Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Concurrent Use of Crocin During Chemoradiation for Esophageal Squamous Cell Carcinoma.

Crocin is the major active carotenoid of saffron (Crocus sativus L.). Its pluripotent effects have led to a growing body of literature investigating its antitumor properties as well as its diverse potentials for mood stabilization, normal tissue protection, and inflammation reduction; However, there is a gap in clinical trials testing this substance in cancer patients. In this randomized, double-blind, placebo-controlled clinical trial, patients with newly diagnosed esophageal squamous cell carcinoma were randomly assigned to either 30 mg/day of crocin or placebo, prescribed during the neoadjuvant chemo-radiotherapy. The primary endpoints were pathological response and toxicity, and secondary endpoints were depression and anxiety levels and survival analysis.

A Review of Drug Abuse, Misuse, and Related Laboratory Challenges.

Various definitions can be considered for drugs and substance abuse. According to the National Institute on Abuse, the use of an over-the-counter drug in a different way than that prescribed to experience or arouse emotion is a simple form of drug abuse. The World Health Organization (WHO) also defines drug abuse as the persistent or sporadic use of drugs that are incompatible or unrelated to acceptable medical practice. With the increasing non-therapeutic use of prescription drugs, serious related consequences have also increased. Therefore, there is a need to know more precisely about the types of substances and drug abuse, which is the most important part of diagnosis and recognizing the tests that cause false positive and negative results. The purpose of this review article is to collect and summarize the most important and more common types of drugs of abuse and review the drugs that cause false results in screening tests. In addition, the most common detection methods of the drug will be reviewed and the advantages and drawbacks of each method will be discussed. In this article, we aimed to point out all the facts about the emerging problems in drug abuse, the methods of screening, and the possible false results in addition to troubleshooting strategies.

A systematic review of emerging technologies to enhance the treatment of ovarian cancer.

The efficacy and safety of chemotherapy are two major challenges when it comes to treating ovarian cancer. The associated undesirable side effects of chemotherapy agents jeopardize the clinical intent and the efficiency of the therapy. Multiple studies have been published describing new developments and novel strategies utilizing the latest therapeutic and drug delivery technologies to address the efficacy and safety of chemotherapeutics in ovarian cancers. We have identified five novel technologies that are available and, if used, have the potential to mitigate the above-mentioned challenges. Nanocarriers in different forms (Nano-gel, Aptamer, peptide medicated formulations, Antibody-drug conjugation, surface charge, and nanovesicle technologies) are developed and available to be employed to target the cancerous tissue. These strategies are promising to improve clinical efficacy and reduce side effects. We have systematically searched and analyzed published data, as well as the authors intent for the described technology on each publication. We narrowed to 81 key articles and extracted their data to be discussed in this review. In summary, the selected articles investigated the pharmacokinetic properties of drugs combined with nanocarriers and found significant improvement in efficacy and safety by reducing the IC50 values and drug doses. These key papers described promising novel technologies in anti-cancer therapeutic approaches to enable sustained drug release and achieve prolonged drug performance near the tumor site or target tissue.

The effect of crocin versus sertraline in treatment of mild to moderate postpartum depression: a double-blind, randomized clinical trial.

Postpartum depression (PPD) is one of the most common conditions among women. This study aimed to investigate the effect of crocin compared to sertraline in women with mild to moderate PPD. This trial study was performed on women with PPD. Patients in two groups received crocin (15 mg) and sertraline (50 mg) daily for 3 months, respectively. Patients have assessed by Beck's Depression Inventory-II (BDI-II) and Beck's Anxiety Inventory (BAI) at 0-12 weeks. A total of 64 patients were examined. The mean of the BDI-II score in the crocin group decreased after 3 months from 20.75 to 4.93 (P = 0.0001). In the sertraline group, the mean score of BDI-II decreased after 3 months from 21.06 to 2.37 (P = 0.0001). The mean of the BAI score in the crocin group decreased significantly after 3 months from 13.75 to 4.06 (P = 0.0001) and in the sertraline group from 12.9 to 2.71 (P = 0.0001). No significant difference was observed between crocin and sertraline after the clinical trial (P = 0.5). No severe side effects were observed during the study in the two groups. The results of this study showed that crocin (15 mg daily) could be useful in treating PPD. Furthermore, this study showed that crocin, with far fewer side effects than chemical drugs, can be widely used in PPD, but due to the small sample size further studies are necessary to confirm such efficiency.

