm. Results: The mean value for oral plasma clearance (CL/F) was 126.59 ml/hr. The corresponding values for apparent volume of distribution (V/F), t1/2 beta, maximum blood concentration (C max), and time to reach the maximum blood concentration (T max) were 334.12 Lit, 1.98 hr, 40.25 ng/ml, and 1.68 hr, respectively. The observed mean values of V/F of propranolol in the present study were comparable with those reported in the literature. However, the mean values of CL/F of propranolol in current study was significantly higher than those reported in other population (P-value<0.001). Conclusion: This study has confirmed that the pharmacokinetic differences are not able to justify over-responsiveness of Iranian population to propranolol. Pharmacodynamic differences in responding to beta blocker drugs by Renin secretion or having a different sensibility to beta receptors might play a role in making our population have a different response to propranolol.