An alternative approach to minimize the risk of coronavirus (Covid-19) and similar infections.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new strain that was discovered in 2019 and has not been previously identified in humans. On December 31st 2019 World Health Organization (WHO) was informed of a cluster of cases with pneumonia of unknown origin from Wuhan City, Hubei province of China. The WHO announced in February 2020 that COVID-19 is the official name of the coronavirus diseases. A total of 519,899 confirmed cases with 23,592 deaths linked to this pathogen as on March 27, 2020 have been reported. Due to increasing number of infected people across the continents and huge loss to human life, the WHO has declared the novel COVID-19 outbreak a pandemic. A pandemic is defined as the "worldwide spread" of a new disease. Currently, no COVID-19 specific treatments have been approved by the United States Food and Drug Administration (US-FDA). However, the current treatment options include hydroxychloroquine, tocilizumab, remdesivir, lopinavir-ritonavir (Kaletra®), and nitazoxanide. In recent past, some natural herbal compounds have demonstrated encouraging anti-viral properties. This article attempted to summarize available information on the reported anti-viral activity of some natural products.

Impact of Herbal Medicines like Nigella sativa, Trigonella foenum-graecum, and Ferula asafoetida, on Cytochrome P450 2C11 Gene Expression in Rat Liver.

AIM: Combined use of herbs and drugs may result in clinically important herb-drug interactions. The majorities of these interactions are thought to be metabolism-based and involve induction or inhibition of cytochrome P450 (CYP). The current study was designed to investigate the effect of some commonly used herbs on rat CYP2C11 gene expression and metabolic activity. METHODS: Wistar rats were treated for 7 days with increasing doses of 3 herbs; Nigella sativa, Trigonella foenum-graecum, and Ferula asafoetida. Thereafter, CYP2C11 mRNA and protein levels were determined by real-time polymerase chain reaction (RT-PCR) and western blot analyses, respectively. In vitro metabolic activity of CYP2C11 was performed on rat hepatic microsomes using tolbutamide as specific substrate. RESULTS: Our results showed that all the 3 herbs significantly inhibited the mRNA and protein expression levels of CYP2C11 in a dose-dependent manner. Furthermore, the in vitro enzyme metabolic activity study showed a significant decrease in the formation of 4-hyroxy-tolbutamide, a tolbutamide metabolite, at the higher doses. The inhibitory effects of the investigated herbs on rat CYP2C11 was in the order: Nigella Sativa > Trigonella foenum-graecum > Ferula asafoetida. CONCLUSIONS: The 3 herbs are strong inhibitor of CYP2C11 expression, which can lead to an undesirable pharmacological effect of clinically used CYP2C11 substrate drugs with a low therapeutic index.

Potential inhibitory effect of herbal medicines on rat hepatic cytochrome P450 2D gene expression and metabolic activity.

The aim of current study was to investigate the effect of some commonly used medicinal herbs on the regulation of rat CYP2D gene expression and its metabolic activity. Wistar albino rats were treated for seven consecutive days with selected doses of five commonly used herbs (Trigonella foenum-graecum, Ferula asafoetida, Nigella sativa, Commiphora myrrha and Lepidium sativum). Thereafter, rat livers were harvested and CYP2D mRNA levels were determined by RT-PCR. The metabolic activity of CYP2D was performed on rat hepatic microsomes using dextromethorphan as specific substrate. All investigated herbs produced inhibition of CYP2D mRNA expression and metabolic activity. The inhibitory potential of investigated herbs on rat CYP2D mRNA was in the following order: Commiphora myrrha > Nigella sativa > Lepidium sativum > Trigonella foenum-graecum > Ferula asafoetida. Whereas, the inhibitory potential of investigated herbs on CYP2D mediated enzyme metabolic activity was found in following order: Nigella sativa > Lepidium sativum > Trigonella foenum-graecum > Commiphora myrrha > Ferula asafoetida. The current study shows that only used herbs reduce CYP2D activity in rat liver microsomes at the transcriptional levels. Such effects could lead to undesirable pharmacological effects of clinically used low therapeutic index CYP2D substrate drugs.

Normal circulating PTH in Saudi healthy individuals with hypovitaminosis D.

