Insulin Signaling Pathway Model in Adipocyte Cells.

BACKGROUND: Worldwide, type 2 diabetes mellitus (T2DM) is one of the most pervasive and fastgrowing disorders, bringing long-term adverse effects. T2DM arises from pancreatic ß-cells deficiency to produce enough insulin or when the body cannot effectively use the insulin produced by such cells. Accordingly, early diagnosis will decrease the long-term effects and high-healthcare costs of diabetes. OBJECTIVE: The objective is developing an integrated mathematical model of the insulin signaling network based on Brännmark's model, which can simulate the signaling events more comprehensively with the added key components. METHODS: In this study, a thorough mathematical model of the insulin signaling network was developed by expanding the previously validated model and incorporating the glycogen synthesis module. Parameters (69 parameters) of the integrated model were evaluated by a genetic algorithm by fitting the model predictions to eighty percent of experimental data from the literature. Twenty percent of the experimental data were used to evaluate the final optimized model. RESULTS: The time-response curves indicate that the GS phosphorylation reaches its maximum in response to 10-7 M insulin after 4 min, while the maximum phosphorylated GSK3 is attained within ~50 min. The doseresponse curves for the GSP and GSK3 of the insulin signaling intermediaries in response to the increased concentration of insulin, after 10 min, in the input from 0-100 nM exhibits a decreasing trend, whereas an increasing trend was observed for the GS and GSK3P. The GSK and GS phosphorylation sensitivity was enhanced by increasing the initial insulin concentration level from 0.001 to 100 nM. However, the sensitivity of GSK3 to insulin concentration changes (from 0.001 to 100 nM) was 3-fold higher than GS sensitivity. CONCLUSION: Considerably, the trends of all signaling components simulated by the expanded model shows high compatibility with experimental data (R2 ≥ 0.9), which approves the accuracy of the proposed model. The proposed mathematical model can be used in many biological systems and combined with the whole-body model of the blood glucose regulation system for a better understanding of the causes and potential treatment of type 2 diabetes. Although, this model is not a complete description of insulin signaling, yet it can make profound contributions to improvements regarding other important components and signaling branches such as epidermal growth factor (EGF) signaling, as well as signaling in other cell types in the model structure of future works.

Effect of prophylactic application of doxycycline at the implant-abutment interface on the outcomes of implant therapy: a split-mouth randomized clinical trial.

OBJECTIVES: Doxycycline hyclate is a controlled-release doxycycline polymer which can locally be applied. This study aimed to assess the effects of the prophylactic application of doxycycline hyclate at the implant-abutment interface on the short-term outcomes of implant therapy. METHOD AND MATERIALS: The present split-mouth randomized clinical trial included 20 subjects who received two mandibular implants bilaterally (40 implants in total). In the test side (n = 20), doxycycline hyclate was injected at the implant-abutment interface at the time of delivery of final prosthesis. No intervention was performed for the control side (n = 20). The marginal bone level on mesial and distal implant surfaces, bleeding on probing, pocket probing depth, and incidence of peri-implant mucositis were recorded at baseline and after 3, 6, and 12 months. RESULTS: Significant differences were found between the test and control sites, all favoring the test group, for marginal bone level changes at mesial and distal implant surfaces as well as for changes in pocket probing depth after 6 and 12 months. Furthermore, the numbers of implants with bleeding on probing and risk of developing peri-implant mucositis were significantly greater in the control group compared to the test group at 3-months, 6-months, and 12-months following baseline. CONCLUSIONS: Within the limitations of this study, it can be concluded that prophylactic application of doxycycline hyclate at the implant-abutment interface results in reduced crestal bone resorption and pocket probing depth levels. In addition, it reduces the risk of developing peri-implant mucositis.

Pharmacokinetic study of high-dose oral rifampicin in critically Ill patients with multidrug-resistant Acinetobacter baumannii infection.

