Evaluation of the effect of topical chamomile (Matricaria chamomilla L.) oleogel as pain relief in migraine without aura: a randomized, double-blind, placebo-controlled, crossover study.

Phytotherapy is a source of finding new remedies for migraine. Traditional chamomile oil (chamomile extraction in sesame oil) is a formulation in Persian medicine (PM) for pain relief in migraine. An oleogel preparation of reformulated traditional chamomile oil was prepared and then standardized based on chamazulene (as a marker in essential oil) and apigenin via gas chromatography (GC) and high-performance liquid chromatography (HPLC) methods, respectively. A crossover double-blind clinical trial was performed with 100 patients. Each patient took two tubes of drug and two tubes of placebo during the study. Visual analog scale (VAS) questionnaires were filled in by the patients and scores were given, ranging from 0 to 10 (based on the severity of pain) during 24 h. Other complications like nausea, vomiting, photophobia, and phonophobia were also monitored. There was 4.48 ± 0.01 µl/ml of chamazulene and 0.233 mg/g of apigenin in the preparation (by correcting the amount with extraction ratio). Thirty-eight patients in the drug-placebo and 34 patients in the placebo-drug groups (a total number of 72 patients as per protocol) completed the process in the randomized controlled trial (RCT). Adapted results from the questionnaires showed that pain, nausea, vomiting, photophobia, and phonophobia significantly (p < 0.001) decreased by using chamomile oleogel on the patients after 30 min. Results supported the efficacy of chamomile oleogel as a pain relief in migraine without aura.

A review on the management of migraine in the Avicenna's Canon of Medicine.

Migraine is a common type of headache which has a deep history dating back thousands of years. Avicenna (980-1032), a Persian scholar, made a great contribution to neurology including headache and migraine. The aim of this study is to consider Avicenna's description about migraine (Shaghighe in Persian language) including definition, etiology and intervention. Also, his definition and treatment approaches were considered based on current concepts and findings. Although Avicenna believed in humoral theory and divided migraine into two categories, hot and cold, and suggested special treatments for them as well as general considerations, most of his definitions and explained pathologies are supported by current concepts of medicine. He believed that the migraine can result from bone of skull and also intra-parenchymal; or from skull underneath membrane (dura-mater); or reaching substances from the painful side or from outer vein and arteries (extra cranial); or from brain and meninges (pia-mater). Furthermore, current findings show most medicinal plants mentioned by Avicenna for the treatment of migraine can have potentially significant effects such as remedies which stop central and peripheral sensitization [anti-neuroinflammatory agents, decreasing nitric oxide level, cyclooxygenase (COX)-2 inhibitors], as well as serotonergics, neuroprotective agents and analgesics.

Report - Renovation of a traditional Ergh-al-Nassa pill (Hab) to a standard Pharmaceutical molded tablet.

The Ergh-al-Nassa pill (Hab) is a traditional combination suggested as one of the most effective preparations useful for treatment of sciatica. Although traditional preparations can be applied as new therapeutic drugs for investigations and clinical trials, they need to be reformulated to achieve pharmacopoeial standards for modern medicine. In this research, based on seven traditional Persian pharmacopeias for Ergh-al-NassaHab, nine different molded tablets were reformulated. Each formulation comprised the same amount of colchicum, ginger, aloe and yellow myrobalan fruit. Sweet almond oil had to be added in the maximum amount needed to be absorbed by the yellow myrobalan fruit according to its particle size (30-40 mesh sizes). The studies were performed in order to optimize the formulation process according to the role of three levels in particle size of the herbal ingredients (60-70, 80-100, 100-150 mesh sizes) and three levels of initial water for granulation. The molded tablets were evaluated according to standard quality controls for tablets (mass uniformity, LOD, hardness, friability, and disintegration time at 20 and 30 min). Myrobalan powdered to 30-40 mesh size absorbed the maximum amount of sweet almond oil (1:0.75 w/v). The best formulations occurred when the particle size of colchicum, ginger, and aloe was 60-70 mesh size with an initial moisture content of 0.47 ml per 1g of dried powder. The outcome of this research is a pharmaceutical standardized formulation from the traditional Ergh-al-Nassa pill which can be suggested as a sample drug discovery based on traditional knowledge.

