Evaluating the factors affecting clinical outcomes in critically ill COVID-19 unvaccinated patients admitted to the intensive care unit in a lower-middle-income country.

Background: COVID-19, the most destructive pandemic of this century, caused the highest mortality rate among ICU patients. The evaluation of these patients is insufficient in lower-middle-income countries with limited resources during pandemics. As a result, our primary goal was to examine the characteristics of patients at baseline as well as their survival outcomes, and propose mortality predictors for identifying and managing the most vulnerable patients more effectively and quickly. Methods: A prospective analysis of COVID-19 ICU-admitted patients was conducted in our healthcare centre in Iran, from 1 April until 20 May 2020. Ninety-three patients were included in the study, and all were unvaccinated. A multi-variate logistic regression was conducted to evaluate mortality-associated factors. Results: There were 53 non-survivors among our ICU-admitted patients. The mean duration from symptoms' onset to hospitalization was 6.92 ± 4.27 days, and from hospitalization to ICU admission was 2.52 ± 3.61 days. The average hospital stay for patients was 13.23 ± 10.43 days, with 8.84 ± 7.53 days in the ICU. Non-survivors were significantly older, had significantly lower haemoglobin levels and higher creatine phosphokinase levels compared to survivors. They had marginally lower SpO2 levels at admission, higher vasopressor administrations, and were intubated more significantly during their ICU stay. The use of immunosuppressive drugs was also significantly higher in non-survivors. Logistic regression revealed that a one-point increase in APACHE II score at ICU admission increased mortality by 6%, and the presence of underlying diseases increased mortality by 4.27 times. Conclusion: The authors presented clinical mortality prediction factors for critically ill patients infected with COVID-19. Additional studies are necessary to identify more generalized mortality indicators for these patients in lower-middle-income countries.

Successful management of severe generalized tetanus in a 23-year man with phenobarbital adjuvant: A case report.

Generalized tetanus is still a global concern with a mortality rate of up to 50%, especially in low and middle-income countries. We reported a 23-year-old man from Afghanistan admitted to emergency department, with the chief complaint of generalized severe spasms and lockjaw. The patient had skin lesions and had never been vaccinated against tetanus. He intubated and admitted to the intensive care unit (ICU) with diagnose of severe generalized tetanus. After receiving tetanus immunoglobulin and intravenous metronidazole, a combination therapy of midazolam, propofol, atracurium, and morphine was administered. Due to the refractory muscular spasms intravenous phenobarbital started and little by little recovery was achieved. The patient receiving the first two doses of the Td vaccine, and discharged on Day 42 of hospitalization with no symptom recurrence. This case management showed adding phenobarbital to severe tetanus treatment regimen could significantly reduce refractory spasm caused by tetanus, also decrease other medication requirement.

Remdesivir Administration in COVID-19 Patients With Renal Impairment: A Systematic Review.

BACKGROUND: Remdesivir (RDV) is the main antiviral for the treatment of moderate to severe forms of Coronavirus disease 2019 (COVID-19). Several studies revealed a shortening time to clinical improvement of COVID-19 and mortality benefits in patients receiving RDV. The patients with renal disease were excluded from large clinical trials of RDV, and the probable nephrotoxicity of the drug, its metabolites, and the vehicle (sulfobutylether-ß-cyclodextrin) have led to the recommendation against using RDV in patients with an estimated glomerular filtration rate of <30 mL/min. AREAS OF UNCERTAINTY: This systematic review aimed to collect data about the necessity and safety administration of RDV in the setting of renal impairment. DATA SOURCES: Search through databases including MEDLINE, ScienceDirect, Cochrane Library, and PubMed was performed. The studies were carried out in adults and enrolled patients with different types of renal impairment (ie, acute kidney injury, chronic kidney disease, kidney transplant, and renal replacement therapy) were included. Eligible studies were assessed, and required data were extracted. RESULTS: Twenty-two cross-sectional studies, cohorts, case reports, and case series were included in this review. The mortality rate was between 7.3% and 50%, and various severity of COVID-19 was included in the studies. None of them reported an increase in adverse effects attributed to RDV administration. A decrease in inflammatory mediators and other benefits were obvious. CONCLUSIONS: Although the manufacturer's labeling does not recommend RDV administration in patients with severe renal impairment, it seems that nephrotoxicity is less concerning in the population of these patients. Moreover, RDV may be helpful in acute kidney injury induced by the viral invasion of COVID-19. To the best of our knowledge, this is the first systematic review of the use of RDV in kidney failure. Larger, well-designed, and pharmacokinetic studies are required to have a safe and logical recommendation about the use of RDV in patients with renal disorders.