Biochemical responses as early and reliable biomarkers of organophosphate and carbamate pesticides intoxication: A systematic literature review.

Inhibition of cholinesterase (ChE) activity has been long considered as the main diagnostic method of organophosphate (OP) and carbamate pesticides poisoning; however, it has been shown that ChE activity may also be altered due to exposure to other non-organophosphorus toxicants and variety of different medical conditions. Hence, to avoid misdiagnosis, we aimed to systematically review available documents to look for additional biomarkers of OP and carbamate poisoning. The electronic databases in addition to Google scholar were searched for eligible articles on March 2022 using "organophosphate," "carbamate," and "biomarker" including all their similar terms. After collecting the relevant documents, the data were extracted and described qualitatively. In total, data of 66 articles from 51 human and 15 animal studies were extracted. Findings demonstrated that enzymes such as ß-glucuronidase, neuropathy target esterase, amylase, and lipase, in addition to hematological indicators such as CBC, CRP, lactate dehydrogenase, and CPK have high sensitivity and accuracy in the diagnosis of OP poisoning. Findings suggest that using various markers for diagnosis of OP intoxication is helpful for appropriate management, and early identifying the patients at risk of death. The suggested biomarkers also help to avoid misdiagnosis of OP poisoning with other similar conditions.

Effect of crocin on diabetic patients: A placebo-controlled, triple-blinded clinical trial.

OBJECTIVE: The purpose of this study was to evaluate the effect of Saffron and its active ingredient, crocin, as a natural antioxidant in the treatment of type II diabetes. METHODS: A total of 150 uncontrolled type 2 (non-insulin-dependent) diabetic patients were selected based on inclusion criteria, randomly divided into three groups (crocin, saffron and placebo) for three months' clinical trial. Fasting blood glucose (FBS), insulin level, glycosylated hemoglobin (HbA1c), lipid profile, kidney and liver function tests were performed before and three months after the study. The patients were followed every two weeks for possible clinical side effects. RESULTS: Our results showed that after three months of treatment with crocin and saffron, FBS reduction was significant in all groups (P-value < 0.05). In addition, reduction of HbA1c was significant in the crocin and saffron groups compared to placebo group. Comparison between groups showed that treatment with crocin and saffron led to a significant reduction in HbA1c than placebo, and FBS level significantly reduced only in crocin compared to saffron and placebo groups. In addition, changes in lipid profile were not significant in any of the three groups. Also, there was no significant difference in liver and liver parameters in all three groups. Inter-group comparison of insulin levels showed significant difference only between the saffron and placebo groups. CONCLUSION: Crocin can be effective in controlling the level of FBS and HbA1c in patients with type 2 diabetes.

Retinoprotective Effects Of Crocin And Crocetin via Anti-Angiogenic Mechanism in High Glucose-Induced Human Retinal Pigment Epithelium Cells.

BACKGROUND: Diabetic retinopathy (DR) is one of the most common side effects of diabetes. We aimed to investigate the effects of crocin and crocetin (as a deglycosylated form of crocin in blood stream) in gene expression or protein levels of vascular endothelial growth factor (VEGF), vascular endothelial growth factor-receptor1 (VEGFR-1), matrix metalloproteinases2 (MMP-2), matrix metalloproteinases9 (MMP-9) and thrombospondin-2 (TSP-2) in high glucose cell culture media. METHODS: The retinal pigment epithelium (RPE) cells were exposed to high glucose (HG, 30 mM glucose concentration) and normal glucose (NG, 24.5 mM mannitol + 5.5 mM glucose) for six days. RPE cells were treated in four treatment groups (crocin, crocetin, Bevacizumab, and crocin + Bevacizumab). Gene expressions were measured using quantitative real-time PCR, and protein levels were evaluated by western blot. RESULTS: Findings showed that VEGF gene expression and protein level significantly decreased in all treatment groups. In addition, reduction in VEGFR1 gene expression was significantly higher in Bevacizumab and crocin + Bevacizumab groups than other groups. Only crocin and crocetin could reduce the gene levels of MMP-2 and MMP-9. In addition, TSP-2 protein levels increased when HG cells were exposed to crocin or crocin + Bevacizumab groups. CONCLUSION: Our data showed that crocin and crocetin have anti-VEGF function similar to Bevacizumab, act as an anti-angiogenic agent. Also, crocin and crocetin could decrease MMP-2 and MMP-9 gene levels being inflammatory and angiogenesis factors. As a result, crocin and crocetin have protective effects against angiogenesis and inflammation in DR.

