Research in Pharmaceutical Sciences
Volume:16 Issue: 4, Aug 2021

Microemulsions are gaining an increased interest in transdermal drug delivery. Microemulsions are stable, easy to prepare, and provide high solubilizing capacity for various drugs. The aim of this work was to prepare microemulsions from jojoba oil for transdermal delivery of ketorolac and lidocaine HCl with improved permeation.

Microemulsions based on jojoba oil as the oil phase were formulated for transdermal delivery of lidocaine HCl and ketorolac. Brij 97 was selected as surfactant and hexanol as cosurfactant. Pseudoternary phase diagrams were constructed. Selected microemulsion formulations were characterized for their physical properties and in vitro drug permeation.

Water-in-oil microemulsions were obtained with droplet sizes not more than 220 nm. The viscosity of the microemulsions was linked to the viscosity of the surfactant used. Improved drug permeation rates were observed for both model drugs. The significant increase in permeation rate in presence of hexanol was due to its impact on skin integrity as indicated by the histopathological study. Drug permeation enhancements were caused by the surfactant, the cosurfactant used, jojoba oil itself, and the microemulsion formulation. Higher surfactant content showed lower lag times and better flux.

Jojoba oil microemulsions are considered promising vehicles for transdermal delivery of ketorolac and lidocaine HCl with improved drug permeation. Jojoba oil-based microemulsion would present a safe and effective means for delivering drugs through the skin.

Although pain is one of the most common symptoms of diseases, it is often mismanaged due to limited access to painkillers and ineffectiveness, unacceptable side effects, or the possibility of abuse. However, an alternative approach to existing analgesics is to indirectly increase endogenous pain relief pathways by neprilysin (an enkephalinase) inhibitors. This enzyme breaks down and inactivates enkephalin, dynorphin, endorphins, and their derivatives.

In this project, a new series of racecadotril-tetrazole-amino acid derivatives 15a-l was synthesized and characterized on the basis of IR, 1H and 13C NMR, mass spectrometry, and elemental analysis. The antinociceptive activity of synthesized compounds was assessed by a hot plate, tail-flick, and formalin assays in mice. Docking was used to identify the possible interactions between neprilysin and synthesized compounds.

Most of the synthesized compounds showed moderate to good analgesic effects in hot plat and tail-flick test in comparison to morphine and racecadotril. Compounds 15l and 15j were the most potent compounds. The synergistic analgesic effect of compounds 15l and 15j with morphine and the antagonistic effect of naloxone on the activity of these compounds confirm that the analgesic effect of compounds 15l and 15j could be mediated through the opioidergic system. The negative and high binding energy of docking simulation of the most potent compounds in the catalytic site of neprilysin was also in good agreement with the inhibitory activity of test compounds.

Racecadotril-tetrazole-amino acid derivatives, as potential antinociceptive agents, demonstrated moderate to good antinociceptive activities comparable with morphine and higher than racecadotril.

Omeprazole (OMP) is broadly used for the treatment of gastroesophageal reflux and other acid-related diseases. The current study aimed to prepare enteric-coated nanoparticles containing OMP to achieve a stable powder formulation easily prescribed in children.

The nanoparticles were formed by complex coacervation method using chitosan (CTS) and Eudragit L100/55 (EU) and the impact of various formulation variables (the concentrations of EU solution and its volume ratio to CTS solution) were assessed using 32 fractional design. The mean particle size (PS), zeta potential (ZP), encapsulation efficiency (EE), and drug loading (DL) were determined. Finally, the pharmacological effects of the optimized OMP enteric nanoparticles were evaluated by an in vivo antiulcer study using Sprague-Dawley rats.

The highest desirability value was for formulation F5 (containing EU concentration 4 mg/mL and EU/CTS volume ratio 2:1). PS, ZP, EE, and DL of the optimized OMP-loaded nanoparticles were confirmed 810 ± 14 nm, -38.2 ± 1.8 mV, 83.1± 4.2%, and 13.1± 1.5%, respectively. in vitro release studies showed the pH sensitivity of nanoparticles and OMP release was pH-dependent. in vivo pharmacological assessment revealed that the optimized formulation was able to protect rat stomach against ulcer formation induced by indomethacin compared to the group that received normal saline which demonstrated severe peptic ulcer and hemorrhagic spots.