Melatonin as adjunctive therapy in patients admitted to the Covid-19.

Objective: Coronavirus has disrupted the natural order of the world since September 2019 with no specific medication. The beneficial effects of melatonin on sepsis and viral influenza were demonstrated previously, but its effects on covid-19, especially COVID -19 ICU, is unclear. Therefore, our aim was to determine the effects of melatonin in COVID-19 ICU patients. Methods: This is a retrospective cohort study in which the records of patients admitted to COVID -19 ICU of (XXX) during March to June 2020 were reviewed. According to inclusion criteria, patients who received 15 mg of melatonin daily were called MRG and the rest were called NMRG. Results: Thirty-one patients were included and analyzed, of which twelve patients were in MRG. Demographic and clinical characteristics, and laboratory data were similar between two groups at ICU admission. Melatonin had no significant effect on ICU duration, CRP and ESR, also the trend of changes was in favor of melatonin. Nevertheless, melatonin significantly reduced the NLR (OR = -9.81, p = 0.003), and also declined mortality marginally (p = 0.09). Melatonin was well tolerated with no major adverse effects, moreover the thrombocytopenia occurrence was significantly lower in MRG (p = 0.005). In MRG, survival increased and mortality risk decreased, although the difference between groups wasn't significant (p = 0.37), which might be related to the small sample-size. Conclusion: Our study showed that melatonin is unlikely to reduce mortality among COVID19 patients and with no significant effect on disease-specific biochemical parameters.

Predictors of Mortality among COVID-19 Patients Admitted to Intensive Care Units: A Single-Center Study in Tehran, Iran.

BACKGROUND: Iran was one of the first countries to become an epicenter of the coronavirus disease 2019 (COVID-19) epidemic. However, there is a dearth of data on the outcomes of COVID-19 and predictors of death in intensive care units (ICUs) in Iran. We collected extensive data from patients admitted to the ICUs of the one of the tertiary referral hospitals in Tehran, Iran, to investigate the predictors of ICU mortality. METHODS: The study population included 290 COVID-19 patients who were consecutively admitted to the ICUs of the Sina hospital from May 5, 2021, to December 6, 2021, a period that included the peak of the epidemic of the delta (δ) variant. Demographic data, history of prior chronic diseases, laboratory data (including markers of inflammation), radiologic data, and medication data were collected. RESULTS: Of the 290 patients admitted to the ICUs, 187 (64.5%) died and 103 (35.5%) survived. One hundred forty-one (141, 48.6%) were men, and the median age (10th percentile, 90th percentile) was 60 (41, 80). Using logistic regression models, older age, history of hypertension, high levels of inflammatory markers, low oxygen saturation, substantial lung involvement in computed tomography (CT) scans, and gravity of the disease as indicated by the WHO 8-point ordinal scale were primary predictors of mortality at ICU. The use of remdesivir and imatinib was associated with a statistically non-significant reduction in mortality. The use of tocilizumab had almost no effect on mortality. CONCLUSION: The findings are consistent with and add to the currently existing international literature. The findings may be used to predict risk of mortality from COVID-19 and provide some guidance on potential treatments.

Reversible blindness after erroneous prescription of closantel: A case report.