PURPOSE: Although rifampicin (RIF) is used as a synergistic agent for multidrug-resistant Acinetobacter baumannii (MDR-AB) infection, the optimal pharmacokinetic (PK) indices of this medication have not been studied in the intensive care unit (ICU) settings. This study aimed to evaluate the PK of high dose oral RIF following fasting versus fed conditions in terms of achieving the therapeutic goals in critically ill patients with MDR-AB infections. METHODS: 29 critically ill patients were included in this study. Under fasting and non-fasting conditions, RIF was given at 1200 mg once daily through a nasogastric tube. Blood samples were obtained at seven time points: exactly before administration of the drug, and at 1, 2, 4, 8, 12, and 24 h after RIF ingestion. To quantify RIF in serum samples, high-performance liquid chromatography (HPLC) was used. The MONOLIX Software and the Monte Carlo simulations were employed to estimate the PK parameters and describe the population PK model. RESULTS: The mean area under the curve over the last 24-h (AUC0-24) value and accuracy (mean ± standard deviation) in the fasting and fed states were 220.24 ± 119.15 and 290.55 ± 276.20 µg × h/mL, respectively. There was no significant difference among AUCs following fasting and non-fasting conditions (P > 0.05). The probability of reaching the therapeutic goals at the minimum inhibitory concentration (MIC) of 4 mg/L, was only 1.6%. CONCLUSION: In critically ill patients with MDR-AB infections, neither fasting nor non-fasting administrations of high-dose oral RIF achieve the therapeutic aims. More research is needed in larger populations and with measuring the amount of protein-unbound RIF levels.

Cinnamon and its possible impact on COVID-19: The viewpoint of traditional and conventional medicine.

The COVID-19 global epidemic caused by coronavirus has affected the health and other aspects of life for more than one year. Despite the current pharmacotherapies, there is still no specific treatment, and studies are in progress to find a proper therapy with high efficacy and low side effects. In this way, Traditional Persian Medicine (TPM), due to its holistic view, can provide recommendations for the prevention and treatment of new diseases such as COVID-19. The muco-obstruction of the airway, which occurs in SARS-CoV-2, has similar features in TPM textbooks that can lead us to new treatment approaches. Based on TPM and pharmacological studies, Cinnamomum verum (Darchini)'s potential effective functions can contribute to SARS-CoV-2 infection treatment and has been known to be effective in corona disease in Public beliefs. From the viewpoint of TPM theories, Cinnamon can be effective in SARS-CoV-2 improvement and treatment through its anti-obstructive, diuretic, tonic and antidote effects. In addition, there is pharmacological evidence on anti-viral, anti-inflammatory, antioxidant, organ-o-protective and anti-depression effects of Cinnamon that are in line with the therapeutic functions mentioned in TPM.Overall, Cinnamon and its ingredients can be recommended for SARS-CoV2 management due to multi-targeting therapies. This review provides basic information for future studies on this drug's effectiveness in preventing and treating COVID-19 and similar diseases.

Effect of Volume and Renewal of the Storage Media on the Release of Monomer from Dental Composites.

This study evaluated the effect of the volume and renewing of storage media on monomer leachability from dental composite. Samples of two dental composites (BEAUTIFIL II Gingiva (BG) and Filtek Bulk-Fill Flowable (FBF)) were stored after polymerization in 1 and 3 milt storage media (ethanol/water 75%) for seven days. Refreshing of storage media was done in half of the samples of each group. The amounts of releasing monomers (UDMA, BisGMA, TEGDMA) in storage media were measured by high-performance liquid chromatography (HPLC). Data was analyzed using two-way ANOVA and t-test (α = 0.05). Elution of TEGDMA and UDMA from both composites was significantly higher in 3 mL storage media. In groups with refreshing of storage media, BisGMA had higher amounts of release. Saturation makes the storage media volume important factor in monomer elution. Refreshing of storage media had significant effect on monomer release before the elution of 50% of total released monomer.

Pharmacokinetic Behavior of Phenytoin in Head Trauma and Cerebrovascular Accident Patients in an Iranian Population.

OBJECTIVE: Acute brain injury is one of the leading causes of morbidity and mortality worldwide. Phenytoin has been commonly used as an anticonvulsant agent for the treatment or prophylaxis of seizures following acute brain injury. After a severe head injury, several pharmacokinetic changes occur. The aim of this study is the comparative evaluation of phenytoin serum concentration in patients with traumatic and nontraumatic brain injury (TBI). METHODS: This prospective observational study was performed on twenty adult brain injury patients who were admitted to an Intensive Care Unit and required phenytoin for the treatment or prophylaxis of postinjury seizures. For all the patients, phenytoin serum concentration was determined in three scheduled time points. Phenytoin serum concentration and pharmacokinetic parameters were compared between patients with TBI and cerebrovascular accident (CVA). FINDINGS: The Vmaxand Kmwere significantly higher in head trauma (HT) patients than the CVA group. The phenytoin concentration (Cp) and the Cp/dose ratio were significantly higher in the CVA group patients during the first sampling (P < 0.05). The Acute Physiology and Chronic Health Evaluation П (APACHE П) score was significantly lower than the baseline at the end of the study in each group of patients (P < 0.05). In addition, no significant correlation was observed between Vmax, Km, Cp, Cp/dose ratio, and APACHE II scores at the time of sampling. CONCLUSION: Due to significant differences in phenytoin plasma concentration and pharmacokinetic parameters between HT and CVA patients, close attention must be paid to the pharmacokinetic behavior of phenytoin in the efforts to improve the patient's outcome after a severe HT.