Recent studies in the Middle East have shown an increased incidence of vitamin D deficiency across this region of year-round sunlight. There is scarcity of information, however, as to the levels of 1,25-dihydroxyvitamin D [1,25(OH)2D], the active form of vitamin D, and its associations with cardiometabolic parameters in an Arab cohort and this study aims to fill this gap. In a cross-sectional study, 33 male and 43 female (22 children and 54 adults, total 76) Saudis with previously established low levels of serum 25-hydroxyvitamin D [25(OH)D] (<50 ng/ml or 20 nmol/l) were recruited. Anthropometrics were obtained and fasting blood samples were taken for a routine measurement of glucose, lipid profile, calcium, and albumin, while serum 25(OH)D, 1,25-(OH)2D, and intact PTH were quantified using specific ELISAs. Serum calcium, intact PTH, and 1,25(OH)2D were all within the normal range in both children and adults in both genders. In all subjects, serum 1,25(OH)2D was not associated with intact PTH, while circulating 1,25(OH)D inversely correlated with systolic blood pressure (p=0.01) and waist circumference (p=0.04). Thus, vitamin D deficient Saudi children and adults with normal levels of 1,25-(OH)2D also had normal circulating calcium and PTH. This study suggests that local cutoffs should be set that will be of clinical significance in the identification of those at true risk for harder end-points, such as secondary hyperparathyroidism and bone-related diseases.

Hypovitaminosis D associations with adverse metabolic parameters are accentuated in patients with Type 2 diabetes mellitus: a body mass index-independent role of adiponectin?

BACKGROUND: Hypovitaminosis D has been associated with an increased prevalence of Type 2 diabetes mellitus (DMT2) and metabolic syndrome manifestations. The purpose of this study was to examine the association between 25-hydroxy-vitamin D (25-OH-VitD) levels and indices of insulin resistance (IR), including adipocytokines, in a Saudi population with or without DMT2. SUBJECTS AND METHODS: A total of 266 subjects (153 DMT2 and 113 healthy controls) aged 26-80 yr were randomly selected from the existing Biomarkers Screening in Riyadh Program (RIYADH Cohort). Subjects were assessed clinically, anthropometry was performed, morning blood chemistries, including fasting glucose (FG), triglycerides, total cholesterol, LDL cholesterol (LDL-C), and HDL cholesterol were obtained. Homeostasis model assessment of IR (HOMA-IR) was calculated, and serum 25-OH-VitD, leptin, adiponectin, resistin, insulin, high sensitivity CRP (hsCRP), and tumor necrosis factor α concentrations were measured using specific assays. RESULTS: In DMT2 subjects, negative correlations between 25-OH-vitD and body mass index (BMI), FG, insulin, HOMA-IR, cholesterol, LDL-C, and hsCRP were observed, while a positive correlation between 25-OH-VitD and adiponectin was detected. The later remained significant after controlling for BMI. Interestingly, only weak and nonsignificant associations between 25-OH-VitD and metabolic parameters were observed in the control group, whereas, when the entire population was examined, negative correlations were evident primarily between 25-OH-VitD and FG, HOMA-IR, total cholesterol, LDL-C. These associations remained significant after controlling for BMI. CONCLUSIONS: These results suggest that hypovitaminosis D associations with metabolic disturbances are accentuated in DMT2. The BMIindependent positive correlation between 25-OH-VitD and adiponectin suggests a potential role for this adipocytokine as a link between 25-OH-VitD and IR in patients with DMT2.

Urinary iodine is associated with insulin resistance in subjects with diabetes mellitus type 2.

BACKGROUND: Diabetes Mellitus (DM) is a major health problem worldwide and its prevalence in Saudi Arabia has reached 31.6%. Patients with diabetes mellitus are at an increased risk of thyroid disease. The purpose of this study was to examine the urinary excretion of iodine in type 2 DM (T2DM) patients, and to assess the clinical implication of iodine status on T2DM. METHODS: A total of 266 adult Saudis aged 18-55 years (109 T2DM patients and 157 healthy controls) were randomly selected from the Riyadh Cohort Study. Subjects were assessed for anthropometry, morning blood chemistries including fasting glucose, and lipid profile; serum concentrations of leptin, adiponectin, resistin, insulin, aPAI, hsCRP, Ang II, TNF-α, TSH, T3, T4, urine creatinine, urine iodine were measured using specific assays. RESULTS: The concentration of urine iodine was significantly lower in T2DM than in healthy control subjects (84.6±2.3 vs. 119.4±3.4, p<0.001), which remained significant after creatinine correction and controlling for age (p=0.01). Furthermore, urinary iodine is negatively correlated with waist, hips, SAD, glucose, insulin, HOMA-IR triglyceride, resistin, angiotensin II (Ang II), and CRP, while it was positively associated with TSH. CONCLUSIONS: The decreased levels of iodine concentration in T2DM patients and its likely deleterious effects on metabolic functions calls for a systematic approach to thyroid disease screening in diabetic patients. Routine annual urinary iodine determination is recommended and should target T2DM patients at risk of thyroid dysfunction.