Our results indicated that the enteric EU/CTS nanoparticles were successfully prepared via a complex coacervation method and their efficacy could be comparable with commercial OMP pellets.

Paracetamol is the most implicated xenobiotic in inducing hepatotoxicity. Our study aimed to determine the impact of some kaempferol glycosides isolated from the leaves of Cedrela odorata L. on paracetamol hepatotoxicity.

The methanolic extract of dried leaves of C. odorata L. was subjected to the combination of spectroscopic methods (1H and 13CNMR). Six kaempferol glycosides were isolated: kaempferol-3-O--D-glycopyranoside (astragalin), kaempferol-3-O--L-rhamnopyranoside, kaempferol-3-O--D-rutinoside, kaempferide-3-O--D-rutinoside, kaempferide-3-O--Drutinosyl-7-O--Drhamnopyranoside, and kaempferol-3-O--D- rutinosyl-7-O-α-D-arabinopyranoside. Fifty-four female Swiss Albino mice were divided randomly into 9 groups including (1) control negative (1 mL/kg saline; IP), (2) control positive (paracetamol 300 mg/kg; IP), (3) silymarin 50 mg/kg (IP). Animals of groups 4-9 were injected with 6 different samples of isolated compounds at 100 mg/kg (IP). One h later, groups 3-9 were injected with paracetamol (300 mg/kg IP). Two h later, tissue samples were taken from all animals to assess nitrotyrosine, c-Jun N-terminal protein kinase (c-JNK), Raf -1kinase, and oxidative stress biomarkers viz. reduced glutathione (GSH) and malondialdehyde (MDA).

Isolated glycosides had a prominent anti-apoptotic effect via inhibition of c-JNK and Raf1 kinase. They also exerted a powerful antioxidant effect by modulating the oxidative stress induced by paracetamol via increasing GSH, reducing MDA and nitrotyrosine concentrations compared to positive control. The glycoside (1) showed a better effect than silymarin (standard) in ameliorating the formation of nitrotyrosine, Raf-1 kinase, c-JNK, and GSH.

Kaempferol glycosides isolated for the first time from C. odorata L. leaves exerted antioxidant and antiapoptotic effects via amelioration of oxidative stress and inhibition of Raf/ MAPK pathway.

Plaque psoriasis is a chronic inflammatory disease with skin manifestations that affect the patients' quality of life negatively. The prevalence of psoriasis is approximately 2-3% worldwide and appears to be still on the increase. Due to the stigma problems, psoriasis has a significant effect on one's life that is often overlooked. The current study aimed to conduct the cost-utility evaluation and budget impact analysis of adding-on apremilast ahead of biologic therapy in the treatment of moderate to severe plaque psoriasis. The psoriatic patients who did not undergo the conventional systemic therapy were eligible to enter the defined sequences.

An excel-based Markov model with 40 cycles of 3 months, each of which was adopted to compare the outcomes of each exclusively administered sequence in the treatment of moderate to severe plaque psoriasis. Two exclusive therapeutic sequences were considered. In the first sequence, apremilast was followed by biologics and in the second one, biologics were administered initially without apremilast. The results were extrapolated up to 10 years. The designed Markov model was also used in budget impact analysis. The cost-saving potential of the new treatment was accounted for the next 5 years.

Incremental cost and incremental effect were reported in the base case scenario. Using the sequence consisting apremilast provided an additional 0.10 quality-adjusted life years and decreased total costs by about 11,100 USD per patient. These results were in line with the findings from sensitivity analysis. The cost-saving over 5 years is estimated to be around 30 million dollars for the Iran market following the use of the new treatment.

In the treatment of moderate to severe plaque psoriasis, apremilast supplementation prior to biological treatments is more cost-effective than biological treatment alone.

