Efficacy and Safety of a Biosimilar Liraglutide (Melitide®) Versus the Reference Liraglutide (Victoza®) in People with Type 2 Diabetes Mellitus: A Randomized, Double-Blind, Noninferiority Clinical Trial.

INTRODUCTION: Liraglutide effectively controls blood glucose level and reduces body weight. The aim of this study was to compare the efficacy and safety of a biosimilar liraglutide (Melitide®; CinnaGen, Tehran, Iran) to the reference liraglutide (Victoza®; Novo Nordisk, Bagsvaerd, Denmark) in people with type 2 diabetes mellitus (T2DM). METHODS: In this phase 3 clinical noninferiority trial, adult patients with inadequately controlled T2DM and with hemoglobin A1C (HbA1C) levels of 7-10.5% on at least two oral glucose-lowering drugs with stable doses for at least 3 months were randomized to receive Melitide® (n = 150) or Victoza® (n = 150) 1.8 mg/day for 26 weeks. The primary outcome was assessment of the noninferiority of Melitide® to Victoza® in terms of change in HbA1C level with a prespecified margin of 0.4%. The secondary outcomes were the assessment of additional efficacy parameters (including the proportion of patients achieving HbA1C levels of < 7%), the incidence of adverse events, and immunogenicity. RESULTS: Of the 300 participants enrolled in this study, 235 were included in the per-protocol analysis (112 in the Melitide® group and 123 in the Victoza® group). The mean (standard deviation) changes in HbA1C were - 1.76% (1.22) in the Melitide® group and - 1.59% (1.31) in the Victoza® group. The upper limit of the 95% one-sided confidence interval (CI) of the mean difference between Melitide® and Victoza® in lowering HbA1C was lower than the predefined margin (mean difference - 0.18, 95% CI - 0.5 to 0.15). Similar findings were obtained with the intention-to-treat analysis. No statistically significant differences were observed between the two study arms regarding the proportion of patients achieving HbA1C < 7% (p = 0.210), other efficacy parameters (p > 0.05), and reported adverse events (p = 0.916). Furthermore, none of the patients developed anti-liraglutide antibodies. CONCLUSION: The biosimilar liraglutide (Melitide®) was noninferior in efficacy and comparable in safety when compared with the reference liraglutide. TRIAL REGISTRATION: NCT03421119.

Insulin fibrillation: Strategies for inhibition.

Insulin and its homologous are the most utilized protein drugs due to their role in diabetic patients' treatment. Insulin forms amyloid-like fibrils in vivo at the injection site. Therefore, the study of its fibrillation mechanism and designing efficient inhibitors have high importance in the pharmaceutical industry. Insulin fibrils are formed at both acidic and neutral pH in vitro. Overall, this process involves the dissociation of hexameric form to monomeric, partially dissociating the native monomeric form, nuclei formation, and finally converting oligomers to large ordered aggregates. Intermediate and terminal species are different pathologically. This review is focused on the research works dedicated to the inhibition of insulin fibril formation. The inhibitors include various polyphenols, natural compounds, nanoparticles, and synthetic chemicals/peptides, as well as the classification of inhibitors targets concerning protein fibrillation. Although most inhibitors stabilize the native structure of the protein and prevent the formation of partially folded species, there are other inhibitors that hinder other steps in the course of fibrillation. Also, several inhibitors were able to dissociate the pre-existing fibrils. Finding inhibition strategies could be beneficial for developing new inhibitors that are more efficient and can block the amyloid pathway in a specific desired stage.

Berberis integerrima hydro-alcoholic root extract and its constituent berberine protect against cisplatin-induced nephro- and hepato-toxicity.

