Zataria multiflora affects pulmonary function tests, respiratory symptoms, bronchodilator drugs use and hematological parameters in chronic obstructive pulmonary disease patients: A randomized doubled-blind clinical trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Zataria multiflora is employed as an antitussive, anti-spasmodic, analgesic and etc. Agent in traditional medicine. The modern medical studies are also confirmed effects of this plant for treatment of respiratory problems via anti-inflammatory, anti-oxidant and immunomodulatory properties. AIM OF STUDY: We evaluated efficacy of Z. multiflora on tests of pulmonary function, respiratory symptoms, inhaled bronchodilator drugs use, and hematological factors in COPD patients. METHODS: Patients (n = 45) were randomly grouped in the following three groups: placebo group (P), groups received Z. multiflora extract 3 and 6 mg/kg/day (Z3 and Z6). FEV1 and MEF25-75, respiratory symptoms, inhaled bronchodilator drugs use and hematological factors were evaluated before and 1-2 months after treatment. RESULTS: Z. multiflora led to significant enhancement of FEV1 (p < 0.05 to p < 0.01). Respiratory symptoms were also considerably ameliorated following treatment with extracts for 1 and 2 months compared to baseline values (p < 0.05 to p < 0.001). In groups received extract, inhaled bronchodilator drugs use was remarkably declined at the end of study (both, p < 0.05). Reduction of total WBC was observed 1-2 months after treatment in treated groups with extract compared to baseline values (p < 0.05 to p < 0.001). Neutrophils were remarkably declined in Z3 and Z6 groups after 2-monthes compared to 1-month treatment (p < 0.05 to p < 0.01). CONCLUSION: The evidence show therapeutic effect of this herb on COPD patients which could be result from properties that help to decrease inflammation.

Novel hits for autosomal dominated polycystic kidney disease (ADPKD) targeting derived by in silico screening on ZINC-15 natural product database.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disorder that leads to growth cysts in the kidney, ultimately resulting in loss of function. Currently, no effective drug therapy can be safely used in the clinic. So, looking for effective therapeutic drugs is urgent for treating ADPKD. Our natural product library was prepared based on the ZINC-15 database. Lipinski's rule of five, drug-likeness, and toxicity screening of the designed library were evaluated. Swiss model online server was used for modeling of GANAB target. Finally, docking-based screening against ADPKD targets was done by MOE 2019 software. The top 14 favorable druglike and non-toxic hits were selected for docking studies. Our results showed that compound-10 (ZINC 6073947) as a sesquiterpene coumarin had more negative binding interaction into the active site of PPARG, OXSR1, GANAB, AVPR2, and PC2 with docking scores of -8.22, -7.52, -6.98, -6.61 and -6.05 kcal/mol, respectively, in comparison to Curcumin, as a natural product that is now in phase 4 clinical trial in ADPKD disease, with an affinity of -8.03, -6.42, -6.82, -5.84 and -5.10 kcal/mol, respectively. Furthermore, seven sesquiterpene coumarins similar to compound 10 were generated and docked. Farnesiferol B (16), compared to compound-10, showed binding affinity of -8.16, -6.4, -7.46, -6.92, and -6.11 kcal/mol against the above targets, respectively. Molecular dynamics, which was done on the compound-10 and 16 (Farnesiferol B) in complex with PPARG, GANAB, and AVPR2, showed more negative binding free-energy than Pioglitazone, Miglitol, and Tolvaptan as FDA-approved drugs for each target, respectively.Communicated by Ramaswamy H. Sarma.

Crosslinked hydrogel loaded with chitosan-supported iron oxide and silver nanoparticles as burn wound dressing.

