Potential value of serum progranulin as an activity biomarker in rheumatoid arthritis patients: Relation to musculoskeletal ultrasonographic evaluation

Aim of the work

To determine the serum progranulin levels in rheumatoid arthritis (RA) patients and to study its relation with disease activity assessed clinically and by ultrasound (US).

Clinical significance of fibromyalgia syndrome in different rheumatic diseases: Relation to disease activity and quality of life

Objective

To describe the frequencies of fibromyalgia syndrome (FMS) in various rheumatic diseases; rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and Behçets disease (BD) patients and to study the relation to clinical manifestations and quality of life (QoL).

Effect of a single intrastriatal rotenone injection on oxidative stress and neurodegeneration in the rat brain

We investigated the effect of a single injection of rotenone into the striatum on the development of oxidative stress, nigrostriatal cell injury and motor alterations in rats. Rotenone (1, 3, 5 and 9 mM; 5 μL/rat) or the vehicle (dimethyl sulfoxide) was injected into the right striatum. Control rats received the vehicle only. Rats were allowed to recover from the operation and were tested for behavioural changes on 7th and 30th days after rotenone injection. Biochemical markers of oxidative stress including malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide, paraoxonase 1 (PON1) activity and Q10 enzyme as well as monoamine neurotransmitters in the brain were determined after 30 days of rotenone treatment. Histopathology and tyrosine hydroxylase immunohistochemistry were also performed. Results: Intrastriatal injection of rotenone at 9 mM caused immediate death of rats. No mortality was observed with the lower concentrations of the pesticide. Rotenone at 1–5 mM resulted in increased brain oxidative stress in a dose-dependent manner. MDA increased by 23.5–64.9 %, while GSH decreased by 20.4–24.1 % in the contralateral cerebral hemisphere. Nitric oxide increased by 20.2–41.7 % in ipsilateral cortex. PON1 activity decreased by 12.5–38.2 % in ipsilateral cerebral cortex and by 31.2–65.3 % in ipsilateral striatum, respectively, but coenzyme Q10 increased in the ipsilateral cortex by 21–26.3 %. There was decreased dopamine and serotonin in the ipsilateral striatum after rotenone injection. Tyrosine hydroxylase immunoreactivity was markedly decreased in ipsilateral substantia nigra in the rotenone-treated in contrast to the vehicle-treated rats. Rotenone increased the number of degenerated cells in substantia nigra in a dose-dependent manner. It also caused depletion of pigment granules from cells. Degenerative changes were also observed in the contralateral hippocampus and cortex especially after the highest dose of rotenone. The number of spontaneous rears made during 30 min in the cylinder was decreased in both limbs; the decrease being more evident in the ipsilateral side. Thus, a single intrastriatal injection of rotenone (a) caused a significant nigrostriatal degeneration and loss of dopamine and serotonin from the striatum; (b) elicited cell degeneration in the hippocampus and cortex; (c) induced oxidative stress and neuronal injury (this latter effect of rotenone was not region specific); and (d) the motor deficits (decreased rearing activity) occurred in both limbs.     

Hepatoprotective effects of the nitric oxide donor isosorbide-5-mononitrate alone and in combination with the natural hepatoprotectant, silymarin, on carbon tetrachloride-induced hepatic injury in rats

The aim of this study was to investigate the effect of the nitric oxide donor isosorbide-5-mononitrate (5-ISMN) alone or in combination with the natural hepatoprotectant with anti-oxidant activity silymarin on the carbon tetrachloride (CCl₄)-induced hepatic injury in rats. 5-ISMN (1.8, 3.6 or 7.2 mg/kg), silymarin (25 mg/kg) or 5-ISMN (1.8, 3.6 or 7.2 mg/kg) combined with silymarin was given once daily orally simultaneously with CCl₄ and for 15 days thereafter. Liver damage was assessed by determining serum enzyme activities and hepatic histopathology. 5-ISMN given at the above doses conferred significant protection against the hepatotoxic actions of CCl₄ in rats, reducing serum alanine aminotransferase (ALT) levels by 31.2, 39.3 and 61.6%, respectively, when compared with controls. Serum aspartate aminotransferase (AST) levels decreased by 19.8, 22.7 and 59.4%, respectively, while alkaline phosphatase (ALP) decreased by 26.1 and 32.6% by the drug at 3.6 and 7.2 mg/kg, respectively. When silymarin was added to 5-ISMN (1.8, 3.6 or 7.2 mg/kg), ALT decreased by 32.8, 59.6, 70.2% and AST by 28.7, 50.3, 60%, when compared with CCl₄ control group levels. Silymarin in combination with 3.6 or 7.2 mg/kg 5-ISMN resulted in 37.5 and 39.2% reductions in ALP when compared with CCl₄ control group. Meanwhile, silymarin alone reduced ALT, AST and ALP levels by 65.9, 52 and 62.3%, respectively. Blood levels of reduced glutathione were markedly decreased in CCl₄-treated rats. Reduced glutathione levels were increased by the administration of 5-ISMN and restored to near normal values by silymarin treatment. Histopathological alterations by CCl₄ were markedly reduced after treatment with 5-ISMN alone or in combination with silymarin. Histopathologic examination of the livers of CCl₄-treated rats administered 5-ISMN at 7.2 mg/kg showed marked restoration of the normal architecture of the liver tissue and minimal fibrosis. Silymarin co-administered with 5-ISMN resulted in further improvement of the histologic picture. These results indicates that treatment with 5-ISMN protects against hepatocellular necrosis induced by CCl₄. The study suggests a potential therapeutic use for 5-ISMN in combination with silymarin in liver injury.     