BACKGROUND: This study determined the potential hepato- and renal protective role of berberine and hydroalcohol extract of Berberis integerrima (barberry) against cisplatin-induced acute liver and kidney injury. METHODS: Animals were dedicated into six groups (n = 7 per group): control, control+Ber (berberine, 0.4 mg/kg/day during 10 days, i.p.), control+B.E (barberry extract, 160 mg/kg/day during 10 days, i.p.), Cis (cisplatin, 8 mg/kg on 7th day, i.p.), Cis+Ber (berberine, 100 mg/kg/day during 10 days; cisplatin, 8 mg/kg on 7th day), Cis+B.E (barberry extract, 160 mg/kg/day during 10 days; cisplatin, 8 mg/kg on 7th day). After placing the rats in metabolic cages for 24 h, blood, urine, liver and kidney tissue samples were collected. RESULTS: Compared to control, control+Ber and control+B.E groups, cisplatin administration led to kidney and liver dysfunction. These happened with diminished activities of antioxidant enzymes, increased levels of malondialdehyde, Toll-like receptor 4 gene expression and histological damages in hepatic and renal tissues. Berberine and barberry extract administration decreased all the changes. CONCLUSIONS: An intensification in enzymatic oxidant status, decrease in lipid peroxidation with decrease in TLR4 gene expression level indicate that barberry extract may be a potential candidate in combating cisplatin-induced oxidative stress and inflammation in liver and kidney tissues through its constituent berberine.

Enhanced Solubility and One-Step Purification of Functional Dimeric Carboxypeptidase G2.

Carboxypeptidase G2 is a bacterial enzyme that catalyzes methotrexate conversion to its inactive forms which are then eliminated via a non-renal pathway in patients with renal disorders during a high-dose methotrexate administration. Due to the increasing demand of this enzyme, it was of interest to simplify its production process. For this reason, we developed a method for production and one-step purification of this enzyme using an intein-mediated system with a chitin-binding affinity tag. The carboxypeptidase G2 gene from Pseudomonas RS16 was optimized, synthesized, cloned into the pTXB1 expression vector and finally transformed into Escherichia coli BL21 (DE3) cells. The optimal condition for the enzyme soluble expression was achieved in 2×YT medium containing 1% glucose at 25°C for 30 h with 0.5 mM IPTG. The enzyme without intein was expressed as inclusion bodies indicating the importance of intein for the protein solubility. The expressed homodimer protein was purified to homogeneity on a chitin affinity column. The Km and kcat values of 6.5 µM and 4.57 s-1, respectively, were obtained for the purified enzyme. Gel filtration analysis indicated that the resulting recombinant protein was a dimer of 83 kDa. Fluorescence and circular dichroism spectroscopy confirmed the enzyme tertiary and secondary structures, respectively. The use of intein-mediated system provided the possibility of the one-step carboxypeptidase G2 purification, paving the way to the application of this enzyme in pharmaceutics.

Cancer-associated-platelet-inspired nanomedicines for cancer therapy.

Platelets, with hemostasis and thrombosis activities, are one of the key components in the blood circulation. As a guard, they rapidly respond to any abnormal blood vessel injury signal and release their granules' contents, which induce their adhesion and aggregation on wound site for hemostasis. Recently, increasing evidence has indicated that platelets are critically involved in the growth and metastasis of cancer cells by releasing a variety of cytokines and chemokines to stimulate cancer cell proliferation and various angiogenic regulators to accelerate tumor angiogenesis. Platelets also secrete active transforming growth factor beta (TGF-ß) to promote the epithelial-mesenchymal transition of cancer cells and their extravasation from primary site, and form microthrombus on the surface of cancer cells to protect them from immune attack and high-speed shear force in the circulation. Therefore, blocking platelet-cancer cell interaction may be an attractive strategy to treat primary tumor and/or prevent cancer metastasis. However, systemic inhibition or depletion of platelets brings risk of severe bleeding complication. Cancer-associated-platelets-targeted nanomedicines and biomimetic nanomedicines coated with platelet membrane can be used for targeted anticancer drug delivery, due to their natural targeting ability to tumor cells and platelets. In the current review, we first summarized the platelet mechanisms of action in physiological condition and their multiple roles in cancer progression and conventional antiplatelet therapeutics. We then highlighted the recent progress on the design and fabrication of cancer-associated-platelet-targeted nanomedicines and platelet membrane coating nanomedicines for cancer therapy. Finally, we discussed opportunities and challenges and offered our thoughts for the future development. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Biology-Inspired Nanomaterials > Lipid-Based Structures.

The prevalence of comorbid depression in patients with type 2 diabetes: an updated systematic review and meta-analysis on huge number of observational studies.