Preliminary Study on Cost-Effective L-Tryptophan Production from Indole and L-Serine by E. coli Cells.

BACKGROUND: L-tryptophan is used widespread in the pharmaceutical industry. The majority of L-Trp production depends on microbial processes that produce L-tryptophan from indole and L-serine. These processes are very costly due to the costs of precursors, especially L-serine. Use of inexpensive substitutions as the L-serine source of L-tryptophan production enables us to reach a cost-effective process. In this paper, effect of Triton X-100 on L-Trp production and the ability to use Iranian cane molasses as inexpensive L-serine source was investigated. METHODS: Escherichia coli (E. coli) ATCC 11303 cells were grown in 10-L fermenter containing minimal medium supplemented with beet molasses as an inexpensive carbon source and indole as tryptophan synthase inducer. Whole cells of stationary phase were used as biocatalyst for L-Trp production. Triton X-100 addition to the production medium as indole reservoir was investigated. Then, cane molasses was used as L-Ser source in L-Trp production medium. Amount of L-Tryptophan and theoretical yield of L-Trp production was determined by HPLC and by a colorimetrically method on the basis of remaining indole assay, respectively. RESULTS: As a result, triton X-100 increased L-Trp production three times. Also, the result showed that 0.68 mM L-Tryptophan was produced in the presence of cane molasses at 37°C for 8 hr. CONCLUSION: This result showed that cane molasses of Qazvin sugar factory includes significant amounts of L-Ser that makes it a suitable substitution for L-Ser in L-Trp production. Therefore, it has the potential to be used for cost-effective L-Trp production in industrial scale.

Relationship Between Palpitation and Mental Health.

BACKGROUND: 'Palpitation' is one of the most common complaints in patients referring to cardiologists. In modern medicine era, these patients suffer from much distress and some cases are known to be difficult to treat. Although the clinician's first duty is obviously to search for an organic basis for this symptom, the diagnostic evaluation is frequently unrevealing. However, clinical experience suggests that psychiatric causes are relatively common. OBJECTIVES: This research aimed to screen for mental disorders in patients complaining of palpitation and healthy persons in order to perform a preliminary comparison between them. PATIENTS AND METHODS: This is a case-control study to screen mental disorders. The target population consisted of adult volunteers with benign palpitation and their matched healthy persons. They were referred during a 10-month-period to the cardiology outpatient's clinic of Mostafa Khomeini hospital in Tehran, Iran. Sampling was accidental and eventually 110 participants comprised the sample size. The measuring tool was GHQ-28 (28-item general health questionnaire) and the main variable was the questionnaire score obtained from the Likert scoring method. RESULTS: Comparing two groups showed that the number of participants with the scores more than cut-off point in palpitation group was significantly more than healthy person group (85.4% vs. 43.6% with P < 0.001). Also the total score of GHQ-28 and scores of its subscale (somatization, anxiety, and social dysfunction) in patients complaining of palpitation were significantly more than those of the healthy participants (34.2 vs. 25.7, 8.9 vs. 6.4, 9.4 vs. 6.4, and 12.3 vs. 10.8, respectively with P < 0.001, P = 0.001, P < 0.001, and P < 0.007, respectively). CONCLUSIONS: Palpitation is the most common symptom in psychiatric disorders such as anxiety and somatization disorders. According to the results of this study, psychiatric causes have an important role in Iranian patients complaining of palpitations (benign form). Considering this fact may lead to a more effective treatment of benign palpitations.

Heart palpitation relief with Melissa officinalis leaf extract: double blind, randomized, placebo controlled trial of efficacy and safety.