Armenian bole: a historical medicinal clay.

The medical use of earths and minerals is probably as old as the history of mankind. Particular types of clays and earths are still being used worldwide as therapeutic agents in the folk medicine of different countries. From the 19th century, the medicaments included in countries' pharmacopeias whose exact pharmacological activity or the chemistry of their active components was not known gradually decreased in number, despite their popularity among patients. With today's analytical armamentarium it may be time to reconsider returning some of those compounds to pharmacopeias. By using modern techniques in the past two decades, researchers have studied the active components of healing clays and their pharmacological properties. Many of them possess valuable therapeutic properties which could be used in modern medicine in pharmaceutical dosage forms. Our knowledge about the medical substances that our ancestors used through centuries could be used today as an evidence base for further clinical and pharmacological research. One of these substances is Armenian bole. In this work we studied the historical perspective of its therapeutic use in different countries. Also a sample sold in the market in Iran was purchased and X-ray diffraction analysis was performed on it to find out its chemical composition.

The Roadmap of Plant Antimicrobial Peptides Under Environmental Stress: From Farm to Bedside.

Antimicrobial peptides (AMPs) are the most favorable alternatives in overcoming multidrug resistance, alone or synergistically with conventional antibiotics. Plant-derived AMPs, as cysteine-rich peptides, widely compensate the pharmacokinetic drawbacks of peptide therapeutics. Compared to the putative genes encrypted in the genome, AMPs that are produced under stress are active forms with the ability to combat resistant microbial species. Within this study, plant-derived AMPs, namely, defensins, nodule-specific cysteine-rich peptides, snakins, lipid transfer proteins, hevein-like proteins, α-hairpinins, and aracins, expressed under biotic and abiotic stresses, are classified. We could observe that while α-hairpinins and snakins display a helix-turn-helix structure, conserved motif patterns such as ß1αß2ß3 and ß1ß2ß3 exist in plant defensins and hevein-like proteins, respectively. According to the co-expression data, several plant AMPs are expressed together to trigger synergistic effects with membrane disruption mechanisms such as toroidal pore, barrel-stave, and carpet models. The application of AMPs as an eco-friendly strategy in maintaining agricultural productivity through the development of transgenes and bio-pesticides is discussed. These AMPs can be consumed in packaging material, wound-dressing products, coating catheters, implants, and allergology. AMPs with cell-penetrating properties are verified for the clearance of intracellular pathogens. Finally, the dominant pharmacological activities of bioactive peptides derived from the gastrointestinal digestion of plant AMPs, namely, inhibitors of renin and angiotensin-converting enzymes, dipeptidyl peptidase IV and α-glucosidase inhibitors, antioxidants, anti-inflammatory, immunomodulating, and hypolipidemic peptides, are analyzed. Conclusively, as phytopathogens and human pathogens can be affected by plant-derived AMPs, they provide a bright perspective in agriculture, breeding, food, cosmetics, and pharmaceutical industries, translated as farm to bedside.

Immunomodulatory Peptides as Vaccine Adjuvants and Antimicrobial Agents.

The underdevelopment of adjuvant discovery and diversity, compared to core vaccine technology, is evident. On the other hand, antibiotic resistance is on the list of the top ten threats to global health. Immunomodulatory peptides that target a pathogen and modulate the immune system simultaneously are promising for the development of preventive and therapeutic molecules. Since investigating innate immunity in insects has led to prominent achievements in human immunology, such as toll-like receptor (TLR) discovery, we used the capacity of the immunomodulatory peptides of arthropods with concomitant antimicrobial or antitumor activity. An SVM-based machine learning classifier identified short immunomodulatory sequences encrypted in 643 antimicrobial peptides from 55 foe-to-friend arthropods. The critical features involved in efficacy and safety were calculated. Finally, 76 safe immunomodulators were identified. Then, molecular docking and simulation studies defined the target of the most optimal peptide ligands among all human cell-surface TLRs. SPalf2-453 from a crab is a cell-penetrating immunoadjuvant with antiviral properties. The peptide interacts with the TLR1/2 heterodimer. SBsib-711 from a blackfly is a TLR4/MD2 ligand used as a cancer vaccine immunoadjuvant. In addition, SBsib-711 binds CD47 and PD-L1 on tumor cells, which is applicable in cancer immunotherapy as a checkpoint inhibitor. MRh4-679 from a shrimp is a broad-spectrum or universal immunoadjuvant with a putative Th1/Th2-balanced response. We also implemented a pathway enrichment analysis to define fingerprints or immunological signatures for further in vitro and in vivo immunogenicity and reactogenicity measurements. Conclusively, combinatorial machine learning, molecular docking, and simulation studies, as well as systems biology, open a new opportunity for the discovery and development of multifunctional prophylactic and therapeutic lead peptides.