AIMS: Depression is a common co-morbidity in patients with type 2 diabetes mellitus (T2DM). Untreated depression in these patients adversely affects self-care activities and other diabetes complications. The aim of this study is to estimate the prevalence of depression among patients with T2DM by conducting a meta-analysis of observational studies. METHODS: MEDLINE, Web of Science, Science Direct, and Google Scholar databases were searched for all observational studies that assessed depression in T2DM. Relevant articles were searched using the combination of Medical Subject Heading (MeSH) terms of "depression", "depressive disorder", and "diabetes mellitus" published between January 2007 and July 2018. Random effects model was used to estimate the weighted prevalence rates and 95% CI using "metaprop program in STATA 11". RESULTS: In total, the 248 included studies (with 273 reported prevalence) identified 83,020,812 participants; of them, 23,245,827 (28%; 95% CI 27, 29) suffered from different severity levels of depressive disorders. The prevalence of depression was separately reported in 137,372 males and 134,332 females. Of them, 31,396 males (23%, 95% CI: 20, 26) and 45,673 females (34%, 95% CI: 31, 38) were depressed. Compared with global estimate, depression prevalence was lower in Europe (24%) and Africa (27%), but higher in Australia (29%) and Asia (32%). The prevalence in America was equal to the estimated prevalence in the world (28%). Depression was more common in subjects younger than 65 compared with elderlies (31% vs. 21%). CONCLUSION: Our findings demonstrated that almost one in four adults with T2DM experienced depression. Given the high prevalence of depressive disorders in diabetic patients, screening these patients for co-morbid depression and its relevant risk factors is highly recommended.

Hyperuricemia in systemic lupus erythematosus: is it associated with the neuropsychiatric manifestations of the disease?

OBJECTIVES: To assess the association between hyperuricemia and different neuropsychiatric manifestations and stroke risk factors in systematic lupus erythematosus (SLE) patients. METHODS: This study was conducted on 204 SLE patients who were admitted to a tertiary referral center. A standardized questionnaire was completed for all the participants and the medical records were reviewed regarding the occurrence of arterial or venous thrombotic events, stroke, seizure, depression, headache, psychosis, and peripheral neuropathy. In addition blood samples were drawn to obtain serum uric acid, triglyceride (TG), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and total cholesterol levels. RESULTS: Hyperuricemia (serum uric acid ≥6mg/dl for women and ≥7mg/dl for men) was detected in 16.1% of SLE patients and was significantly associated with the occurrence of stroke (OR, 2.38; 95%CI, 1.2-7.24), and peripheral neuropathy (OR, 3.49; 95% CI, 1.52-12.23), independent of hypertension and hyperlipidemia. Hyperuricemia was also significantly associated with hypertension (OR, 7.76; 95% CI, 2.72-15.76), hyperlipidemia (OR, 5.05; 95% CI, 1.59-11.32), and history of arterial thrombosis (OR, 4.95; 95% CI, 1.98-15.34), independent of age and body mass index. CONCLUSIONS: Hyperuricemia in SLE patients is independently associated with the occurrence of stroke and peripheral neuropathy. It is also independently associated with hypertension, hyperlipidemia, and history of arterial thrombosis, which are the major stroke and myocardial infarction risk factors in SLE patients.

Hyperuricemia in systemic lupus erythematosus: is it associated with the neuropsychiatric manifestations of the disease? / Hiperuricemia no lúpus eritematoso sistêmico: está associada a manifestações neuropsiquiátricas da doença?

ABSTRACT Objectives: To assess the association between hyperuricemia and different neuropsychiatric manifestations and stroke risk factors in systematic lupus erythematosus (SLE) patients. Methods: This study was conducted on 204 SLE patients who were admitted to a tertiary referral center. A standardized questionnaire was completed for all the participants and the medical records were reviewed regarding the occurrence of arterial or venous thrombotic events, stroke, seizure, depression, headache, psychosis, and peripheral neuropathy. In addition blood samples were drawn to obtain serum uric acid, triglyceride (TG), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and total cholesterol levels. Results: Hyperuricemia (serum uric acid ≥6 mg/dl for women and ≥7 mg/dl for men) was detected in 16.1% of SLE patients and was significantly associated with the occurrence of stroke (OR, 2.38; 95%CI, 1.2-7.24), and peripheral neuropathy (OR, 3.49; 95% CI, 1.52-12.23), independent of hypertension and hyperlipidemia. Hyperuricemia was also significantly associated with hypertension (OR, 7.76; 95% CI, 2.72-15.76), hyperlipidemia (OR, 5.05; 95% CI, 1.59-11.32), and history of arterial thrombosis (OR, 4.95; 95% CI, 1.98-15.34), independent of age and body mass index. Conclusions: Hyperuricemia in SLE patients is independently associated with the occurrence of stroke and peripheral neuropathy. It is also independently associated with hypertension, hyperlipidemia, and history of arterial thrombosis, which are the major stroke and myocardial infarction risk factors in SLE patients.