Gender-specific associations between insulin resistance, hypertension, and markers of inflammation among adult Saudis with and without diabetes mellitus type 2.

PURPOSE: In view of the important roles of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and the acute phase reactant C-reactive protein (CRP) in glucose metabolism and pathogenesis of diabetes mellitus type 2 (DMT2), we assessed gender-specific differences and relative associations of these inflammatory biomarkers to insulin resistance (IR) and risk markers for DMT2. MATERIALS AND METHODS: Serum levels of TNF-α, IL-6 and CRP were determined in 119 clinically diagnosed DMT2 cases, 114 non-DMT2 subjects with IR, and 97 age-matched controls. Fasting blood samples were collected and serum glucose levels, lipid profile, and inflammatory markers were analyzed. RESULTS: In women, a significant association between elevated levels of IL-6 and risk of developing IR [Odds ratio (OR), 4.389, 95 % Confidence Interval (CI) 1.6-11.52, p = 0.004] was found. Significant associations were also found between elevated levels of CRP and risk of hypertension only in female subjects [OR (95% CI) 2.153 (1.04-4.53), p = 0.046]. While, in male subjects, a significant association between elevated levels of TNF-α and risk of developing IR [OR (95% CI) 2.32 (1.09-4.93), p = 0.029] was found. CONCLUSION: The present study showed apparent gender differences in the association of IL-6, CRP, and TNF-a with risks of IR and hypertension, and this could be attributed to sexual dimorphism in fat distribution.

Effect of black seed on dextromethorphan O- and N-demethylation in human liver microsomes and healthy human subjects.

OBJECTIVE: To investigate the effects of black seed on the metabolic activities of CYP3A4 and CYP2D6 in human liver microsomes and in human subjects using dextromethorphan as a probe drug. METHODS: CYP2D6-mediated O-demethylation and CYP3A4-mediated N-demethylation of dextromethorphan (DEX) to dextrorphan (DOR) and 3-methoxymorphinan (3-MM), respectively, were utilized to assess the metabolic activities of the two enzymatic pathways. In the in vitro experiments, DEX was incubated with microsomes and NADPH in absence or presence of black seed extract (10-100 microg/ml) and the formation of the metabolites were measured by HPLC. In the clinical study, four healthy volunteers received a single oral dose of DEX 30 mg alone in phase I, and along with last dose of black seed (2.5 g twice daily for seven days) in phase II. Activities of the two enzymes were evaluated based on the urinary metabolic ratios (MRs), which were calculated from eight-hour urine collections. DEX and its metabolites were assayed in urine samples by HPLC following a liquid-liquid extraction. RESULTS: Black seed extracts significantly inhibited the formation of both metabolites in microsomes. The maximum inhibition was observed at the highest extract concentration (i.e., 100 microg/ml), which was about 80% and 60% for DOR and 3-MM, respectively. In the clinical study, the urinary MRs of DEX/DOR and DEX/3-MM increased by factors of 127 and 1.6-fold, respectively, after consumption of black seed. CONCLUSION: Black seed significantly inhibited CYP2D6 and CYP3A4 mediated metabolism of DEX in human liver microsomes and healthy human volunteers indicating that it has the potential to interact with CYP2D6 and CYP3A4 substrates.

Community pharmacists' knowledge, attitudes and practices towards herbal remedies in Riyadh, Saudi Arabia.

There is an increasing trend towards consumption of complementary and alternative herbal products in many parts of the world. A cross-sectional sample of 115 community pharmacists in Riyadh, Saudi Arabia was visited and information on knowledge, attitudes and practices towards herbal remedies was collected using a structured questionnaire. All pharmacists acknowledged dispensing herbal products through their pharmacies. Ginseng was the most widely used product (47%), followed by ginkgo (23%), valerian (17%) and S.t John's wort (3.5%). In general, pharmacists had poor awareness about potential herb-drug interactions. While 56% of participating pharmacists expressed concerns about the safety of herbal remedies, 30% considered them to be harmless. Community pharmacists need to be better informed about herbal products.