Effects of fluconazole on the pharmacokinetics and pharmacodynamics of antimony in cutaneous leishmaniasis-infected hamsters

Pentavalent antimony (Sb^V) compounds are the drugs of choice for the treatment of all forms of leishmaniasis. For 20 years there has been an interest in antifungal azoles for treating leishmaniasis, with variable success. In the current study, we examined the effects of co-administration of fluconazole (FLZ) on the pharmacokinetics and pharmacodynamics of Sb^V in cutaneous leishmaniasis-infected hamsters. Hamsters were divided into four groups. All hamsters were injected with 0.1 mL of 1 × 10⁸ promastigotes/mL into the right foot on Day 1. Treatment was started 5 days after the infection. The antimony group received 80 mg/kg/day of Pentostam^® intramuscularly whilst the FLZ group received FLZ 20 mg/kg/day orally for 14 days. The combination group received both Pentostam^® and FLZ at the above mentioned doses for 14 days. Animals in the control group received no treatment. The infected footpads were measured on Days 1 and 14. A pharmacokinetic study was conducted on Days 1 and 14 of treatment, representing single- and multiple-dose pharmacokinetics, respectively. Blood samples were collected at different time intervals up to 24 h. Sb^V was determined using flameless atomic absorption spectrophotometry. Pharmacokinetic parameters were calculated using a non-compartmental analysis. In the single-dose study, there was no statistically significant difference in any of the pharmacokinetic parameters of Sb^V when given alone or with FLZ. However, on Day 14 a significant increase in peak plasma concentration (C_max) (three-fold) and area under the concentration–time curve (AUC) (four-fold) of antimony was observed when Sb^V was co-administered with FLZ. A statistically significant prolongation of the terminal half-life from 1.63 to 8.67 h (P < 0.05) was also observed. A significant reduction in clearance was detected. However, FLZ had no effect on the pharmacodynamics of Sb^V as measured by footpad sizes. In conclusion, FLZ did not improve the therapeutic effect of Sb^V when given concomitantly despite the significant increase in blood concentration and prolongation of the elimination half-life of Sb^V.     

Hemostatic system and COVID-19 crosstalk: A review of the available evidence

Since the discovery of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its resultant coronavirus disease 2019 (COVID-19) pandemic, respiratory manifestations have been the mainstay of clinical diagnosis, laboratory evaluations, and radiological investigations. As time passed, other pathological aspects of SARS-CoV-2 have been revealed. Various hemostatic abnormalities have been reported since the rise of the pandemic, which was sometimes superficial, transient, or fatal. Mild thrombocytopenia, thrombocytosis, venous, arterial thromboembolism, and disseminated intravascular coagulation are among the many hemostatic events associated with COVID-19. Venous thromboembolism necessitating therapeutic doses of anticoagulants is more frequently seen in severe cases of COVID-19, especially in patients admitted to intensive care units. Hemorrhagic complications rarely arise in COVID-19 patients either due to a hemostatic imbalance resulting from severe disease or as a complication of over anticoagulation. Although the pathogenesis of coagulation disturbance in SARS-CoV-2 infection is not yet understood, professional societies recommend prophylactic antithrombotic therapy in severe cases, especially in the presence of abnormal coagulation indices. The review article discusses the various available evidence on coagulation disorders, management strategies, outcomes, and prognosis associated with COVID-19 coagulopathy, which raises awareness about the importance of anticoagulation therapy for COVID-19 patients to guard against possible thromboembolic events.     