Effect of crocin versus fluoxetine in treatment of mild to moderate obsessive-compulsive disorder: A double blind randomized clinical trial.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a common disabling disorder. Crocin, the active component of the saffron plant (Crocus Sativus L.) has various pharmacological activities. The present study compared the efficacy and safety of crocin and fluoxetine in treatment of mild to moderate OCD. METHODS & MATERIALS: Fifty patients with OCD, aged 18 to 60 years, were randomized to receive either crocin (15 mg) or fluoxetine (20 mg) capsules for 8 weeks. Eligible participants received one capsule/day in the first month, which followed by two capsules daily in the second month. The patients were evaluated using Yale-Brown Obsessive-compulsive scale (Y-BOCS) and Hamilton Anxiety Rating scale (HARS). RESULTS: The mean Y-BOCS score in both groups decreased significantly during 2 months (p-value = 0.0001). Also, HARS score in the crocin group was changed from 17.16 to 13.04 whereas, in the fluoxetine group was decreased from 18.28 to 12.34. The results indicated no difference between the two groups in Y-BOCS and HARS score changes after 2-month trial (p-value >0.5). Also, fewer adverse effects were reported in the crocin group compared to the fluoxetine group. CONCLUSION: According to our study, it seems that crocin is effective in treatment of patients with mild to moderate OCD with possibly fewer adverse effects compared to fluoxetine.

Pharmacological Effects of Saffron and its Constituents in Ocular Disorders from in vitro Studies to Clinical Trials: A Systematic Review.

INTRODUCTION: Some medicinal plants have shown promising therapeutic potential for the management of the diseases. We aimed to systematically review the literature wherein the therapeutic effects of saffron have been studied on eye disorders. METHODS: A systematic literature search was performed in PubMed, Scopus, Web of Science, Google scholar and other databases using eye disorders and saffron as key terms. No strict inclusion criteria were defined, and almost all clinical studies, as well as in vivo and in vitro studies were included. The reported data in each study were extracted and then qualitatively described. RESULTS: Finally, 78 articles were found but only 29 relevant articles were included. Nine articles were clinical trials and 20 articles were studies conducted on cellular and molecular aspects of saffron on eye disorders. According to the included studies, crocin prevented the pro-inflammatory response in retinal cells and decreased glucose levels in diabetic mice. Also, crocetin prevented retinal degeneration and saffron protected photoreceptors from light-induced damage in retinal cells. Saffron also improved visual function in age-related macular edema and decreased intraocular pressure in patients with glaucoma. In addition, it was shown that crocin can improve best corrected visual acuity and decrease central macular thickness in patients with diabetic maculopathy. CONCLUSION: The results of this review indicated that saffron and its main ingredients such as crocin could be a potential candidate for the treatment of ocular disease especially eye inflammation; however, further clinical studies are needed to confirm such efficiency.

Docetaxel-Loaded Mixed Micelles and Polymersomes Composed of Poly (caprolactone)-Poly (ethylene glycol) (PEG-PCL) and Poly (lactic acid)-Poly (ethylene glycol) (PEG-PLA): Preparation and In-vitro Characterization.