RESUMO Objetivos: Avaliar a associação entre a hiperuricemia e diferentes manifestações neuropsiquiátricas e os fatores de risco para AVE em pacientes com lúpus eritematoso sistêmico (LES). Métodos: Este estudo foi feito em 204 pacientes com LES que foram internados em um centro de referência de atenção terciária. Todos os participantes preencheram um questionário padronizado e os prontuários médicos foram analisados quanto à ocorrência de eventos trombóticos arteriais ou venosos, acidente vascular encefálico, convulsão, depressão, cefaleia, psicose e neuropatia periférica. Além disso, foram coletadas amostras de sangue para se mensurarem os níveis de ácido úrico, triglicerídeos (TG), lipoproteínas de alta densidade (HDL), lipoproteínas de baixa densidade (LDL) e colesterol total do sangue. Resultados: A hiperuricemia (ácido úrico sérico ≥ 6 mg/dL para mulheres e ≥ 7 mg/dL para homens) foi detectada em 16,1% dos pacientes com LES e esteve significativamente associada à ocorrência de AVE (OR, 2,38; IC 95%, 1,2-7,24) e neuropatia periférica (OR, 3,49; IC 95%, 1,52-12,23), independentemente da hipertensão arterial e da hiperlipidemia. A hiperuricemia também esteve significativamente associada à hipertensão arterial (OR, 7,76; IC 95%, 2,72-15,76), hiperlipidemia (OR, 5,05; IC 95%, 1,59-11,32) e história de trombose arterial (OR, 4,95; 95% CI, 1,98-15,34), independentemente da idade e do índice de massa corporal. Conclusões: A hiperuricemia em pacientes com LES está independentemente associada à ocorrência de acidente vascular encefálico e neuropatia periférica. Também está independentemente associada à hipertensão, hiperlipidemia e história de trombose arterial, que são os principais fatores de risco para acidente vascular encefálico e infarto agudo do miocárdio em pacientes com LES.

[Hyperuricemia in systemic lupus erythematosus: is it associated with the neuropsychiatric manifestations of the disease?] / Hiperuricemia no lúpus eritematoso sistêmico: está associada a manifestações neuropsiquiátricas da doença?

OBJECTIVES: To assess the association between hyperuricemia and different neuropsychiatric manifestations and stroke risk factors in systematic lupus erythematosus (SLE) patients. METHODS: This study was conducted on 204 SLE patients who were admitted to a tertiary referral center. A standardized questionnaire was completed for all the participants and the medical records were reviewed regarding the occurrence of arterial or venous thrombotic events, stroke, seizure, depression, headache, psychosis, and peripheral neuropathy. In addition blood samples were drawn to obtain serum uric acid, triglyceride (TG), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and total cholesterol levels. RESULTS: Hyperuricemia (serum uric acid ≥ 6mg/dl for women and ≥ 7mg/dl for men) was detected in 16.1% of SLE patients and was significantly associated with the occurrence of stroke (OR, 2.38; 95%CI, 1.2-7.24), and peripheral neuropathy (OR, 3.49; 95% CI, 1.52-12.23), independent of hypertension and hyperlipidemia. Hyperuricemia was also significantly associated with hypertension (OR, 7.76; 95% CI, 2.72-15.76), hyperlipidemia (OR, 5.05; 95% CI, 1.59-11.32), and history of arterial thrombosis (OR, 4.95; 95% CI, 1.98-15.34), independent of age and body mass index. CONCLUSIONS: Hyperuricemia in SLE patients is independently associated with the occurrence of stroke and peripheral neuropathy. It is also independently associated with hypertension, hyperlipidemia, and history of arterial thrombosis, which are the major stroke and myocardial infarction risk factors in SLE patients.