Burns can result in infection, disability, psychosocial and economic issues. Advanced wound dressings like hydrogel absorb exudate and maintain moisture. Considering the antimicrobial properties of silver nanoparticles and iron oxide nanoparticles, the efficiency of cross-linked hydrogel loaded with chitosan-supported iron oxide and silver nanoparticles for burn wounds repair was investigated in animal model. Cellulose hydrogel dressing made from carboxymethylcellulose and hydroxyethylcellulose crosslinked with different concentrations of citric acid (10, 15, 20, and 30%) was produced. The physicochemical characteristics of the synthetized hydrogels including Fourier-Transform Infrared spectroscopy, Thermal behavior, Swelling properties, and Scanning Electron Microscope (SEM) were evaluated. The silver nanoparticles and iron nanoparticles were produced and the characteristics, cytotoxicity, antimicrobial activities and their synergistic effect were investigated. After adding nanoparticles to hydrogels, the effects of the prepared wound dressings were investigated in a 14-day animal model of burn wound. The results showed that the mixture comprising 12.5 ppm AgNps, and IONPs at a concentration ≤100 ppm was non-cytotoxic. Moreover, the formulations with 20% CA had a swelling ratio of almost 250, 340, and 500 g/g at pHs of 5, 6.2, and 7.4 after one hour, which are lower than those of formulations with 5 and 10% CA. The total mass loss (59.31%) and the exothermic degradation happened in the range of 273-335 °C and its Tm was observed at 318.52 °C for hydrogels with 20% CA. Thus, the dressing comprising 20% CA which was loaded with 12.5 ppm silver nanoparticles (AgNPs) and 100 ppm iron oxide nanoparticles (IONPs) indicated better physicochemical, microbial and non-cytotoxic characteristics, and accelerated the process of wound healing after 14 days. It was concluded that the crosslinked hydrogel loaded with 12.5 ppm AgNPs and 100 ppm IONPs possesses great wound healing activity and could be regarded as an effective topical burn wound healing treatment.

Cost-effectiveness and budget impact analysis of lisdexamfetamine versus methylphenidate for patients under 18 with attention-deficit/hyperactivity disorder in Iran.

BACKGROUND: Lisdexamfetamine (LDX) and Methylphenidate (MPH) are stimulant agents that have been shown to provide significant benefits in the management of attention-deficit/hyperactivity disorder (ADHD) in patients. AIM: This study aimed to assess the cost-effectiveness and the budget impact of LDX compared to MPH as the first-line treatment for ADHD. METHODS: A one-year cost-effectiveness analysis (CEA) was conducted to compare the effects of LDX and MPH in reducing disease symptoms and patient costs and improving quality of life (QoL) from a social perspective. Clinical data were obtained using the EQ-5D questionnaire. In contrast, economic data were sourced from the official website of the Iranian Food and Drug Association (FDA), the national book of tariffs, and specific questionnaires designed to evaluate patients' direct and indirect costs. 197 patients were included in the study, including individuals who sought psychiatric evaluation at a hospital in Mashhad and those who obtained ADHD medications from governmental pharmacies. The cost-effectiveness of the study medicine was assessed using the decision tree method, and the results were presented as the Incremental Cost-Effectiveness Ratio (ICER). Deterministic Sensitivity Analysis (DSA) and Probabilistic Sensitivity Analysis (PSA) were performed to assess the robustness of the findings. Additionally, a Budget Impact Analysis (BIA) was conducted over five years, considering three different scenarios, to evaluate the financial implications of incorporating LDX into the national pharmaceutical system. RESULTS: The ICER for LDX therapy compared to MPH was estimated at USD 264.28 (with an incremental cost of USD 54.9, incremental effectiveness of 0.208, and Quality-Adjusted Life Years (QALYs) gained of 0.765). The PSA indicated a 0.994% probability of LDX being cost-effective, considering a threshold of USD 2450 per QALY. Furthermore, the DSA revealed that the acquisition cost of LDX influenced the model's sensitivity. The BIA demonstrated that incorporating LDX into Iran's healthcare system would result in a financial burden of approximately $368,566 in the first year, representing an additional cost of $11,154 compared to the non-availability of this medicine and the use of previous medications. It is projected that by 2027, the financial burden of treating ADHD with LDX will reach approximately USD 443,879 over five years, amounting to an increase of $71,154 compared to the absence of this medicine. CONCLUSION: From a social perspective, the inclusion of LDX in the treatment regimen for ADHD is associated with higher costs and an increased financial burden. However, based on our analysis, LDX appears to be a cost-effective choice for managing ADHD in Iran when compared to MPH.

Effects of Trehalose Administration in Patients with Mucopolysaccharidosis Type III.