Community pharmacists' knowledge, attitudes and practices towards herbal remedies in Riyadh, Saudi Arabia

There is an increasing trend towards consumption of complementary and alternative herbal products in many parts of the world. A cross-sectional sample of 115 community pharmacists in Riyadh, Saudi Arabia was visited and information on knowledge, attitudes and practices towards herbal remedies was collected using a structured questionnaire. All pharmacists acknowledged dispensing herbal products through their pharmacies. Ginseng was the most widely used product [47%], followed by ginkgo [23%], valerian [17%] and St John's wort [3.5%]. In general, pharmacists had poor awareness about potential herb-drug interactions. While 56% of participating pharmacists expressed concerns about the safety of herbal remedies, 30% considered them to be harmless. Community pharmacists need to be better informed about herbal products

Bioequivalence of Jusline following subcutaneous administration in healthy subjects.

OBJECTIVE: The aim of the current work is to evaluate the pharmacokinetic and pharmacodynamic profile of a new human insulin preparation (jusline) following subcutaneous administration in healthy subjects, and to compare this profile with Humulin insulin. METHODS: 20 healthy male subjects received a single dose of 0.2 U/kg of test (Jusline) or reference insulin (Humulin) during an euglycemic clamp keeping blood sugar constant (90 +/- 5 mg/dl) by changing the glucose infusion rate. Pharmacokinetic and pharmacodynamic measurements were taken from blood measurements of glucose, insulin, and C-peptide levels for tested insulin formulations. RESULTS: The mean values of the individual AUC ratios were well within the 90% confidence interval (100.5% for Regular, 101.9% for NPH, and 100.0% for Premixed Regular/NPH (30/70)). Similarly, Cmax and tmax were within the bioequivalence limit (80 - 125%). The maximum GIR were 10.20 mg/kg/min and 9.72 mg/kg/min for Jusline Regular and Humulin Regular, respectively. The maximum GIR were 7.09 mg/kg/min and 7.91 mg/kg/min for Jusline NPH and Humulin NPH, respectively. The maximum GIR and tGIRmax were 6.39 mg/kg/min and 6.63 mg/kg/ min for Jusline Premixed Regular/NPH (30/70) and Humulin Premixed Regular/NPH (30/70), respectively. Both insulin products produced similar suppression of endogenous C-peptide level (-29.76% to -50.22%). CONCLUSION: The present study demonstrated that after subcutaneous administration, there are no significant differences between Jusline and Humulin to promote peripheral glucose uptake.

Effect of valerian, valerian/hops extracts, and valerenic acid on glucuronidation in vitro.

Valerian preparations alone or in combination with hops are popular over-the-counter products used for sleep disturbances or anxiety. Therefore, it is important to characterize the effect of these products on the activity of human drug-metabolizing enzymes. The inhibitory effects of valerian and valerian/hops extracts as well as valerenic acid (a major constituent of valerian) on glucuronidation were evaluated in human liver microsomes and with expressed uridine 5'-diphosphate (UDP)-glucuronosyltransferases (UGT). Methanolic extracts of two herbal preparations caused significant reductions in the rate of formation of acetaminophen, oestradiol, morphine, and testosterone glucuronides. Oestradiol glucuronidation at the 3-hydroxy position was inhibited by nearly 87% in microsomal incubations. In addition, marked reductions in UGT1A1 and UGT2B7 activities were observed in the presence of the herbal extracts using oestradiol and morphine as probe substrates, respectively. Valerenic acid also demonstrated significant inhibitory effects on the glucuronidation of acetaminophen, oestradiol, and morphine with both microsomes and expressed UGTs. The relatively low IC50 values obtained for valerenic acid in microsomal incubations may indicate that this essential oil contributes to the effects observed with herbal extracts in inhibiting glucuronidation in vitro. Overall, these findings suggest that valerian-containing products may interfere with the glucuronidation of endo- and xenobiotics.

High-performance liquid chromatographic assay for acetaminophen glucuronide in human liver microsomes.

