Structure-based virtual screening and molecular dynamics simulation studies to discover new SARS-CoV-2 main protease inhibitors.

Computational methods were used to filter two datasets (> 8,000 compounds) based on two criteria: higher binding affinity for MPRO than cocrystallized inhibitor and binding interactions with MPRO catalytic dyad (Cys145 and His41). After virtual screening involving ranking and reranking, eleven compounds were identified to satisfy these criteria and analysis of their structures revealed an unparallel common features among them which could be critical for their interactions with MPRO. However, only the topmost scoring compound (AV-203: K i = 0.31 µM) exhibited relatively stable binding interaction during the period of 50 ns MD simulation and thus is a suitable template for drug development.

SRMS142-based solid lipid microparticles: application in oral delivery of glibenclamide to diabetic rats.

P90Gylation refers to the modification of lipid molecules by one or more phospholipid chains. Phospholipon 90G (P90G) contains about 94.0% of phosphatidylcholine stabilized with 0.1% ascorbyl palmitate and is a safe (GRAS) FDA-approved parenteral excipient with wide applications in drug delivery. P90Gylated-Softisan 142 conjugate, otherwise referred to as (SRMS142), has numerous advantages: wetting, solubilization, drug stabilization, emulsification, and modified release. Here, we report an evaluation of solid lipid microparticles (SLMs) formulated from SRMS142 systems as an alternative carrier system for oral glibenclamide administration in diabetic rats. The result of our findings showed that SRMS142 generated an imperfect matrix with numerous spaces that accommodated glibenclamide in a concentration-dependent manner up to 60.58%. The blood glucose-lowering effect of the SLMs was higher than that of a commercial sample.

Preparation and evaluation of mucin-gelatin mucoadhesive microspheres for rectal delivery of ceftriaxone sodium.

Soluble mucin (S-mucin) processed from the small intestines (ileal region) of freshly slaughtered pigs via homogenization, dialysis, centrifugation and lyophilization and its admixtures with type A gelatin were dispersed in an aqueous medium and used to formulate ceftriaxone sodium-loaded mucoadhesive microspheres by the emulsification cross-linking method using arachis oil as the continuous phase. The release profile of ceftriaxone sodium from the microspheres was evaluated in both simulated gastric fluid (SGF) without pepsin (pH 1.2) and simulated intestinal fluid (SIF) without pancreatin (pH 7.4). The microspheres were further evaluated as possible novel delivery system for rectal delivery of ceftriaxone sodium in rats. Release of ceftriaxone sodium from the microspheres in both release media was found to occur predominantly by diffusion following non-Fickian transport mechanism and was higher and more rapid in SIF than in SGF. The results obtained from this study may indicate that ceftriaxone sodium could be successfully delivered rectally when embedded in microspheres formulated with either type A gelatin alone or its admixtures with porcine mucin; hence providing a therapeutically viable alternative route for the delivery of this acid-labile third generation cephalosporin.

Evaluation of mucin as a release enhancer for rectal delivery of glibenclamide.

In this work mucin was evaluated as a release and absorption enhancer for glibenclamide from rectal glycerogelatin suppository. Glycerogelatin suppositories containing different ratios of glibenclamide to I-mucin (insoluble), S-mucin (soluble) and sodium salicylate respectively, were formulated using the fusion method. The suppositories were evaluated using standard parameters. Release studies were carried out in phosphate buffer (pH 7.6). The pharmacodynamic (PD) evaluation of the formulations was carried out on normoglycaemic albino rats. The results of the physical tests showed that the suppositories possessed high resistance to rupture and had uniformity of weight and drug contents. The erosion times of the suppositories with I-mucin, S-mucin and sodium salicylate were shorter than glycerogelatin suppositories BP without any release enhancer (control). Analysis of the release data showed that the release pattern was bi-phasic with initial fast release and subsequent slow release of the glibenclamide from the suppositories. The release mechanism followed first order kinetics. All the suppositories containing either S-mucin, I-mucin or sodium salicylate showed better glibenclamide release than the control without any release enhancer (p < 0.05). The pharmacodynamic studies showed that the overall glucose lowering effect in rats was greater in S-mucin suppositories than in sodium salicylate and I-mucin suppositories. The results of this study indicated that mucin extracted from Bovine spp. could be used to enhance the release and subsequent absorption of glibenclamide from rectal glycerolgelatin suppositories.

Melt extrusion bioadhesive delivery of diclofenac sodium granules using theobroma oil.