Surgeons and surgery from ancient Persia (5,000 years of surgical history).

The development of surgery is indebted to scientists and surgeons from various civilizations throughout history. The present study considers surgery in the ancient Persian civilization. It highlights aspects of the subject, such as findings of the first trephinated skulls in Iran; surgeons' social class (kareto baesaza in the Avestan language-dating back 3,000 years); surgical operations such as cesarean section and procedures to treat breast cancer; and the use of anesthetic compounds and surgical practice in the military. It is hoped that this catalogue of historical evidence of surgical practice in ancient Persian civilization will contribute to the history of surgery, as an important field in medical science.

Hypericum perforatum L. and the Underlying Molecular Mechanisms for Its Choleretic, Cholagogue, and Regenerative Properties.

Any defects in bile formation, secretion, or flow may give rise to cholestasis, liver fibrosis, cirrhosis, and hepatocellular carcinoma. As the pathogenesis of hepatic disorders is multifactorial, targeting parallel pathways potentially increases the outcome of therapy. Hypericum perforatum has been famed for its anti-depressive effects. However, according to traditional Persian medicine, it helps with jaundice and acts as a choleretic medication. Here, we will discuss the underlying molecular mechanisms of Hypericum for its use in hepatobiliary disorders. Differentially expressed genes retrieved from microarray data analysis upon treatment with safe doses of Hypericum extract and intersection with the genes involved in cholestasis are identified. Target genes are located mainly at the endomembrane system with integrin-binding ability. Activation of α5ß1 integrins, as osmo-sensors in the liver, activates a non-receptor tyrosine kinase, c-SRC, which leads to the insertion of bile acid transporters into the canalicular membrane to trigger choleresis. Hypericum upregulates CDK6 that controls cell proliferation, compensating for the bile acid damage to hepatocytes. It induces ICAM1 to stimulate liver regeneration and regulates nischarin, a hepatoprotective receptor. The extract targets the expression of conserved oligomeric Golgi (COG) and facilitates the movement of bile acids toward the canalicular membrane via Golgi-derived vesicles. In addition, Hypericum induces SCP2, an intracellular cholesterol transporter, to maintain cholesterol homeostasis. We have also provided a comprehensive view of the target genes affected by Hypericum's main metabolites, such as hypericin, hyperforin, quercitrin, isoquercitrin, quercetin, kaempferol, rutin, and p-coumaric acid to enlighten a new scope in the management of chronic liver disorders. Altogether, standard trials using Hypericum as a neo-adjuvant or second-line therapy in ursodeoxycholic-acid-non-responder patients define the future trajectories of cholestasis treatment with this product.

Humanizing plant-derived snakins and their encrypted antimicrobial peptides.