BACKGROUND AND AIM: Mucopolysaccharidosis type III (MPS III) is a rare autosomal recessive lysosomal storage disease (LSD) caused by a deficiency of lysosomal enzymes required for the catabolism of glycosaminoglycans (GAGs), mainly in the central nervous system. Trehalose has been proposed as a potential therapeutic agent to attenuate neuropathology in MPS III. We conducted a single-arm, open-label study to evaluate the efficacy of trehalose treatment in patients with MPS IIIA and MPS IIIB. METHODS: Five patients with MPS III were enrolled. Trehalose was administrated intravenously (15 g/week) for 12 weeks. Health-related quality of life and cognitive function, serum biomarkers, liver, spleen, and lung imaging were assessed to evaluate trehalose efficacy at baseline and trial end (week 12). RESULTS: TNO-AZL Preschool children Quality of Life (TAPQOL) scores increased in all patients, and the mean scores for quality of life were increased after the intervention. Serum GAG levels were reduced in all treated patients (however, the differences were not statistically significant). Alanine aminotransferase (ALT) levels were reduced in all patients post-treatment (p=0.0039). The mean levels of aspartate transaminase (AST) were also decreased after 12 weeks of treatment with Trehalose. Decreased serum pro-oxidant-antioxidant balance and increased GPX activity were observed at the end of the study. Decreases in mean splenic length were observed, whereas the liver volume did not change. CONCLUSION: Improvements in health-related quality of life and serum biomarkers (GAGs, liver aminotransferase levels, antioxidant status), as well as liver and spleen size, were found following 3 months of trehalose administration in patients with MPS IIIA and MPS IIIB.

Simultaneous determination of mometasone furoate and calcipotriol in a binary mixture by validated HPLC and chemometric-assisted UV spectrophotometric methods and identification of degradation products by LC-MS.

Objectives: A new binary mixture containing mometasone furoate (MF) and calcipotriol (CP) is suggested to manage psoriasis; since the combined stability profile of these drugs is poorly understood. Materials and Methods: Herein MF, CP, and their mixtures were subjected to various stress conditions. Also, stability-indicating HPLC was developed and validated according to ICH guidelines with Box-Behnken design. The degradation products (DPs) were predicted in silico and identified using LC-MS. The bioactivity and toxicity of DPs were studied using molecular docking and alamarBlue assay, respectively. Spectroscopic techniques of the first derivative, first-derivative ratio, and the mean-centering of ratio spectra were also used to determine MF and CP in the mixture because of spectra overlapping. Results: The major degradants for MF in alkaline conditions were DP1, DP2, and DP3, while in thermal and UV conditions, only DP1 was generated. CP gave one degradant in all conditions. No new impurity was observed in the MF and CP mixtures. The results of spectrophotometry showed good linearity in the range of 4-50 and 2-20 µg/ml, while linearity for HPLC was in the range of 4-50 and 0.5-2.5 µg/ml for MF and CP, respectively. Recovery was 99.61-100.38% for UV and 100.4% for HPLC methods of MF and 100.6-101.4% for UV and 99.5% for HPLC methods of CP. Conclusion: The developed methods can be used as simple, accurate, precise, and rapid techniques for routine quality control of MF and CP mixtures.

Recent Progresses in Analytical Perspectives of Degradation Studies and Impurity Profiling in Pharmaceutical Developments: An Updated Review.

Forced degradation studies have been used to simplify analytical methodology development and achieve a deeper knowledge about the inherent stability of active pharmaceutical ingredients (API) and drug products. This provides insight into degradation species and pathways. Identification of impurities in pharmaceutical products is closely related to the selection of the most appropriate analytical methods like HPLC-UV, LC-MS/MS, LC-NMR, GC-MS, and capillary electrophoresis. Herein, recent trends in analytical perspectives during 2018-April 14, 2021, are discussed based on forced and impurity degradation profiling of pharmaceuticals. Literature review showed that several methods have been used for experimental design and analysis conditions such as matrix type, column type, mobile phase, elution modes, detection wavelengths, and therapeutic category. Thus, since these factors influence the separation and identification of the impurities and degradation products, we attempted to perform a statistical analysis for the developed methods according to the abovementioned factors.

The effect of two-month treatment with Zataria multiflora on inflammatory cytokines, pulmonary function testes and respiratory symptoms in patients with chronic obstructive pulmonary disease (COPD).