ETHNOPHARMACOLOGICAL RELEVANCE: In Traditional Iranian Medicine (TIM), Melissa officinalis L. is commonly regarded as an effective therapy for heart palpitations. OBJECTIVE: Heart palpitation is a common complaint that is often benign and associated with a marked distress that makes the condition difficult to treat. Herbal medicines provide an alternative to conventional drugs for treating various kinds of diseases. This study was done as a double blind randomized placebo-controlled clinical trial to evaluate the efficacy and safety of the dried extract of M. officinalis on adults suffering from benign palpitations. MATERIALS AND METHODS: Eligible volunteers were randomly assigned as outpatients to a 14 day treatment with 500 mg twice a day of lyophilized aqueous extract of M. officinalis leaves (or placebo). Participants in the tests, physicians and researchers were blind to group assignments. Both primary and secondary outcomes were patient-reported. Primary outcomes were obtained from two measures: mean frequency of palpitation episodes per week, derived from patients׳ diaries, and mean intensity of palpitation estimated through Visual Analogue Scale (VAS) in a self-report questionnaire. Psychiatric symptoms (somatization, anxiety and insomnia, social dysfunction and severe depression) were evaluated as secondary outcomes by General Health Questionnaire-28 (GHQ-28), before and after intervention. RESULTS: Fifty-five volunteers out of 71 recruited study subjects completed the trial. Results showed that 14-day of treatment with lyophilized aqueous extract of M. officinalis leaves reduced frequency of palpitation episodes and significantly reduced the number of anxious patients in comparison to the placebo (P=0.0001, P=0.004 resp.). Also, M. officinalis extract showed no indication of any serious side effects. CONCLUSION: Lyophilized aqueous extract of M. officinalis leaves may be a proper and safe herbal drug for the treatment of benign palpitations.

Optimization of L-Tryptophan Biosynthesis From L-Serine of Processed Iranian Beet and Cane Molasses and Indole by Induced Escherichia coli ATCC 11303 Cells.

BACKGROUND: L-tryptophan is an important ingredient in medicines, especially in neuromedicines such as antidepressants. Many commercial processes employ various microorganisms with high tryptophan synthase activity to produce L-tryptophan from indole and L-serine, but these processes are very costly due to the costs of precursors, especially L-serine. OBJECTIVES: For this reason, we studied the ability to use processed Iranian cane and beet molasses as L-serine sources for L-tryptophan production, which enables us to reach a cost-effective process. MATERIALS AND METHODS: Whole cells of Escherichia coli ATCC 11303 were induced for L-tryptophan synthase by addition of indole to the growth medium and bacterial cells harvested from the growth medium were used as biocatalysts in the production medium. Conditions of the production medium were optimized and Iranian cane and beet molasses were processed by solvent extraction with ethanol and n-butanol and used as L-serine sources of the production medium. Amount of L-tryptophan and theoretical yield of L-tryptophan production were determined by High Performance Liquid Chromatography and by a colorimetrical method on the basis of the remaining indole assay, respectively. RESULTS: L-tryptophan production increased by 15 folds, when indole was used as an inducer. L-tryptophan was produced from processed Iranian beet molasses in satisfactory amounts (0.53 mM) and no exogenous pyridoxal phosphate was required as a cofactor under our experimental conditions. CONCLUSIONS: The obtained results proved that Iranian beet molasses include significant amounts of L-serine that makes them a suitable substitution for L-serine. Findings of the present study give impetus to use of Iranian beet molasses for cost-effective L-Trp production in the amino acid industry.

Clinical pharmacokinetics of tacrolimus in Iranian liver transplant recipients.

Tacrolimus, a cornerstone of immunosuppressive therapy in solid organ transplantation, has a narrow therapeutic range with considerable inter-individual and intra-individual pharmacokinetic variability. To date, there is no information on the pharmacokinetics of tacrolimus in Iranian liver transplant recipients. This study was designed to determine pharmacokinetic properties of orally administered tacrolimus in Iranian adult liver transplant recipients. Tacrolimus doses and steady state whole blood trough concentrations as well as patient demographic and clinical data were obtained retrospectively using the 30 included patients' medical records. Pharmacokinetic parameters were estimated by using a nonlinear mixed effect model program (Monolix version 3.1). Absorption rate constant was fixed at two hours(-1). Drug apparent clearance (CL/F), apparent volume of distribution (Vd/F), and elimination half life (t½ß) were calculated. The administered dose of tacrolimus to the patients ranged from 0.02 to 0.14 mg/Kg/day. Tacrolimus blood trough concentrations varied widely within the range of 1.8 to 30 ng/mL. The mean values of CL/F, Vd/F, and t½ß were found to be 9.3 ± 0.96 L/h, 101 ± 29 L, and 7.5 hours, respectively. The pharmacokinetics of tacrolimus was highly variable among our patients. CL/F, Vd/F, and t½ß of tacrolimus in this study were comparable to reported values from Italian heart transplant patients but somewhat different from reported ones from other solid organ transplant populations.