Due to safety restrictions, plant-derived antimicrobial peptides (AMPs) need optimization to be consumed beyond preservatives. Herein, 175 GASA-domain-containing snakins were analyzed. Factors including charge, hydrophobicity, helicity, hydrophobic moment (µH), folding enthalpy, folding heat capacity, folding free energy, therapeutic index, allergenicity, and bitterness were considered. The most optimal snakins for oral consumption as preservatives were from Cajanus cajan, Cucumis melo, Durio zibethinus, Glycine soja, Herrania umbratica, and Ziziphus jujuba. Virtual digestion of snakins predicted ACE1 and DPPIV inhibitory as dominant effects upon oral use with antihypertensive and antidiabetic properties. To be applied as a therapeutic in parenteral administration, snakins were browsed for short 20-mer encrypted fragments that were non-toxic or with eliminated toxicity using directed mutagenesis yet retaining the AMP property. The most promising 20-mer AMPs were Mr-SNK2-1a in Morella rubra with BBB permeation, Na-SNK2-2a(C18W), and Na-SNK2-2b(C16F) from Nicotiana attenuata. These AMPs were cell-penetrating peptides (CPPs), with a charge of +6, a µH of about 0.40, and a Boman-index higher than 2.48 Kcalmol-1. Na-SNK2-2a(C18W) had putative activity against gram-negative bacteria with MIC lower than 25 µgml-1, and Na-SNK2-2b(C16F) was a potential anti-HIV with an IC50 of 3.04 µM. Other 20-mer AMPs, such as Cc-SNK1-2a from Cajanus cajan displayed an anti-HCV property with an IC50 of 13.91 µM. While Si-SNK2-3a(C17P) from Sesamum indicum was a cationic anti-angiogenic CPP targeting the acidic microenvironment of tumors, Cme-SNK2-1a(C11F) from Cucumis melo was an immunomodulator CPP applicable as a vaccine adjuvant. Because of combined mechanisms, investigating cysteine-rich peptides can nominate effective biotherapeutics.

Startup-Based Learning as an Innovative Method for Pharmacy Education: Medicinal Plants Course Model.

Background: Familiarizing students with knowledge-based businesses is one of the goals emphasized in the developed educational systems worldwide. This study aimed to design a startup-based learning model (SBL). Methods: As a qualitative research study, startup teams were formed by the pharmacy students of Shiraz University of Medical Sciences in 2020. This model was used to train 120 students as pharmaceutical entrepreneurs through related lectures, simulations, and field activities. We employed this model for students to become familiar with the various stages of examining market needs, knowledge-based company registration, intellectual property, logo design, and even pharmaceutical product development. Students' feedback was assessed with a questionnaire designed by the team of researchers, and its results were used to analyze the course and improve the quality of the proposed model. Results: Most of the studied indices revealed that the students rated this model as good or excellent. Satisfaction with more important indices includes student creativity and ideation in educational activity (60.7%), attractive presentation (60.4%), teamwork among learners (62.2%), appropriateness of evaluation method (65.4%), understanding how to make herbal remedies (49.1%), learner participation in the educational activity (74.8%), entrepreneurial motivation (60.7%), and applicability (64.4%). Conclusion: We found this model effective in boosting students' satisfaction, creativity, and entrepreneurial spirit. Lecturers also play a facilitator role in addition to specialized training. Therefore, in this model, both lecturers and students can grow more and make education more attractive. This study, for the first time, demonstrated that SBL could be applied in education systems and make the students more interested in educational content and help them to prepare for the job market.

Rosa damascena together with brown sugar mitigate functional constipation in children over 12 months old: A double-blind randomized controlled trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Rosa × damascena Herrm., known as damask rose, is a bushy shrub that is found abundantly in Fars province, Iran. This species has been used in Iranian traditional practices for the treatment of abdominal pain and constipation, as gastrointestinal diseases. Brown sugar (Saccharum officinarum L.) has also shown laxative effects in pediatric patients with functional constipation. AIM OF STUDY: This study aimed to compare the effects of Polyethylene Glycol (PEG) and a syrup made of R. damascena and brown sugar on the treatment of functional constipation in children aged above 12 months. MATERIALS AND METHODS: This double-blind randomized clinical trial was performed on 100 patients. One group received PEG and the other received an herbal syrup containing the decocted extract of 0.1 g R. damascena petals mixed with 0.85 g brown sugar per 1 mL. The patients were followed up for two and four weeks and their progresses were recorded. RESULTS: The cure rate was 100% in the R. damascena group and 91.7% in the control group. R. damascena and brown sugar syrup had an odds ratio of 1.09 in the treatment of functional constipation compared to PEG, but the difference was not statistically significant. The only adverse effect detected in the R. damascena group after four weeks was the bad taste of the medication that was too sweet. Nonetheless, this could be solved during the pharmaceutical processes. CONCLUSION: The R. damascena extract and brown sugar syrup can be used as an effective, safe, and inexpensive agent in the treatment of functional constipation.

Potentials of Antitussive Traditional Persian Functional Foods for COVID-19 Therapy†.