Carbopol 941 (C-941), a bioadhesive polymer and theobroma oil (TEO) were used in the formulation of melt extrusion bioadhesive tablets (MEBT) of diclofenac (DC). Different batches of the MEBT were formulated using different combinations of C-941 granules containing DC and TEO. The bioadhesive properties of the tablets were studied using a tensiometer by measuring the bioadhesive strength generated when the tablet interacts with the mucus of everted hog jejunum. Some physical properties of the tablets evaluated were weight uniformity, crushing strength, friability, tablet thickness and diameter liquefaction time and absolute drug content. Release of DC from the MEBT was carried out in simulated intestinal fluid (SIF), pH 7.2. The tablets had low liquefaction times and were highly bioadhesive. Result of the study indicated that TEO could be used in the formulation of MEBT of DC granulated with C-941 for prolonged and controlled delivery of DC.

Some physical properties of tabletted seed of Garcinia kola (HECKEL).

The formulation of Garcinia kola seeds into tablet dosage form and evaluation of some physical properties of the tablets are presented. A chemical assay was conducted on the dry, powdered seeds as well as the crude aqueous extract of the seeds. The dry powdered seeds contain 0.003% of flavonoids while the crude extract contained 0.007% of flavonoids based on rutin used as the standard. The powdered material (50 mg) and crude extract (10 mg) were formulated into tablets using the wet granulation method. Named binders were evaluated in these formulations. The various tablet parameters were evaluated, namely: weight variation, thickness and diameter, hardness, friability, disintegration time, dissolution profile and content uniformity. The results indicated that the tablets had good disintegration time, dissolution and hardness/friability profiles. Tablets formulated with starch had the best disintegration properties but were consequently very friable. Tablets formulated from 10 mg of the crude extract needed a larger proportion of diluents, which affected the tablet properties.

Release of indomethacin from bioadhesive tablets containing carbopol 941 modified with Abelmuschus esculentus (okra) gum.

Carbopol 941 (C-941) and Abelmuschus esculentus gum (Okra gum, AEG) were used as bioadhesive polymers in the formulation of mucoadhesive indomethacin tablets. Different batches of the tablet compacts were formulated based on different combination ratios of the polymers. The bioadhesive properties of the tablets were studied using a tensiometer: Tablets coated with 50% w/v solution of Eudragit I. 100 in ethanol, were also prepared and evaluated. The following tablet physical properties were evaluated: hardness, uniformity of weight, disintegration time, friability, and absolute drug content. Release studies were determined in simulated intestinal fluid (SIF pH 7.2) without pancreatin, and in 0.1 N solution of HCl. Result obtained indicated that tablets with equal ratio of C-941 and AEG (1:1) gave the highest bioadhesive strength for both the coated and uncoated tablets. The percentage of drug released ranged from 53-90% for uncoated tablets in 0.1 N HCl and SIF, and 9-16% for coated tablets in 0.1 N HCl, and 63-100% for coated tablets in SIF after 8 hrs.

The use of solid self-emulsifying systems in the delivery of diclofenac.

Goat fat and Tween 65 admixtures were used to formulate self-emulsifying tablets containing diclofenac. The tablets were formulated by pour moulding using a plastic mould. The tablets were evaluated using the following parameters: weight uniformity, absolute drug content, and liquefaction time. The dissolution profile of diclofenac from the self-emulsifying tablets was determined in simulated gastric fluid (SGF) without pepsin. Results obtained indicated that diclofenac could be comfortably administered in the form of self-emulsifying tablets using goat fat and Tween 65 admixtures.

In vitro antimicrobial interactions of arthemeter with some 4-quinolones.

Bacterial infections often co-exist with acute malarial attacks. The effect of combining arthemeter (a new antimalarial) with some commonly used 4-quinolones (ciprofloxacin, pefloxacin, norfloxacin and nalidixic acid) was investigated in-vitro with a view to providing data for the design of drug regimens for the treatment of such infections. While arthemeter demonstrated no antibacterial activity whatsoever against any of the test microorganisms (E. coli and Staph. aereus), the 4-quinolones shared marked activity. Comparative analyses of the activity of each quinolone alone and in combination with arthemeter showed 0% 43.8%, 44.9% and -12.2% change in the minimum inhibitory concentration (MIC) of nalidixic acid pefloxacin, ciprofloxacin and norfloxacin respectively against E. coli and -17.5%, 22.3% 35.8% and 50.9% change in the MICs of the same respective drugs against Staph. aureus. These changes in MIC were statistically significant (Pf0.05). With respect to infections caused by E. coli and E. coli, the combination of artemether with ciprofloxacin or pefloxacin proves to be a rational chemotherapeutic regimen when such infection co-exist with malaria.

Charge-oriented modelling in charge-transfer systems.

Various mechanisms are often used toxplain the charge-transfer interactions between various electron donors and acceptors. Commonly accepted mechanisms are those in witch the acceptors forms a weak interaction of the Lewis acid--Lewis base type. A modelling approach is applied in this study to examine this mechanism as well as other mechanism. A charge-oriented mechanism is proposed in solvent systems that may not favour this mechanism of interaction.