Effect of food stimulated liquids and thermocycling on the monomer elution from a nanofilled composite.

The present study was aimed to evaluate the effects of food simulating liquids and thermocycling on the elution of monomers from a nanofilled resin composite in different immersion times. Five Specimen discs were made from a nano-hybrid composite (Supreme 3M) for each group (Total = 180) and immersed in distilled water (control), citric acid, lactic acid, and 75% aqueous ethanol solution. The discs were removed after 24 h, 48 h, 72 h, 1 wk, 4 wk, and 12 wk. Three groups of samples underwent thermocycling for 1000, 2000 and 3000 cycles. The solutes were analyzed with HPLC for detection of eluted monomers. The results showed that the amount of released TEGDMA was significantly higher than that of Bis-GMA; however, there were not any significant differences between the amount of released Bis-GMA and UDMA. Moreover, the highest amount of monomers was released from samples immersed in ethanol solution; samples immersed in citric acid and lactic acid significantly released more monomers than those immersed in distilled water. Furthermore, the immersion time in aqueous ethanol solution had an increasing effect on the release of monomers. In addition, the higher amounts of monomers were release from samples immersed in ethanol and citric acid which underwent a higher number of thermal cycles. In conclusion, food and drink stimulated liquids used in this study increased the amount of some of the monomers released from composite resin. Thermal shocks and storage time are other factors that increased the release of monomers from the composite resin.

Clinical pharmacokinetics of oral versus sublingual administration of tacrolimus in adult liver transplant recipients.

OBJECTIVES: Oral tacrolimus administration is the common route of drug delivery. Recent studies suggest sublingual administration of tacrolimus as an alternative route may produce comparable drug trough levels with similar or even lower doses than the oral route, especially in lung transplant recipients; however, most of this research does not encompass intraindividual variations compared between the 2 routes. This study sought to compare the bioavailability and blood trough concentrations of orally and sublingually administered tacrolimus in adult liver transplant recipients by considering intraindividual variations in tacrolimus pharmacokinetics properties. MATERIALS AND METHODS: Six adult liver transplant recipients received their tacrolimus either orally or sublingually within 2 consecutive days. Blood samples to determine tacrolimus concentrations were gathered at 0, 0.5, 1, 2, 4, 6, and 12 hours after oral and sublingual tacrolimus administration. Mean data values were used to calculate the pharmacokinetics parameters via the feathering or residual method, using the 1-compartment, first-order elimination pharmacokinetics model. Compared pharmacokinetics parameters included drug bioavailability, maximum blood concentration (C(max)), time to reach maximum blood level (T(max)), and trough blood concentrations. RESULTS: Trough whole blood levels, area under the concentration-time curve, T(max), and C(max) after oral and sublingual administration of tacrolimus were not significantly different (10.4 ± 7.4 vs 11.2 ± 11.3 ng/mL for trough blood concentration, 181.5 ± 114.1 vs 160.8 ± 115.9 ng.h/mL for AUC, 1.9 ± 1.2 vs 1.4 ± 0.7 h for T(max), and 19.9 ± 10.8 vs 17.2 ± 11.7 ng/mL for C(max)). A double-peak phenomenon was observed in some concentration-time profiles. CONCLUSIONS: Sublingual tacrolimus administration does provide therapeutic drug concentrations in adult liver transplant recipients. Therefore, sublingual tacrolimus may confidently be considered as an alternative route to oral administration in patients who are unable to swallow their drugs.

Oral lorazepam prevents seizure during high-dose busulfan in children undergoing hematopoietic stem cell transplantation: a prospective study.

High-dose Busulfan in combination chemotherapy has been used commonly for hematopoietic stem cell transplantation. It crosses the blood-brain barrier and could cause seizure. Benzodiazepines have been used as anticonvulsant prophylaxis. This is a prospective study using oral lorazepam together with busulfan-based conditioning regimen in 30 children undergoing hematopoietic stem cell transplantation. The dose of lorazepam used ranged from 0.017 to 0.039 mg/kg (median = 0.026 mg/kg) per dose. None of the patients developed seizure while receiving oral lorazepam or within 72 hours of the last dose of Busulfan. Oral lorazepam was tolerated by the patients, but all patients needed dose reduction due to some adverse effects. In the authors' experience, oral lorazepam is a useful anticonvulsant prophylaxis for children receiving high-dose busulfan.