A 20-year-old girl was referred with vision loss upon closantel use. Plasma exchange and high-dose corticosteroid pulse therapy were administered. A 2.5-year follow-up showed improved vision and increased layer thickness of the peripheral nerve fiber. Early treatment with plasma exchange and high-dose corticosteroid therapy can be beneficial to reverse closantel toxicity.

Pentoxifylline effects on hospitalized patients with COVID19: A randomized, double-blind clinical trial.

Pentoxifylline (PTX) has broad-spectrum properties such as anti-inflammatory, anticoagulant, and antiviral effects. The aim of this study was to evaluate the efficacy and safety of PTX in hospitalized patients with COVID-19. This double-blind, placebo-controlled randomized clinical trial was conducted on hospitalized patients with COVID-19. The recruited patients were randomly (1:1) assigned to the PTX group and the placebo group. The intervention group received PTX capsules at a dose of 400 mg three times a day for 10 days along with the national regimen, including interferon plus lopinavir/ritonavir and hydroxychloroquine. The primary outcome was the improvement of clinical scores. The secondary outcomes, on the other hand, were improvement in inflammatory and oxidative stress factors and hospital complications. From a total of 102 patients who met the inclusion criteria, 72 individuals completed the study and were analyzed. No significant differences were shown in demographics and baseline clinical characteristics. Clinical scores was not significant between the two groups (P = 0.31 and 0.07 for day 5 and 11, respectively). Although the mean serum levels of interleukin-6 (IL-6) and glutathione changed significantly after 5 days in the PTX group (P = 0.03 and p = 0.04), ICU admission, intubation, and hospital stay did not differ between the two groups. The results of our study did not show any superiority of PTX over placebo in improving the clinical outcomes of patients with COVID-19. Although PTX had a beneficial effect on IL-6 and showed an acceptable safety profile, it did not offer any clinical benefit for COVID-19 complications.

Plant Polyphenols: Natural and Potent UV-Protective Agents for the Prevention and Treatment of Skin Disorders.

Nowadays, destructive and immunosuppressive effects from long-term exposure to UV radiation have been fully investigated and documented in the literature. UV radiation is known as the main cause of skin aging and carcinogenesis. Hence, skin protection against anti-oxidative and immunosuppressive processes is highly in demand. Now, plant polyphenols have been found as a versatile and natural tool for the prevention and treatment of various skin diseases. The presence of a large number of hydroxyl groups in the cyclic structure of polyphenols has induced valuable biological activities. Among them, their UV protective activity has attracted lots of attention due to promising efficacy and simple instruction to use.

Anti-cholinesterase and Neuroprotective Activities of Sweet and Bitter Apricot Kernels (Prunus armeniaca L.).

Apricot (Prunus armeniaca L.) is a fruit cultivated in various parts of the world. Both sweet and bitter kernels of apricot have been used for the treatment of different diseases such as loss of memory in Iranian traditional medicine (ITM). In the present study, the inhibitory activity of sweet and bitter extracts of apricot kernels towards cholinesterase (ChE) enzymes, both acetyl and butyrylcholinesterase was examined through Ellman's method. In addition, neuroprotectivity of aqueous extracts and amygdalin were investigated against H2O2-induced cell death in PC12 neurons. Among them, the best acetylcholinesterase (AChE) inhibitory activity (IC50 = 134.93 ± 2.88 µg/mL) and neuroprotectivity (P-value < 0.0001) were obtained by the aqueous extract of bitter type. It was found that all extracts showed no butyrylcholinesterase (BChE) inhibitory activity.

Novel N-benzylpyridinium moiety linked to arylisoxazole derivatives as selective butyrylcholinesterase inhibitors: Synthesis, biological evaluation, and docking study.