Methamphetamine (METH) abuse has devastating consequences on the nervous system. There are limited therapy choices in METH abuse with reduced effectiveness and elevated recurrence rates. Thymoquinone (TQ), the most bioactive constituent of Nigella sativa seeds exerts neuroprotective effects mainly via antioxidant properties. This study aimed to evaluate the effect of TQ against METH-induced striatal neurotoxicity and hyperlocomotor activity in mice.

Our groups of animals received METH (10 mg/kg) four times a day with 2 h intervals. Normal saline or TQ (5, 10, or 20 mg/kg) was injected intraperitoneally 30 min before METH administration. Control and sham groups received vehicle or TQ, respectively. The rectal temperature and behavioral tests including the open field for locomotor activity and rotarod for motor coordination were evaluated. The level of superoxide dismutase (SOD), as well as pathological changes, were also assessed in the striatum region.

No significant differences in rectal temperatures were observed among treated groups. Administration of METH increased locomotor activity and did not change motor coordination. TQ co-administration with METH significantly reduced the central and total locomotion and the mean latency to fall off the rotarod in a dose-dependent manner compared with the METH group. TQ also alleviated the METH-induced decrease in the activity of SOD.TQ, especially at the high dose, reduced the METH-induced reactive gliosis level.

In conclusion, TQ prevents the enhanced locomotor activity, antioxidant impairment, and morphological striatal damage caused by METH in mice. TQ may be a potential candidate for the treatment of specific METH-induced brain disorders or neurological diseases.

Marine algae are potential renewable and sustainable sources of bioactive natural products which can be utilized in nutraceutical and pharmaceutical industries.

Different extracts (methanol, chloroform, and ethyl acetate) of red algae, Laurencia snyderiae, was evaluated for their antioxidant potential, with various antioxidant assessment assays, cytotoxic properties (using MTT colorimetric assay), and phytochemical constituents (total phenolic and flavonoid contents). The GC-MS analyses of the algal methanolic extract and its apoptotic effects on the human colon carcinoma cell line (HT29) were also investigated.

The total phenolic content in the methanol, chloroform, and ethyl acetate extracts of L. snyderiae was 3.6 ± 0.12, 3.2 ± 0.41, and 3.3 ± 0.35 μg/mg of gallic acid, respectively. Among different algae extracts, chloroform extract showed significantly chelating ability (IC50 = 0.027 mg/mL) and reducing power activity (IC50 = 0.082 mg/mL), while the highest DPPH scavenging activity (IC50 = 0.058 mg/mL) exhibited in the methanol extract compared to the other extracts. The methanolic extract was found to have a higher cytotoxicity effect on colon carcinoma cells with IC50 70.2 µg/mL. The viability of the cancer cells was increased with the decrease in the concentration in different extracts. GC-MS analysis of the algal methanolic extract revealed the presence of active antitumor constituents and apoptosis-based cytotoxicity against colon cancer cells through the DNA damage was also confirmed.

Based on these results, the red algae L. snyderiae possesses potent bioactive constituents and can use as additional resources as a natural antioxidant and antitumor agent in the pharmaceutical and nutraceutical area.

Nicotine is an alkaloid found in many nutrients and tobacco that can cause infertility in men. Gallic acid is a powerful antioxidant that possesses antimutagenic and anticancer activities. This study aimed to determine the potential protective effect of gallic acid against nicotine-induced testicular toxicity in male mice.

In this in vivo study, forty-eight mice were equally divided into eight groups intraperitoneally receiving normal saline (control), nicotine (0.6 mg/kg), gallic acid (5, 10, and 15 mg/kg), and gallic acid (5, 10, and 15 mg/kg) plus nicotine. Nicotine was injected intraperitoneally for 14 days and gallic acid was administered concomitantly with nicotine and continued for 7 days later. Then, body and testicular weights, the sperm parameters (viability, number, motility, and morphology of sperm), and testicular histology were evaluated. Also, serum levels of nitric oxide, total antioxidant, superoxide dismutase, malondialdehyde, and testosterone were measured.