Patterns of Primary Immunodeficiency Disorders Among a Highly Consanguineous Population: Cairo University Pediatric Hospital’s 5-Year Experience

Introduction

Primary immunodeficiency disorders (PIDs) are heterogeneous disorders that mainly present with severe, persistent, unusual, or recurrent infections in childhood. Reports from different parts of the world indicate a difference between Western and Eastern populations.

Aim

The aim of this study was to report on the different patterns of PIDs and identify subgroup characteristics in a highly consanguineous population in Egypt.

Methods

We performed a retrospective chart review for children below 18 years diagnosed with PID at Cairo University Pediatric Hospital from 2010 to 2014.

Results

Four hundred seventy-six children were diagnosed with PID disorders. Major categories included combined immunodeficiency disorders, which constituted a large proportion (30 %) of cases, along with predominantly antibody disorders (18 %) followed by syndromic combined disorders (16.8 %), phagocytic disorders (13.2 %), immune dysregulation disorders (10.5 %), and autoinflammatory disorders (9 %).

Conclusion

PIDs have different patterns within inbred populations with high consanguinity.

     

Design of freeze-dried Soluplus/polyvinyl alcohol-based film for the oral delivery of an insoluble drug for the pediatric use

Abstract

Spironolactone (SL) is a poorly water-soluble drug. Being poorly soluble affects its dissolution rate which in turn affects its oral bioavailability. This work aimed to prepare freeze-dried SL-Soluplus®/polyvinyl alcohol (PVA) oral thin film in an attempt to enhance the drug solubility on one hand and at the same time prepare a solid dosage form convenient for the pediatric use. SL-Soluplus®/PVA films were prepared using polyethylene glycol 400 (PEG 400) as a plasticizer applying the solvent-casting technique. The prepared films were evaluated for their thickness, tensile strength, and in vitro dissolution studies. Box–Behnken design (17 runs) was applied to optimize the effects of the formulation variables on the film properties. The optimized film formulation was freeze-dried after casting so as to enhance the drug dissolution. Moreover, the optimized freeze-dried film was re-characterized in vitro and evaluated in vivo in human volunteers to investigate its palatability and satisfaction. The results showed that the optimized formulation composed of 10% polymer concentration containing Soluplus®:PVA (0.33:0.66) and plasticized with 30% PEG 400 possessed the highest desirability value (0.836). Freeze-drying of the optimized formulation succeeded to improve SL in vitro dissolution due to the preparation of a more porous film compared to the non-freeze-dried one. In vivo evaluation of the optimized freeze-dried film showed high satisfaction among the participating volunteers concerning the ease of administration and sensation thereafter, where all the film specimens dissolved without the need for water and no film residues remained in the mouth following film dissolution. In conclusion, freeze-dried Soluplus®/PVA-based oral thin film proved to be a successful carrier for the oral delivery of insoluble drugs like SL for pediatrics.     

The efficacy of Origanum majorana nanocubosomal systems in ameliorating submandibular salivary gland alterations in streptozotocin-induced diabetic rats

Diabetes mellitus is a challenging health problem. Salivary gland dysfunction is one of its complications. Current treatments possess numerous adverse effects. Therefore, herbal extracts have emerged as a promising approach for safe and effective treatment. However, they are required in large doses to achieve the desired effect. Accordingly, Origanum majorana extract (OE) was incorporated into nano-sized systems to enhance its biological effects at lower dosages. OE was standardized against rosmarinic acid (RA) and then loaded into nano-cubosomal (NC) systems via a 2³ full-factorial design. Two optimum nano-systems at different drug loads (2.08 or 1.04 mg-RA/mL) were selected and assessed in vivo to compare their effects in streptozotocin-induced diabetic rats against conventional OE (2.08 mg-RA/mL). Blood glucose was evaluated weekly. Submandibular salivary glands were processed for histopathological examination and nuclear factor-erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), and p38-MAPK gene expression analysis. NC systems were successfully prepared and optimized where the optimum systems showed nano-sized vesicles (210.4–368.3 nm) and high zeta potential values. In vivo results showed a significant lower blood glucose in all treated groups, with an exceptional reduction with NC formulations. Marked histopathological improvement was observed in all OE-treated groups, with OE-NC4 (2.08 mg-RA/mL) demonstrating the best features. This was supported by RT-PCR; where the OE-NC4 group recorded the highest mean value of Nrf2 and the least mean values of Keap1 and p38-MAPK, followed by OE-NC3 and OE groups. In conclusion, OE-loaded NC enhanced the anti-hyperglycemic effect of OE and ameliorated diabetic gland alterations compared to conventional OE. Thus, cubosomal nano-systems could be anticipated as potential carriers for the best outcome with OE.