ETHNOPHARMACOLOGICAL RELEVANCE: Zataria multiflora Boiss. (Z. multiflora) is a valuable medicinal plant that has been used in Iranian traditional and folk medicine as an antiseptic, carminative, diaphoretic, diuretic, anti-spasmodic and analgesic herbal medicine. This plant has been also used to relieve cough in common cold and respiratory tract disorders. The previous studies reported the pharmacological effects of Z. multiflora such as anti-inflammatory and anti-oxidant properties in respiratory disorders in animal models and clinical studies. AIM OF THE STUDY: The effects of Z. multiflora extract on inflammatory cytokines, pulmonary function tests (PFT), and respiratory symptoms in chronic obstructive pulmonary diseases (COPD) patients were investigated. MATERIALS AND METHODS: COPD patients (41 cases) were divided to three groups including placebo group (P) and groups received 3 and 6 mg/kg/day Z. multiflora extract (Z3 and Z6) for two months. Inflammatory cytokines, PFT values, and respiratory symptoms were assessed before treatment (stage 0), one (stage I) and two (stage II) months after treatment. RESULTS: Serum levels of TNF-α and IL-8 were significantly decreased after two months treatment compared to baseline values in Z3 and Z6 groups. The PFT values including forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were significantly increased during two months treatment with Z3 and Z6. The peak expiratory flow (PEF) was also significantly increased after one-month treatment with Z6. The respiratory symptoms including cough, chest tightness, modified medical research council (mMRC) dyspnea scale were significantly improved after one and two treatments with both doses of Z. multiflora compared to baseline values. CONCLUSION: The results suggest the potential therapeutic effect of Z. multiflora in COPD patients through reduction of inflammatory cytokines, increasing PFT values and improvement of respiratory symptoms.

Evaluating the efficacy of photodynamic therapy with indocyanine green in the treatment of keloid.

BACKGROUND: This study aimed to evaluate the efficacy of photodynamic therapy (PDT) with topical indocyanine green (ICG) in the treatment of keloid lesions. METHODS: In this pilot study, fifteen keloids (6 lesions on the sternal area, 3 on the shoulders, 2 on the abdomen, 2 on the legs, and 2 on the forearms) were selected. To enhance drug penetration, pretreatment with CO2 laser was performed. Then Lesions were covered with 0.2% transfersomal ICG gel with 1 mm thickness and occluded with light-proof plastic nylon for 2 h. Afterward, it was wiped off and underwent photodynamic therapy with source LumaCare with 730 nm probe and fluence of 23 J/cm2 every week for 6 sessions. Patients were also assessed 6 and 12 weeks after the treatment for any recurrences. The Patient and Observer Scar Assessment Scale (POSAS) was used to evaluate the scars. RESULTS: The mean POSAS score significantly reduced by 23.69% from 46.86 at baseline to 35.76 at the 6th treatment session (P< 0.001). The mean scores of patient and observer overall opinion significantly decreased by 16.35% (P< 0.001) and 12.31% (P = 0.001) respectively. No side effects were observed during treatment and after 3 months of follow-ups. After discontinuation of therapy, the mean score of POSAS significantly increased by 13.77% to 40.80. (P = 0.001) CONCLUSION: According to our study, ICG-PDT is an effective and safe treatment for keloid. However, due to the recurrence following discontinuation of treatment, further studies are needed.

The effect of standardized honey on mucosal healing of the nose and paranasal sinuses after polypectomy: A randomized controlled, double blind pilot study.

OBJECTIVES: Nasal polyposis (NP) is a chronic inflammatory disease. Honey has several anti-microbial, anti-oxidants, healing, and anti-inflammatory properties which may reduce the need for steroids in this situation. Therefore, the aim of this study is to show the effect of standardized honey on mucosal healing of the nose and paranasal sinuses after polypectomy. DESIGN AND METHOD: In this double-blind, randomized, placebo-controlled clinical trial, 28 patients with nasal polyposis underwent functional endoscopic sinus surgery (FESS). Besides common post-op medications, normal saline (as a placebo) and diluted processed honey were used separately in the two nostrils of each patient. Two endoscopic follow-ups using the Philppot-Javer (P-J) scoring system were performed to assess the healing and recurrence of polyps on either side. The secondary outcome measure was the patients' satisfaction rate. RESULTS: The patients' mean age was 38.03±11.9 years. 15(57.7%) had a positive prick test and also 15(57.7%) had dense eosinophilic infiltration in their surgical specimens. In the first and second follow-up sessions, total P-J scores showed better results for honey in comparison to the normal saline side but that results were not significantly different (P=0.93, P=0.07); whereas it is fair to say that in the second follow-up, the ethmoid and maxillary sinuses demonstrated a greater difference compared to the other sites based on their averages but there were not significantly meaningful (P=0.05, P=0.06). The total score also showed better results for honey in comparison to the normal saline side but was statistically insignificant (P=0.07). CONCLUSION: Diluted honey seems to have certain positive effects in reducing post-operative edema and the recurrence of nasal polyps in at least the ethmoid and maxillary sinuses; although this positive effect did not result in significant changes. (www.actabiomedica.it).