Microwave irradiation was used to synthesize poly (caprolactone)-poly (ethylene glycol) (PEG-PCL) and poly (lactic acid)-poly (ethylene glycol) (PEG-PLA) copolymers that are composed of biodegradable polymers including PEG, PLA, and PCL. These copolymers were used for loading docetaxel in nanoparticles. Single emulsion-solvent evaporation technique was applied for preparing the PEG-PLA and PEG-PCL mixed nanoparticles (micelles and polymersomes) with different proportions, including 0:1, 1:1, 3:1, 1:3, and 1:0. The unimodal gel permeation chromatography curve showed low polydispersity of the di-block copolymers. The in-vitro drug release curves of formulations were compared. Micelles and polymersomes of 75% PEG-PCL and 25% PEG-PLA (P5 and M5) have the lowest burst release (5%) at the same period compared to the other copolymers. The dynamic light scattering and TEM results clarified that the size and shape of the formulations are uniform. The cytotoxicity effect of P5 and M5 was evaluated in different cell lines. The best one was found to P5 with half maximal inhibitory concentration (IC50) between 1.48-11.79 µg/mL. The pro-apoptotic effect of P5 was confirmed with flow cytometry study. These mixed micelles (M5) and polymersomes (P5) was found to be superior formulations than non-mixed ones.

Herbal medicine as a promising therapeutic approach for the management of vascular dementia: A systematic literature review.

Vascular dementia (VaD) generally refers to memory deficits and cognitive abnormalities that are resulted from vascular disease. In this study, we aimed to systematically review the literature wherein therapeutic effects of medicinal plants have been studied on VaD. A systematic literature search was performed in the PubMed, Scopus, Web of Science, Google Scholar, and other databases using VaD, and medicinal plants as key terms. No strict inclusion criteria were defined, and almost all clinical studies were included. A total of 524 articles were found, of which only 28 relevant articles with 3461 studied patients were included to this systematic review. The results showed that medicinal plants, particularly Sancaijiangtang and Ginkgo biloba could improve behavioral and psychological symptoms, working memory, Mini-Mental State Examination, and activities of daily living as well as neuropsychiatric features. It was also shown that the age, average progression of the disease, and the type of folk medicines effective in treating the disease are important factors in the management of VaD. The results of this review indicated that herbal therapy can be a potential candidate in the treatment of VaD; however, further studies are needed to confirm such efficiency.

Plant toxins and acute medicinal plant poisoning in children: A systematic literature review.

BACKGROUND: For many years, medicinal plants and herbal therapy have been widely used in different societies for the treatment of various diseases. Besides their therapeutic potency, some of the medicinal plants have strong toxicity in human, especially in children and elderly. Despite common beliefs that natural products are safe, there have been few reports on their toxicities. MATERIALS AND METHODS: In the present study, we aimed to systematically review the literature wherein acute plant poisoning and herbal intoxication have been reported in pediatric patients. After literature search and selection of the appropriate documents, the desired data were extracted and described qualitatively. RESULTS: A total of 127 articles with overall 1453 intoxicated cases were collected. The results of this study showed that some medicinal plants can cause acute poisoning and complications such as hepatic and renal failure in children. CONCLUSION: The findings of this survey showed that acute plant poisoning can be life?threatening in children, and since a single?ingested dose of toxic plants can cause acute poisoning, parents should be aware of these toxic effects and compare the side effects of self?medication with its potential benefits.

Effects of Crocin on Diabetic Maculopathy: A Placebo-Controlled Randomized Clinical Trial.

OBJECTIVE: Diabetic macular edema (DME) is one of the most important sight-threatening complications in patients with diabetes. Owing to neuroprotective properties, crocin, as the main constituent in saffron, is thought to be useful in the treatment and prevention of diabetic maculopathy. The aim of this trial was to evaluate the effects of crocin as a supplement on reducing inflammation in patients with diabetic maculopathy. DESIGN: Double-masked, placebo controlled, phase 2 randomized clinical trial. METHODS: Participants: In this study, 101 eyes of 60 patients with refractory diabetic maculopathy to conventional therapy including macular photocoagulation and intravitreal injection of anti-vascular endothelial growth factor agent (bevacizumab) with or without steroid (triamcinolone) were studied in 3 groups. INTERVENTION: Patients in the crocin groups received 5 mg or 15 mg crocin tablets per day for 3 months, whereas patients in the placebo group received 1 placebo tablet per day during the study. The best-corrected visual acuity (BCVA) and central macular thickness (CMT) were measured before, every month during, and 3 months after intervention. Biochemical blood tests were also evaluated before and after trial. MAIN OUTCOME MEASURES: The BCVA and CMT were evaluated as the primary outcomes, whereas HbA1c and fasting blood sugar (FBS) were studied as the secondary outcomes in this trial. RESULTS: One hundred and one eyes were enrolled in this trial and were divided into 3 groups (crocin 5 mg, n = 34; crocin 15 mg, n = 33; and placebo, n = 34). According to our data, administration of crocin 15 mg tablet per day could significantly decrease HbA1c (P value = .024; 95% confidence interval [CI] 0.3-0.96), and CMT (P value = .005; 95% CI, 32.75-126.99) and improve BCVA (logMAR changes; P value = .012; 95% CI, 0.23-0.69) compared to the placebo group. Although administration of crocin 5 mg tablet per day could clinically improve HbA1c, FBS, CMT, and BCVA, the difference was not significant compared to the placebo group. CONCLUSION: This study indicated the effect of crocin as a potent antioxidant and neuroprotective for treatment of refractory DME in the short term; however, the clinical significance is yet to be proved in a study with larger sample size and longer duration of follow-up and also in treatment-naïve patients.