The results showed that the administration of nicotine significantly reduced testis and body weight, sperm count, viability, normal morphology and motility, seminiferous tubules diameter, testosterone levels, serum levels of total antioxidants, and superoxide dismutase compared to the control group (P < 0.05). It also significantly increased the level of nitric oxide and malondialdehyde (P < 0.05). Increasing the dose of gallic acid along with nicotine significantly increased body weight, sperm count, viability, normal morphology and motility, the diameter of seminiferous, testosterone concentration, total antioxidant levels (P < 0.05). This combination also significantly decreased malondialdehyde and nitric oxide levels compared to the nicotinereceiving group (P < 0.05).

Gallic acid had a protective effect on nicotine-induced testicular toxicity in mice. It can neutralize the harmful effect of nicotine on male fertility in smokers.

Tyrosinase enzyme has a key role in melanin biosynthesis by converting tyrosine into dopaquinone. It also participates in the enzymatic browning of vegetables by polyphenol oxidation. Therefore, tyrosinase inhibitors are useful in the fields of medicine, cosmetics, and agriculture. Many tyrosinase inhibitors having drawbacks have been reported to date; so, finding new inhibitors is a great need.

A variety of 6-hydroxy-3,4-dihydronaphthalenone chalcone-like analogs (C1-C10) have been synthesized by aldol condensation of 6-hydroxy tetralone and differently substituted benzaldehydes. The compounds were evaluated for their inhibitory effect on mushroom tyrosinase by a spectrophotometric method. Moreover, the inhibition manner of the most active compound was determined by Lineweaver-Burk plots. Docking study was done using AutoDock 4.2. The drug-likeness scores and ADME features of the active derivatives were also predicted.

Most of the compounds showed remarkable inhibitory activity against the tyrosinase enzyme. 6-Hydroxy-2-(3,4,5-trimethoxybenzylidene)-3,4-dihydronaphthalen-1(2H)-one (C2) was the most potent derivative amongst the series with an IC50 value of 8.8 μM which was slightly more favorable to that of the reference kojic acid (IC50 = 9.7 μM). Inhibitory kinetic studies revealed that C2 behaves as a competitive inhibitor. According to the docking results, compound C2 formed the most stable enzyme-inhibitor complex, mainly via establishing interactions with the two copper ions in the active site. In silico drug-likeness and pharmacokinetics predictions for the proposed tyrosinase inhibitors revealed that most of the compounds including C2 have proper drug-likeness scores and pharmacokinetic properties.

Therefore, C2 could be suggested as a promising tyrosinase inhibitor that might be a good lead compound in medicine, cosmetics, and the food industry, and further drug development of this compound might be of great interest.

An aqueous extract from the root bark of Pseudocedrela kotschyi and aerial parts of Adenia cissampeloides has been proven in previous research to elicit significant anticoagulant property in vitro. This, therefore, indicates the potential usefulness of this extract in managing thromboembolic disease, a major global health risk. The aim of the present work was to establish the antithrombotic effect of a product made from extracts of the root bark of P. kotschyi and the aerial parts of A. cissampeloides (PAE).

The effect of PAE at 500-2000 mg/kg in inhibiting tail infarction and inflammation, as well as its effect on the microthrombi count, hematological, and coagulation profiles in a carrageenaninduced thrombosis model in Sprague-Dawley rats, was studied.

PAE significantly (P ≤ 0.01-0.001) reduced length of tail infarction and inflammation (redness, swelling, pain, and temperature). Histopathological studies revealed a significant reduction (P ≤ 0.0001) in microthrombi count in the liver and the lungs with PAE treatment. PAE treatment caused a marginal (P ≤ 0.01) increase in prothrombin time but resulted in a significant (P ≤ 0.01- 0.0001) dosedependent increase in activated partial thromboplastin time, with the hematological profile being normal.

PAE showed anticoagulant and antithrombotic effects in vivo, indicative of its potential benefit as a natural product, and cost-effective therapeutic option, and hence could be helpful in thromboembolic therapies.