The effect of trehalose administration on vascular inflammation in patients with coronary artery disease.

BACKGROUND: In recent years, several trials investigated the role of anti-inflammatory agents in reducing cardiovascular events. Trehalose is a natural disaccharide able to reduce inflammation by enhancing macrophage autophagic activity. This action has been demonstrated to attenuate atherosclerotic plaque development in various pro-atherogenic animal models. However, at present, no data about the efficacy of this compound in human subjects have been published. METHODS: We performed a randomized, double-blind trial involving 15 patients with history of myocardial infarction and evidence of systemic inflammation (defined as C-reactive protein > 2 mg/L). The patients were randomly assigned, in 2:1 ratio, to receive either intravenous trehalose (15 g once weekly) or placebo for 12 weeks. The primary efficacy end-point was the change in arterial wall inflammation, assessed by quantifying 18F-FDG PET/CT uptake in carotid arteries and ascending aorta. RESULTS: The MDS TBR change of the index vessel at 3-month follow-up was not significant in treatment and placebo groups. Furthermore, we could not demonstrate any significant difference between the trehalose group and control group in changes of cIMT from baseline to 3 months in the overall population. No significant changes in echocardiographic measurement were noted after trehalose treatment. Except for the change in urea level in placebo group (31.00 ± 6.59 vs. 25.60 ± 6.402 P = 0.038) no other changes were detected after treatment. Also, there was a significant difference between changes in alanine aminotransferase (ALT) trehalose and placebo groups. CONCLUSION: This was the first study that specifically assessed the effects of intravenous trehalose on atherogenesis in human subjects. Trehalose treatment was characterized by an optimal safety profile, but no significant reduction in arterial wall inflammation could be observed. This might be a consequence of the small sample size of this trial. Larger studies are needed to better assess the efficacy of this compound in this clinical context.

Impact of Intravenous Trehalose Administration in Patients with Niemann-Pick Disease Types A and B.

BACKGROUND AND AIMS: Niemann-Pick disease (NPD) types A (NPA) and B (NPB) are caused by deficiency of the acid sphingomyelinase enzyme, which is encoded by the SMPD1 gene, resulting in progressive pathogenic accumulation of lipids in tissues. Trehalose has been suggested as an autophagy inducer with therapeutic neuroprotective effects. We performed a single-arm, open-label pilot study to assess the potential efficacy of trehalose treatment in patients with NPA and NPB patients. METHODS: Five patients with NPD type A and B were enrolled in an open-label, single-arm clinical trial. Trehalose was administrated intravenously (IV) (15 g/week) for three months. The efficacy of trehalose in the management of clinical symptoms was evaluated in patients by assessing the quality of life, serum biomarkers, and high-resolution computed tomography (HRCT) of the lungs at the baseline and end of the interventional trial (day 0 and week 12). RESULTS: The mean of TNO-AZL Preschool children Quality of Life (TAPQOL) scores increased in all patients after intervention at W12 compared to the baseline W0, although the difference was not statistically significant. The serum levels of lyso-SM-509 and lyso-SM were decreased in three and four patients out of five, respectively, compared with baseline. Elevated ALT and AST levels were decreased in all patients after 12 weeks of treatment; however, changes were not statistically significant. Pro-oxidant antioxidant balance (PAB) was also decreased and glutathione peroxidase (GPX) activity was increased in serum of patients at the end of the study. Imaging studies of spleen and lung HRCT showed improvement of symptoms in two patients. CONCLUSIONS: Positive trends in health-related quality of life (HRQoL), serum biomarkers, and organomegaly were observed after 3 months of treatment with trehalose in patients with NPA and NPB. Although not statistically significant, due to the small number of patients enrolled, these results are encouraging and should be further explored.

Evaluation of Anti-lice Topical Lotion of Ozonated Olive Oil and Comparison of its Effect with Permethrin Shampoo.