Coronavirus disease 2019 is a worldwide pandemic resulting in a severe acute respiratory syndrome. Remdesivir is the only FDA-approved drug for hospitalized patients older than age 12. It shows the necessity of finding new therapeutic strategies. Functional foods (FFs) could have co-therapeutic and protective effects against COVID-19 infection. Traditional Persian medicine (TPM), one of the safest and most popular schools of medicine for hundreds of years, has recommended potential FF candidates to manage such a global pandemic. To reveal the potential of TPM in terms of antitussive FFs, traditional Persian pharmacopoeia "Qarabadin-e-Salehi" was searched using the keywords "Soaal" and "Sorfeh." Also, a search of MEDLINE, PubMed Central, Google Scholar, and Science Direct was performed for the relevant literature published from the inception up to March 2021. A combination of search terms including "cough, antitussive, antioxidant, anti-inflammation, antiviral, COVID-19, mucoactive, mucolytic, expectorant, and mucoregulatory" was also applied. The potential mechanism of action in SARS-CoV-2 infection was discussed. Twelve TPM FFs were found including Laooqs, Morabbas, a Saviq, a soup, and a syrup. They are combinations of two to seven ingredients. Natural compounds of mentioned formulations have the main pharmacological mechanisms including antiviral, anti-inflammatory, antioxidant, antihistamine, bronchodilator, immunomodulatory, and mucoactive effects as well as central or peripheral antitussive activities. FFs are cost-effective, easily accessible, and safe options for both treatment and prevention of COVID-19. They might have positive psychological effects along with their pharmacological effects and nutritional virtues. They could also manage persistent respiratory discomforts after recovery from COVID-19.

Anti-Inflammatory Activity and Quality Control of Erysimum cheiri (L.) Crantz.

Wallflower (Erysimum cheiri) is employed as a popular herbal drug in traditional Persian medicine. Topical formulations including cerates, lotions, sitz baths, and poultices for inflammatory disorders such as arthritis, anal fissure, endometriosis, and mastitis are known. However, there is no monograph in current pharmacopoeia for the wallflower drug. The present study is aimed to screen in vitro anti-inflammatory activity of wallflower and perform quality control and characterization tests for different organs of the herb. In this regard, albumin denaturation activity, macroscopic and microscopic, phytochemical, HPTLC, and FT-IR characteristics were investigated. Wallflower showed strong anti-inflammatory activity compared to diclofenac sodium. The root (1.25, 2.5, and 5 mg/mL) and flower (10 mg/mL) extract exhibited higher anti-inflammatory activities than that of other plant organs at the same concentrations. Moreover, total ash was found higher in aerial parts (21.52 ± 0.06%) than flower (11.01 ± 0.03%), root (5.03 ± 0.03%), and seed (6.95 ± 0.06%), while water-soluble ash was higher in seed (34.89 ± 0.26%) than flower (5.00 ± 0.03%), aerial parts (7.16 ± 0.06%), and root (5.04 ± 0.01%). Acid-insoluble ash and sulphated ash were higher in root (9.50 ± 0.04%) and aerial part (28.37 ± 0.57%), respectively. In addition, loss on drying was ranged from 2.20 ± 0.20% in flowers to 6.00 ± 0.10% in aerial parts. On the other hand, HPTLC analysis verified cardenolide compounds in all organs of the herb, and quercetin was detected in the flavonoid fingerprint of acid hydrolysed flowers. According to FT-IR results, the observed spectral region at ~3500 cm-1 attributed to -OH stretching vibration. Also, C-H (~2900-2950 cm-1), isothiocyanate (~2340 cm-1), -C=O (~1740 cm-1), conjugated C=C of the aromatic ring (~1650 cm-1), and structure of the aromatic group (~1200-1000 cm-1) were monitored. This work is the first study to the best of our knowledge, suggesting wallflower as a potential drug candidate with the basis for a monograph in addition to initial in vitro anti-inflammatory data.

Effect of a novel herbal vaginal suppository containing myrtle and oak gall in the treatment of vaginitis: a randomized clinical trial.