A novel series of N-benzylpyridinium moiety linked to arylisoxazole ring were designed, synthesized, and evaluated for their in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. Synthesized compounds were classified into two series of 5a-i and 5j-q considering the position of positively charged nitrogen of pyridinium moiety (3- or 4- position, respectively) connected to isoxazole carboxamide group. Among the synthesized compounds, compound 5n from the second series of compounds possessing 2,4-dichloroaryl group connected to isoxazole ring was found to be the most potent AChE inhibitor (IC50 = 5.96 µM) and compound 5j also from the same series of compounds containing phenyl group connected to isoxazole ring demonstrated the most promising inhibitory activity against BChE (IC50 = 0.32 µM). Also, kinetic study demonstrated competitive inhibition mode for both AChE and BChE inhibitory activity. Docking study was also performed for those compounds and desired interactions with those active site amino acid residues were confirmed through hydrogen bonding as well as π-π and π-anion interactions. In addition, the most potent compounds were tested against BACE1 and their neuroprotectivity on Aß-treated neurotoxicity in PC12 cells which depicted negligible activity. It should be noted that most of the synthesized compounds from both categories 5a-i and 5j-q showed a significant selectivity toward BChE. However, series 5j-q were more active toward AChE than series 5a-i.

Oliveria decumbens, a Bioactive Essential Oil: Chemical Composition and Biological Activities.

Oliveria decumbens is an aromatic plant traditionally used for treatment of infections and gastrointestinal diseases. In the present study, the volatile oil of the plant was obtained by hydrodistillation and analyzed by GC-MS. In addition, antibacterial and anti-Helicobacter pylori activities of this essential oil were determined using disc diffusion and agar dilution methods, respectively. Insecticidal activity was assessed through topical and fumigation application of the essential oil to cabbage looper larvae. Acetylcholinesterase (AChE) inhibition by the essential oil was examined using Ellman's method. Furthermore, its cytotoxic potential against three different cancer cell lines was assessed using the MTT assay. The phenolic monoterpenoids, thymol (38.79%), and carvacrol (36.30%) were identified as major constituents of the essential oil. We observed significant antibacterial activity of the essential oil against H. pylori (MIC=20.4 µg /mL) as well as other tested bacteria, except for Pseudomonas aeruginosa. O. decumbens essential oil showed significant toxicity to cabbage looper larvae with LD50 value of 52.1 µg /larva following topical and fumigant administration. O. decumbens essential oil was considerably inhibitory to acetylcholinesterase activity (IC50 = 0.117 µg/mL). Cytotoxic assay of the volatile oil resulted in IC50 = 0.065, 0.104, and 0.141 µg/mL for MCF-7, T47D and MDA- MB-231 cell lines, respectively. According to our data, this species with high concentrations of thymol and carvacrol could be considered as a natural source for pharmaceutical products.

Novel tacrine-coumarin hybrids linked to 1,2,3-triazole as anti-Alzheimer's compounds: In vitro and in vivo biological evaluation and docking study.

A new series of tacrine-coumarin hybrids linked to 1,2,3-triazole were designed, synthesized, and tested as potent dual binding site cholinesterase inhibitors (ChEIs) for the treatment of Alzheimer's disease (AD). Among them, compound 8e was the most potent anti-AChE derivative (IC50 = 27 nM) and compound 8m displayed the best anti-BChE activity (IC50 = 6 nM) much more active than tacrine and donepezil as the reference drugs. Compound 8e was also evaluated for its BACE1 inhibitory activity and neuroprotectivity against PC12 cells exposed to Aß25-35 which indicated low activity. Finally, in vivo studies by Morris water maze task showed that compound 8e significantly reversed scopolamine-induced memory deficit in rats.

Design and synthesis of novel coumarin-pyridinium hybrids: In vitro cholinesterase inhibitory activity.