BACKGROUND: Pediculosis is an infestation of lice affecting mostly children and spreads by direct contact with the hair of someone infected. Although topical application of a pediculicide such as permethrin shampoo is the most common cure for head lice, the addition of alternative treatments is necessary due to permethrin resistance and some safety concerns, including irritation, burning sensation, tingling, and breathing problems. Recent studies have indicated that ozone, which is an allotropic form of oxygen, may have anti-pediculosis effects. OBJECTIVE: This study focused on the evaluation of an ozonated olive oil topical lotion for the treatment of pediculosis and the comparison of its effects with permethrin shampoo. METHODS: 121 patients with proven head pediculosis were divided into two groups. They were treated with either topical ozonated olive oil lotion or permethrin shampoo for one week. RESULTS: It was shown that the ozonation process enormously improved the physico-chemical properties of olive oil. Specifically, acid and peroxide values increased 60 fold and 200 fold, respectively, while there was a sharp decline for the iodine index (81.8±1.28 to 0 g iodine per 100 g). Additionally, all patients who received the ozonated olive oil lotion were entirely cured after one week of treatment, while those who were treated with permethrin, required to receive more. Statistical analysis of the data also proved this claim. CONCLUSION: The prepared lotion has shown significant effects in controlling head lice. Thus, it can be prescribed as an effective anti-pediculosis medicine which is biocompatible and has high potential.

Zataria multiflora extract influenced asthmatic patients by improving respiratory symptoms, pulmonary function tests and lung inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Anti-inflammatory and anti-oxidant effects of Zataria multiflora Boiss (Z. multiflora) were reported in previous studies which is using in traditional and modern medicine. This plant is traditional used as an anti-tussive agent and for the management of respiratory disorders. AIM OF THE STUDY: The preventive effect of the extract of leaves and stems of Z. multiflora on respiratory symptoms, pulmonary function tests, hematological indices, high sensitivity C-reactive protein (hs-CRP), level of interleukin-10 (IL-10) in the serum and supernatant of cultured peripheral blood mononuclear cells (PBMC) and gene expression of IL-10 in these cells in asthmatic patients was studied. MATERIALS AND METHODS: 36 asthmatic patients in three groups (randomly divided) of placebo group (P), two groups treated with 5 and 10 mg/kg/day doses of Z. multiflora (Z5 and Z10) for two months completed the study. Drugs were administered double-blindly and different variables were assessed before and after (one and two months) starting treatment including respiratory symptoms, pulmonary function tests (PFT), hematological indices, hs-CRP, serum and supernatant levels as well as gene expression of IL-10. RESULTS: Two months treatment with Z5 and Z10 led to significant reduction of respiratory symptoms (p < 0.05 to p < 0.001). Pulmonary function test values in treated groups were also significantly increased two months after starting treatment (p < 0.05 to p < 0.001). Total WBC, monocytes and eosinophils were also decreased in treated groups with the extract at the end of study period (p < 0.05 to p < 0.01). Hemoglobin and hematocrit in Z10 treated group (p < 0.05 and p < 0.01, respectively) and mean corpuscular volume (MCV) in both treated groups (p < 0.05 to p < 0.01) were significantly reduced. In addition, the level of hs-CRP in both treated groups was significantly reduced after two months (p < 0.05 to p < 0.01). IL-10 concentration in Z10 treated group in supernatant of PBMC was also significantly enhanced (p < 0.01). All comparisons were made compared to the baseline (beginning of the treatment) values. CONCLUSION: Z. multiflora improved respiratory symptoms and increased pulmonary function tests in asthmatic patients. In addition, the plant was effective in decrement of inflammatory cells and hs-CRP as well as enhanced IL-10. Therefore, the plant showed possible preventive therapeutic effect on asthma.

Methylene blue for treatment of hospitalized Covid-19 patients: a randomized, controlled, open-label clinical trial, phase 2

ABSTRACT Background: There is no pharmacological intervention on the treatment of hypoxemia and respiratory distress in COVID-19 patients. Objective: The objective of the study was to study the effect of the reduced form of methylene blue (MB) on the improvement of oxygen saturation (SpO2) and respiratory rate (RR). Methods: In an academic medical center, 80 hospitalized patients with severe COVID-19 were randomly assigned to receive either oral MB along with standard of care (SOC) (MB group, n = 40) or SOC only (SOC group, n=40). The primary outcomes were SpO2 and RR on the 3rd and 5th days. The secondary outcomes were hospital stay and mortality within 28 days. Results: In the MB group, a significant improvement in SpO2 and RR was observed on the 3rd day (for both, p < 0.0001) and also the 5th day (for both, p < 0.0001). In the SOC group, there was no significant improvement in SpO2 (p = 0.24) and RR (p = 0.20) on the 3rd day, although there was a significant improvement of SpO2 (p = 0.002) and RR (p = 0.01) on the 5th day. In the MB group in comparison to the SOC group, the rate ratio of increased SpO2 was 13.5 and 2.1 times on the 3rd and 5th days, respectively. In the MB group compared with the SOC group, the rate ratio of RR improvement was 10.1 and 3.7 times on the 3rd and 5th days, respectively. The hospital stay was significantly shortened in the MB group (p = 0.004), and the mortality was 12.5% and 22.5% in the MB and SOC groups, respectively. Conclusions: The addition of MB to the treatment protocols significantly improved SpO2 and respiratory distress in COVID-19 patients, which resulted in decreased hospital stay and mortality. ClinicalTrials.gov: NCT04370288