A rapid and specific high-performance liquid chromatographic assay was developed for the determination of acetaminophen glucuronide formed by human liver microsomes. In addition, incubation conditions were systematically evaluated. Conditions that yielded the optimal rate of acetaminophen glucuronide formation over various concentrations of acetaminophen (0.15-30 mM) consisted of the following: 0.1 M potassium phosphate buffer, 1 mM magnesium chloride, 30 microg/mg alamethicin, 4 mM uridine 5'-diphosphoglucuronic acid at a pH of 7.1. Alamethicin produced higher and more consistent APAPG formation rates compared to Brij-58. Adding saccharolactone to the incubation medium reduced the velocity of the reaction. Acetaminophen glucuronide, acetaminophen, and the internal standard (paraxanthine), were analyzed on a C18 column with UV detection at 250 nm. The mean correlation coefficient (r2) of the standard curves for acetaminophen glucuronide was >0.99 over the range of 0.1-25 nmol. The intra- and inter-day coefficients of variation were <4%. This method is suitable for in vitro studies using acetaminophen glucuronide formation as an index reaction for UGT activity.

Effect of ceftazidime on systemic cytokine concentrations in rats.

The effect of a single dose of ceftazidime on circulating concentrations of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) in a rat model of sepsis was studied. IL-6 concentrations were significantly elevated (100 to 200 times the baseline) 6 h after ceftazidime administration in both septic and nonseptic (control) rats. TNF-alpha concentrations increased significantly in nonseptic (approximately 40 times the baseline) rats but not septic (approximately 2 to 3 times the baseline) rats. Ceftazidime administration was not associated with an increase in endotoxin concentrations. These findings suggest that ceftazidime modulation of proinflammatory cytokine concentrations may be independent of its antimicrobial properties.

Unintended immunomodulation: part I. Effects of common clinical conditions on cytokine biosynthesis.

Cytokines are low molecular weight proteins that act in an autocrine, paracrine and endocrine fashion to regulate and integrate immune effector cell function. Cytokine production is tightly controlled by a complex network of co-stimulatory and feedback loops. The systemic concentrations of some cytokines, most notably tumor necrosis factor and various interleukins, correlate with the extent of inflammation, and the severity of critical illness and patient outcome. Thus, cytokine expression is often monitored and/or manipulated as a therapeutic target in studies of sepsis and other inflammatory conditions. Unfortunately, some therapies designed to modify cytokine response have failed to improve outcomes in sepsis, and some of these therapies have actually been harmful. Several common clinical conditions, as well as, therapeutic interventions significantly influence cytokine expression. Furthermore, the magnitude and extent of these effects may be greater than those produced by immunomodulating therapies. In contrast, other conditions may not produce clinically significant changes in cytokine expression, and must simply be considered when interpreting studies designed to determine the effects of immunomodulation. Some conditions may even result in changes in the inflammatory response and may thus add to the inflammatory burden of a critically ill patient. This review provides intensivists and other clinicians with an overview of the effects of altered physiologic conditions on cytokine expression. This information is important so that studies measuring cytokines can be correctly interpreted and clinical circumstances in which cytokine manipulation is undesirable can perhaps be avoided.

Unintended immunomodulation: part II. Effects of pharmacological agents on cytokine activity.

Cytokines are proteins that are produced by immune and non-immune cells, and they function as mediators to facilitate cellular communication. Their production is regulated by a complex network of co-stimulatory and feedback loops that responds to a variety of stimuli. Several pharmacological agents have been found to alter systemic concentrations and/or the activity of different cytokines via a variety of mechanisms, including changes in biosynthesis, secretion, and/or stability. Many of the agents that modulate cytokine levels commonly are used in the management of critically ill patients. Catecholamines for example, have been found to promote the secretion of anti-inflammatory cytokines, and, therefore, may alter acute inflammatory processes such as sepsis. Antimicrobials have multiple effects on cytokine production, either secondary to the release of endotoxins from gram-negative bacteria or via direct activity on cytokine expression at the transcriptional and/or post-transcriptional level. Pentoxifylline has multiple effects on the immune system, but inhibition of pro-inflammatory cytokine release predominates. The reminder of the known drug-cytokine interactions and their effect on the inflammatory process are discussed. Information on the pharmacodynamic effect of drugs is limited, and our understanding of the clinical significance of these observations awaits further investigation. This review was designed to provide intensivists and other clinicians with useful information regarding the effect of medications on cytokine activity. It is also intended to help researchers and clinicians to optimize the design of studies of pharmacotherapeutic modulation of cytokines and to avoid the use of some agents in clinical circumstances in which cytokine manipulation is undesirable.