CTLA-4 Gene Haplotypes and the Risk of Chronic Hepatitis C Infection; a Case Control Study.

BACKGROUND: The prevalence of hepatitis C virus (HCV) infection is increasing worldwide. Cytotoxic Tlymphocyte-associated protein 4 (CTLA-4) may play a role in the intensity of the disease. The aim of this study was to evaluate the association between genetic variants of the CTLA-4 and HCV infection. METHODS: Restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) was performed as the genotyping assay at four different positions (+49 A>G, -318 C>T, -1722 T>C, and - 1661 A>G). Haplotypes were analyzed using PHASE software. Sixty-five HCV patients and 65 healthy individuals as controls who were referred to the hepatitis clinic in Mashhad, Iran, were recruited. Genomic DNA was extracted from whole blood of participants. RESULTS: In a dominant analysis model of the -1661 position (GG vs. AA+AG), the AA genotype was more common in controls than in patients (adjusted P = 0.0003; OR = 0.15, 95% CI = 0.051 -0.42). The GCAT haplotype was also more prevalent in controls than in patients (adjusted P = 0.01; OR = 0.40, 95% CI = 0.20-0.81). Furthermore, the ACGT/ACGT diplotype was more common in controls than in patients (P = 0.0037; OR = 0.15, 95% CI = 0.04-0.54). In addition, the ACGT/ACAT diplotype was more frequent in patients than controls (adjusted P =0.003; OR = 2.48, 95% CI = 1.37- 4.50). CONCLUSION: Our results indicated that polymorphisms in CTLA-4 and certain haplotypes may affect the risk of HCV infection in our population, although a larger sample size may be required to confirm this association.

Comparison of the prevalence of enteroviruses in blood samples of patients with and without unstable angina.

BACKGROUND: Although the role of enteroviruses has been proved in heart diseases, extensive information is not available on the association between enteroviruses and unstable angina. In the present study, the authors compared the prevalence of enteroviruses in patients with and without unstable angina. METHODS: Blood samples were taken from 51 patients with unstable angina and 55 patients without unstable angina or myocardial infarction that were admitted to Imam Reza and Ghaem hospitals (Mashhad, northeast of Iran). Reverse transcription polymerase chain reaction (RT-PCR) was performed using specific primers for the detection of the enteroviruses in blood samples of study subjects. RESULTS: Patients with and without unstable angina were similar in age with mean ± standard deviation of 62.6 ± 12.8 and 59.7 ± 12.7 years, respectively (P = 0.243) and there were no differences in gender in these two groups (P = 0.174). Prevalence of the enteroviruses in patients with unstable angina was higher only in 66-80 years age group compared to the control group (patients without unstable angina, P = 0.032). There was a higher prevalence of enterovirus RNA positivity in the blood samples of women with unstable angina (75.9%) than those without unstable angina (41.7%, P = 0.011), however, no significant difference was observed in men (P = 0.983). CONCLUSION: Our data showed that enteroviral RNA positivity was higher in patients with unstable angina compared to those without unstable angina. However, the differences between the two groups were not statistically significant.