METHYLENE BLUE FOR TREATMENT OF HOSPITALIZED COVID-19 PATIENTS: A RANDOMIZED, CONTROLLED, OPEN-LABEL CLINICAL TRIAL, PHASE 2.

BACKGROUND: There is no pharmacological intervention on the treatment of hypoxemia and respiratory distress in COVID-19 patients. OBJECTIVE: The objective of the study was to study the effect of the reduced form of methylene blue (MB) on the improvement of oxygen saturation (SpO2) and respiratory rate (RR). METHODS: In an academic medical center, 80 hospitalized patients with severe COVID-19 were randomly assigned to receive either oral MB along with standard of care (SOC) (MB group, n = 40) or SOC only (SOC group, n=40). The primary outcomes were SpO2 and RR on the 3rd and 5th days. The secondary outcomes were hospital stay and mortality within 28 days. RESULTS: In the MB group, a significant improvement in SpO2 and RR was observed on the 3rd day (for both, p < 0.0001) and also the 5th day (for both, p < 0.0001). In the SOC group, there was no significant improvement in SpO2 (p = 0.24) and RR (p = 0.20) on the 3rd day, although there was a significant improvement of SpO2 (p = 0.002) and RR (p = 0.01) on the 5th day. In the MB group in comparison to the SOC group, the rate ratio of increased SpO2 was 13.5 and 2.1 times on the 3rd and 5th days, respectively. In the MB group compared with the SOC group, the rate ratio of RR improvement was 10.1 and 3.7 times on the 3rd and 5th days, respectively. The hospital stay was significantly shortened in the MB group (p = 0.004), and the mortality was 12.5% and 22.5% in the MB and SOC groups, respectively. CONCLUSIONS: The addition of MB to the treatment protocols significantly improved SpO2 and respiratory distress in COVID-19 patients, which resulted in decreased hospital stay and mortality. ClinicalTrials.gov: NCT04370288.

Carvacrol improves pulmonary function tests, oxidant/antioxidant parameters and cytokine levels in asthmatic patients: A randomized, double-blind, clinical trial.

BACKGROUND: Carvacrol effects on inflammatory mediators, lung pathology and tracheal responsiveness were indicated in animal models of pulmonary diseases. PURPOSE: To evaluate carvacrol effects on respiratory symptoms, pulmonary function tests (PFT), oxidative stress markers and cytokine levels in asthmatic patients. STUDY DESIGN: This study was a randomized, placebo-controlled double-blind, clinical trial. METHODS: Thirty-three moderate asthmatic patients were divided to the two groups of: placebo group (n = 16) and carvacrol group (1.2 mg/kg/day, n = 17). Prepared capsules were taken for two months along, 3 times/day along with routine medications. Respiratory symptoms, PFT, and oxidative stress markers were evaluated before the treatment (step 0), and one (step I) and two months (step II) after the beginning of the treatment. However, cytokine levels in serum and supernatant of peripheral blood mononuclear cells (PBMC), and their gene expression were evaluated in step 0 and II. RESULTS: In carvacrol-treated group, respiratory symptoms significantly decreased after one- and two-month treatment with carvacrol compared to pre-treatment values (p < 0.05 to p < 0.001). Compared to step 0, PFT values were significantly increased in step I and II, in treated group with carvacrol (p < 0.05 to p < 0.001). Most oxidative stress markers were improved following carvacrol treatment (p < 0.05 to p < 0.001). Treatment with carvacrol for two-month also significantly improved cytokine levels in serum and supernatant of PBMC, compared to step 0 (p < 0.05 to p < 0.001). However, no significant changes were observed in the above-noted parameters in the placebo group. CONCLUSION: Due to anti-inflammatory and antioxidant effect, carvacrol could be suggested as a therapeutic agent for asthma.