A novel series of coumarin-pyridinium hybrids were synthesized and evaluated as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using Ellman's method. Among synthesized compounds, 1-(3-fluorobenzyl)-4-((2-oxo-2H-chromene-3-carboxamido)methyl)pyridinium bromide (7l) was found to be the most active compound toward AChE (IC50 = 10.14 µM), 1-(3-chlorobenzyl)-3-((2-oxo-2H-chromene-3-carboxamido)methyl)pyridinium bromide (7g) and 1-(2,3-dichlorobenzyl)-3-((2-oxo-2H-chromene-3-carboxamido)methyl)pyridinium chloride (7h) depicted the best BChE inhibitory activity (IC50s = 0.32 and 0.43 µM, respectively). Although most compounds showed moderate to good anti-AChE activity, their anti-BChE activity was more significant and compound 7g was found as the most selective BChE with SI of 101.18. Also, kinetic study of the compounds 7g and 7l displayed a mixed type inhibition for both AChE and BChE. Furthermore, they were evaluated against ß-secretase; however, they showed low inhibitory activity.

Chemodiversity of Nepeta menthoides Boiss. & Bohse. essential oil from Iran and antimicrobial, acetylcholinesterase inhibitory and cytotoxic properties of 1,8-cineole chemotype.

The essential oil of Nepeta menthoides Boiss. & Bohse., from Iran, was analysed by GC/MS. Two types of multivariate analyses were done based on the chemical composition of the investigated sample in this study and 12 other samples reported in the literature to show the chemodiversity in essential oil composition. Antimicrobial, acetylcholinesterase inhibitory and cytotoxic activities of the essential oil and its major component were assessed. Twenty-one compounds were identified, representing 96.81% of the total oil and the major constituent was 1,8-cineole (70.06%). Multivariate analyses revealed two chemotypes, i.e. nepetalactone and 1,8-cineole. The essential oil of the sample investigated in this study which was a 1,8-cineole chemotype and 1,8-cineole showed moderate antimicrobial activity and significantly inhibited the activity of acetylcholinesterase enzyme. Cytotoxicity evaluation against three breast cancer cell lines showed a potent inhibitory activity. Further investigations are necessary to confirm the variety in several populations of N. menthoides.

In vitro cholinesterase inhibitory activity of some plants used in Iranian traditional medicine.

In this study, in vitro evaluation of cholinesterase inhibitory (ChEI) activity of various plants including betel nuts (Areca catechu L.), clove buds (Syzygium aromaticum L.), aerial parts of dodder (Cuscuta chinensis Lam.), common polypody rhizomes (Polypodium vulgare L.) and turpeth roots (Ipomoea turpethum R. Br.) which were recommended for the treatment of AD symptoms in Iranian Traditional Medicine (ITM) is reported. Among them, aqueous extract of A. catechu L. was found as the most potent anti-AChE (IC50 = 32.00 µg/mL) and anti-BChE (IC50 = 48.81 ± 0.1200 µg/mL) agent.

Novel tacrine-1,2,3-triazole hybrids: In vitro, in vivo biological evaluation and docking study of cholinesterase inhibitors.

A new series of tacrine-1,2,3-triazole hybrids were designed, synthesized, and evaluated as potent dual cholinesterase inhibitors. Most of synthesized compounds showed good in vitro inhibitory activities toward both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among them, 7-chloro-N-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-1,2,3,4-tetrahydroacridin-9-amine (5l) was found to be the most potent anti-AChE derivative (IC50 = 0.521 µM) and N-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-1,2,3,4-tetrahydroacridin-9-amine (5j) demonstrated the best anti-BChE activity (IC50 = 0.055 µM). In vivo studies of compound 5l in Morris water maze task confirmed memory improvement in scopolamine-induced impairment. Also, molecular modeling and kinetic studies showed that compounds 5l and 5j bound simultaneously to the peripheral anionic site (PAS) and catalytic sites (CS) of the AChE and BChE.

Synthesis of novel chromenones linked to 1,2,3-triazole ring system: Investigation of biological activities against Alzheimer's disease.

In this work, novel chromenones linked to 1,2,3-triazole ring system were synthesized and evaluated for their anti-ChE activity. Among them, N-((1-(2-chlorobenzyl)-1H-1,2,3-triazol-5-yl)methyl)-8-methoxy-2-oxo-2H-chromene-3-carboxamide (6m) showed good anti-acetylcholinesterase activity (IC50=15.42µM). Also, compound 6m demonstrated neuroprotective effect against H2O2-induced cell death in PC12 neurons, however, it showed no beta-secretase (BACE1) inhibitory activity. Docking and kinetic studies separately confirmed dual binding activity of compound 6m since it targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE.