Haplotype Analysis of Hemochromatosis Gene Polymorphisms in Chronic Hepatitis C Virus Infection: A Case Control Study.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is frequently associated with elevated serum iron markers. Polymorphisms in the hemochromatosis (HFE) genes are responsible for iron accumulation in most cases of hemochromatosis, and may play a role in HCV infection. OBJECTIVES: We aimed to assess the prevalence of HFE gene polymorphisms in a group of Iranian HCV-infected patients, and to explore the association of these polymorphisms with HCV infection. PATIENTS AND METHODS: HFE gene polymorphisms were examined in a total of 69 HCV patients and 69 healthy controls using polymerase chain reaction and restriction fragment length polymorphism techniques. Haplotype and diplotype analyses were performed using PHASE software. RESULTS: In a recessive analysis model of the His63Asp (H63D) locus (HH vs. HD + DD), the HH genotype was more common in patients compared to controls (adjusted P = 0.012; OR = 6.42 [95% CI: 1.51 - 27.33]). Also, in a recessive analysis model of the Cys282Tyr (C282Y) locus (CC vs. CY + YY), the CC genotype was more frequent in patients compared to controls (adjusted P = 0.03; OR = 5.06 [95% CI: 1.13 - 22.06]). In addition, there was a significant association between the HC haplotype and the HCDC diplotype and HCV infection. CONCLUSIONS: Polymorphism in the hemochromatosis gene may confer some degree of risk for HCV infection, and individuals carrying the H and C alleles may be susceptible to this disease; however, a larger sample of HCV patients and healthy individuals may be necessary to further illustrate the role of these polymorphisms in HCV.

Frequency of Human Papillomavirus Genotypes 6, 11, 16, 18 And 31 in Paraffin-Embedded Tissue Samples of Invasive Breast Carcinoma, North- East of Iran.

BACKGROUND &OBJECTIVE: Breast cancer is the most common female malignancy. Detection of DNA of human papillomaviruses (HPVs) in breast carcinomas suggests that the virus may play a role in the pathogenesis of this disease. The aim of this study was to evaluate the frequency of HPVs genotypes 6, 11, 16, 18 and 31 in paraffin-embedded tissue samples of invasive breast carcinomas. METHODS: Three hundred and twenty six paraffin-embedded tissue samples of breast cancer were studied. PCR was performed using specific primers for HPV genotypes. RESULTS: Of total 206 (63.2%) samples positive for Beta-globin gene, 54 (26.2%) were HPV-positive and 152 (73.8%) were negative for HPV. Distribution of HPV genotypes were as follows: 19 (25.7%) were positive for genotype 11, 5 (6.8%) were positive for genotype 6; and 2 cases (2.7%) were positive for both genotypes 6 and 11. Samples were also screened for HPV genotypes 16, 18 and 31 but none was positive. CONCLUSION: The current study confirmed the association of HPV and breast cancer. However, all samples were negative for high-risk HPV types 16, 18 and 31.

Distribution of hepatitis delta virus genotypes in mashhad, northeast iran.

BACKGROUND: Hepatitis delta virus (HDV) is dependent on the hepatitis B virus for transmission and propagation. Based on isolated HDV sequences from different parts of the world, at least three major different genotypes with different geographic distributions are suggested. Studies have shown that genotype 1 is the predominant genotype of HDV in different parts of Iran; however, the genotype distribution of this virus has not been identified in Mashhad, northeast Iran. OBJECTIVES: This current study determines the frequency of HDV major genotypes in Mashhad, Iran. PATIENTS AND METHODS: Twenty-five participants were enrolled in this study. All samples were positive for HBsAg (determined by Enzyme-linked immunosorbent assay (ELISA)) and anti-HDV. RNA extraction and cDNA synthesis was performed. Then, PCR was performed and HDV genotypes were determined by restriction fragment length polymorphism (RFLP). RESULTS: Of 25 patients, 12 (48%) were positive for HDV RNA. Genotype analysis of HDV RNA revealed that the prevalence of HDV genotypes I and II was 83.3% (n = 10) and 16.7% (n = 2), respectively. CONCLUSIONS: This study showed that the most prevalent genotype of HDV in Mashhad was genotype I. It was of interest that in contrast to other provinces of Iran, HDV genotype 2 was observed in Mashhad. Similar studies with larger sample sizes could provide valuable information regarding the molecular epidemiology and geographical distribution. It may also help control and prevent the spread of hepatitis D virus infections. In addition, the genotyping of HDV may predict the severity of the disease.