Safety and tolerability of carvacrol in healthy subjects: a phase I clinical study.

This study was designed to assess safety and tolerability of carvacrol in healthy individuals. Subjects were randomly divided into two groups receiving 1 and 2 mg/kg/day carvacrol. Before and after carvacrol administration, routine blood and urine laboratory tests and spirometry were performed for all participants. The results showed that one-month treatment with carvacrol did not significantly affect the measured variables. In the group receiving 1 mg/kg/day carvacrol, calcium, erythrocyte sedimentation rate (ESR), mean cell volume (MCV), hemoglobin (Hb), and hematocrit (HCT) levels were significantly reduced but creatinine phosphokinase (CPK) was significantly increased, after treatment compared to baseline values (p < 0.05-p < 0.001). There was significant reductions in high-density lipoprotein cholesterol (HDL), total bilirubin, amylase, iron, red blood cells (RBC) count, and HCT after one-month treatment with 2 mg/kg/day carvacrol compared to pretreatment values (p < 0.05-p < 0.01). Although, triglyceride (TG), phosphorus, lactate dehydrogenase (LDH), prothrombin time (PT), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were significantly increased after treatment with carvacrol 1 mg/kg/day (p < 0.05-p < 0.001), all post-treatment measured parameters were within normal range. Treatment with carvacrol 2 mg/kg/day for one month increased FEV1 (p < 0.05). Nevertheless, there was no significant difference in measured variables except LDH, MCH, MCHC, and MCV (p < 0.05-p < 0.01), between the two groups. The results of this phase I study regarding carvacrol effects on healthy subjects, showed clinical safety and tolerability for this agent.

Zataria multiflora affects clinical symptoms, oxidative stress and cytokines in asthmatic patient: A randomized, double blind, placebo-controlled, phase II clinical trial.

BACKGROUND: Z. multiflora effect on clinical symptoms, pulmonary function tests (PFT), oxidative stress and cytokine levels in asthmatic patients were evaluated. METHODS: 36 asthmatic patients were divided to; placebo group (P), two groups treated with Z. multiflora extract (5 and 10 mg/kg/day, as Z5 and Z10, respectively), (n = 12 in each group). Medications were administered three times a day for two months and several parameters were evaluated before treatment (step 0), one (step 1) and two months (step 2) after treatment. RESULTS: Clinical symptoms and PFTs were significantly improved in Z5 and Z10 groups in steps 1 and 2 compared to step 0 (p < 0.05 to p < 0.001). Improvement of oxidative stress, cytokines levels and their gene expression after treatment with both doses of extract were observed in step 2 compared to step 0 (p < 0.05 to p < 0.001). CONCLUSION: These results indicated therapeutic value of Z. multiflora for the management of asthma.

A Randomized, Doubled-Blind Clinical Trial on the Effect of Zataria multiflora on Clinical Symptoms, Oxidative Stress, and C-Reactive Protein in COPD Patients.

The effects of Zataria multiflora on clinical symptoms, pulmonary function tests, oxidative stress, and C-reactive protein levels in chronic obstructive pulmonary disease (COPD) patients were evaluated. Forty-five patients were allocated to 3 groups: placebo group and 2 groups that received 3 and 6 mg/kg/day Z. multiflora extract (Z3 and Z6) for 2 months. Clinical symptoms, pulmonary function tests, oxidative stress, and serum C-reactive protein levels were evaluated pretreatment (step 0) and 1 (step I) and 2 (step II) months after treatment. Clinical symptoms including breathlessness and chest wheeze in Z3- and Z6-treated groups and sputum production only in the Z6-treated group were significantly improved 1 and 2 months after treatment compared with baseline values (P < .01 to P < .001). The FEV1 was significantly increased after 2 months of treatment with Z3 and Z6 (P < .05 to P < .01). Malondialdehyde and nitrite levels were significantly decreased after a 2-month treatment with Z6 compared with step 0 (P < .05 to P < .01). The thiol contents in the Z6 group as well as superoxide dismutase and catalase activities in both groups treated with the extract were significantly increased in step II compared with step 0 (P < .05 to P < .01). The C-reactive protein level at the end of the study was significantly reduced compared with the step 0 in both treated groups (P < .05 for both cases). Two-month treatment with Z. multiflora improved clinical symptoms, pulmonary function tests, oxidative stress, and C-reactive protein in COPD patients. The results suggest that this herbal medicine could be of therapeutic value as a preventive drug for the treatment of COPD.