Novel Tacrine-Based Pyrano[3',4':5,6]pyrano[2,3-b]quinolinones: Synthesis and Cholinesterase Inhibitory Activity.

In order to develop effective anti-cholinesterase compounds, a novel series of pyrano[3',4':5,6]pyrano[2,3-b]quinolinones were designed, synthesized, and evaluated in vitro against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). All derivatives showed very good AChE inhibitory (AChEI) activity (IC50 = 0.37-5.62 µM) compared with rivastigmine (IC50 = 11.07 µM). Among them, 11-amino-12-(2,3-dichlorophenyl)-3-methyl-7,8,9,10-tetrahydropyrano[3',4':5,6]pyrano[2,3-b]quinolin-1(12H)-one (6f) displayed the best inhibitory activity. However, most of the synthesized compounds showed no anti-BChE activity and compounds 6b and 6f were found to be only moderate inhibitors. The most potent anti-AChE compound 6f had low and moderate inhibitory activity and neuroprotective effects against beta-secretase (BACE1) and oxidative stress-induced cell death, respectively. Also, kinetic and molecular docking studies of binding interactions elucidated that compound 6f bound to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE.

Medicinal Plants Used in Iranian Traditional Medicine (ITM) as Contraceptive Agents.

BACKGROUND: In recent years, rapid population growth and unsafe abortions have emerged as controversial health issues in some countries. Hence, safe and effective contraceptive methods or agents have attracted a great deal of attention and the corresponding market has been widely expanded. OBJECTIVE: In this study, we present a review profiting from Iranian Traditional Medicine (ITM) to introduce expedient plants as efficient contraceptive agents. METHODS: Medicinal plants suggested as contraceptive agents were obtained from ITM text books and they were also investigated using search engines to confirm their in vitro and in vivo efficacy. RESULTS: According to credible Iranian medical literature a wide spectrum of plants possesses contraceptive activity and among them, Ruta graveolens, Ricinus communis, Piper nigrum, and Physalis alkekengi were found to be more efficient. CONCLUSION: Complementary and Alternative Medicine (CAM), particularly herbal remedies have received a lot of attention because of their truly healing properties. Focusing on ITM knowledge, there are various comments based on medicinal plants to reduce unsafe abortions leading to better public health in the society.

An Evidence-Based Review on Medicinal Plants Used as Insecticide and Insect Repellent in Traditional Iranian Medicine.

CONTEXT: Insects can be the cause of major ecological problems; they can transmit microbes and parasites that affect humans, and damage food crops, trees, and homes. The total economic cost of insect-related damage and disease is immeasurable. In traditional Iranian medicine (TIM), several medicinal plants have been identified as insecticides or insect repellents, but many of them are still unknown. Therefore, the aim of this study was to review the insecticidal or insect repellent activity of certain medicinal plants described in TIM. EVIDENCE ACQUISITION: Information about medicinal plants proposed as insecticides and insect repellents in the TIM was collected from the TIM literature, and searched in modern medical databases to find studies that confirmed their efficacy. RESULTS: Modern investigations have supported the claims of the insecticidal activity of several plants, including Allium sativum, Artemisia absinthium, Citrullus colocynthis, Laurus nobilis, Mentha pulegium, Myrtus communis, Nerium oleander, Ocimum basilicum, and Origanum majorana. However, in the cases of plants like Iris florentina and Malva sylvestris, there is not enough evidence in modern medicine to prove their effectiveness with regard to their insecticidal and insect repellent activities. CONCLUSIONS: This study confirmed the Iranian traditional medicine claims of the insecticidal and insect repellent activity of certain plants. Further pharmacological and clinical studies are recommended to evaluate the overall efficacy and possible mechanisms underlying these herbs.