BACKGROUND: Uncomplicated infections such as candidiasis, bacterial vaginosis (BV), or trichomoniasis are easy to diagnose and treat. However, about 8% of patients will have a more complicated course with failure to respond to treatment or rapid recurrence of symptoms. There are many suggestions in Traditional Persian Medicine like myrtle (Myrtus communis L.) and oak gall (Quercus infectoria G.Olivier) for treatment of vaginitis. OBJECTIVES: A clinical trial was designed to assess the efficacy of a novel herbal suppository, containing myrtle and oak gall (MOGS) in treatment of vaginitis. METHODS: In a parallel randomized clinical trial, 120 women with vaginitis were randomly assigned to MOGS, metronidazole, or placebo. Formulation was simulated from traditional Persian manuscripts and MGOS was prepared after pharmaceutical optimization processing as well as quantification of gallic acid by HPLC. The study was double-blind for MOGS and placebo and single-blind for metronidazole group. RESULTS: MOGS effectively improved vaginal discharge (p = 0.024 for BV and 0.018 for trichomoniasis) and pH (compared to placebo (p = 0.013) and metronidazole (p = 0.001)). Both MOGS and metronidazole could reverse whiff test. Metronidazole was the best medication for making Nugent score negative (p = 0.005) as well as the best therapy according to laboratory findings to treat BV in comparison with placebo (p = 0.021). While for trichomoniasis, MOGS could improve the disease more successfully (p = 0.001). Both MOGS and metronidazole treated mixed vaginitis (p = 0.002). CONCLUSION: MOGS would be a chance for developing new treatment for trichomoniasis.

Comparison of the efficacy of oral fenugreek seeds hydroalcoholic extract versus placebo in nonalcoholic fatty liver disease; a randomized, triple-blind controlled pilot clinical trial.

OBJECTIVES: The aim of this study is to investigate the therapeutic property of hydroalcoholic extract of Fenugreek seeds in nonalcoholic fatty liver disease (NAFLD) in adult patients. METHODS: This randomized, placebo-controlled, parallel trial was conducted from November 2014 to June 2017. Patients aged between 18 and 70 years old with confirmed NAFLD were recruited from the Motahhari clinic, affiliated to Shiraz University of Medical Sciences, Iran. Participants either received 1 g hydroalcoholic extract of Fenugreek seeds or placebo daily for 3 months. The primary outcomes were changes in serum alanine transaminase and FibroScan controlled attenuation parameter score. Secondary outcome measures were changes in other laboratory data, liver stiffness measure, liver steatosis percent, and anthropometric variables. Participants were randomly assigned to the groups using blocked randomization method. Participants, investigators, and statistician were blinded to treatments allocation. RESULTS: After screening eighty patients, thirty patients met the inclusion criteria and were divided into two groups (1:1). After 3 months, two and four patients did not complete the trial in Fenugreek and placebo group, respectively. The changes in the anthropometrics, laboratories and FibroScan measurements were not statistically significant between the two groups. CONCLUSION: The evidence to prove the efficacy of the Fenugreek seeds' hydroalcoholic extract in NAFLD was not strong enough; hence, further experiments are still needed to assess the possible efficacy of Fenugreek on the treatment of NAFLD.

Accumulation of lignans by in vitro cultures of three Linum species.

Justicidin B, an arylnaphthalene lignan, has strong cytotoxicity on chronic myeloid and chronic lymphoid leukemia cell lines. The first report of the production of justicidin B in a Linum species concerned in vitro culture of Linum austriacum. Therefore, culture characterization and presence of arylnaphthalene-type lignans in calli and plantlets of Linum tenuifolium from section Linastrum, Linum bienne, and Linum glaucum from section Linum were studied. Seed germination of L. tenuifolium in the light and darkness was significantly higher (p < 0.05) than of L. bienne in the light and L. glaucum in the darkness. L. tenuifolium seedling length in the darkness was significantly higher (p < 0.01) than under light conditions. There were no significant differences in the calli and shoot biomass weight, number and length of shoots in three species over one month, while the shoot diameter of L. bienne was significantly different (p < 0.05) from that of L. glaucum. Justicidin B was detected in L. glaucum callus and plantlet cultures by HPLC/MS/UV-DAD and HPLC coupled with a photodiode array detector. This finding is important from pharmaceutical point of view and shows the chemosystematic relation between L. glaucum and L. austriacum and this method will be a powerful tool for detecting natural products in interested and endangered medicinal plants.