Detection of alpha-methyldopa on thin-layer plates using pi-acceptors in 1,4-dioxane.

pi-Acceptors (P-chloranil and chloranilic acid) in 1,4-dioxane were used to detect alpha-methyldopa on thin layer plates. Thin layer plates coated to a thickness of 0.25 mm with silica gel G60 were spotted with solution of alpha-methyldopa from drug formulations and pure alpha-methyldopa solution. The plates were developed in a solvent system of methanol: glacial acetic acid: water (14:5:3). The developed plates were dried and sprayed with pi-acceptors, and further were counter-sprayed with dimethylformamide (DMF). P-Chloranil gave an immediate blue green complex with alpha-methyldopa which intensified on counter-sprayed with DMF. alpha-methyldopa (reference sample and those from drug formulations) gave Rf of 0.85 and excipients from the drug formulations did not interfere with the result.

Susceptibility of some clinical isolates of Staphylococcus aureus to bioactive column fractions from the lichen Ramalina farinacea (L.) Ach.

The antimicrobial activities of two bioactive column chromatographic fractions (RF1 and RF2) from the lichen Ramalina farinacea (L.) were evaluated against 15 clinical isolates of Staphylococcus aureus. The susceptibility pattern of the isolates towards tetracycline (TCN) and ampicillin (AMP) was similarly -evaluated for comparison purposes. The results show that RF1 and RF2 with an MIC(90) ( minimum -inhibitory concentration against 90% of the isolates) of 535.5 and 317 microg/mL respectively, performed generally better than TCN and AMP with an MIC(90) of 976.5 and 357 microg/mL respectively.

Potential use of tea extract as a complementary mouthwash: comparative evaluation of two commercial samples.

OBJECTIVE: To evaluate the potential of using tea extracts as complementary mouthwash and to test the comparative efficacy of two commercial samples. DESIGN: A randomized controlled trial with 30 healthy human volunteers was carried out. The subjects were randomly assigned to 5 groups of 6 subjects per group. The ability of Ndu tea (from Cameroon) and Lipton tea (from Nigeria) to reduce colony forming units (CFU) in the liquid expectorated after 60 seconds of gargling from the mouth of the volunteers at 5 and 60 minutes were evaluated. These were compared to the values obtained from bank water and Minty Brett (thymol 0.047%), a standard antiseptic. SETTING: University of Nigeria, Nsukka, Enugu State, Nigeria. SUBJECTS: Thirty healthy human volunteers (18 males and 12 females, between 22-30 years of age) who met the eligibility requirement of being nonsmokers and not taking any other antimicrobial agent were selected for the study. RESULT: Relative to the bank water, the results indicated that the hot water extract of both teas significantly (p < 0.05) reduced CFU per milliliter in the liquid expectorated after gargling at both 5 and 60 minutes. Minty Brett showed higher activity than both tea extracts; however, unlike Minty Brett both extracts still reduced the CFU per milliliter at time 60 minutes (an indication of longer duration of activity). The combination of the tea extracts with sodium lauryl sulfate (1.2% w/v), a surfactant and emulsifier, significantly increased the antimicrobial activity relative to each tea alone. Comparatively, the activity of Ndu tea was found to be slightly higher than that of Lipton tea but this was not significant (p < 0.05). CONCLUSION: Lipton and Ndu tea extracts potently reduced the CFU per milliliter. This activity was potentiated by sodium lauryl sulfate. Although Minty Brett had more potent antimicrobial activity, both tea extracts have longer duration of activity. The results indicate the potential usefulness of tea extracts as a complementary mouthwash.

Drug adsorption studies on pregelatinized gladiolus starch.

A comparative evaluation of the adsorption properties of pregelatinized gladiolus starch and activated charcoal on such drugs as chloroquine phosphate, aspirin, ampicillin and caffeine has been made. Results indicate that the adsorption capacity increases with increase in concentration of adsorbent used. Pregelatinized gladiolus starch exhibited a higher complexation affinity for chloroquine phosphate than activated charcoal, while the reverse was observed in the case of aspirin. The adsorption of caffeine and ampicillin was insignificant with the adsorbents. The desorption profile was slower for the pregelatinized gladiolus starch than for activated charcoal. This slow release property might be exploited in formulations where sustained-release is the desired goal.

Studies of the complexation of chloranilic acid with proguanil.

Studies on the complexation between chloranilic acid and proguanil has been carried out. The chloranilic acid acted as a pi-electron donor. The stoichiometric relationship in the complex was determined by employing the Job's method of continuous variation. The results indicate that the complex exhibits a purple colour and absorbs maximally at 520 nm. Spectrophotometric studies show that the method could be useful in the analysis of proguanil.

Mechanistic appraisal of the charge-transfer complexes of promethazine with chloranil: a modelling approach.

Various mechanisms are often used to explain the interaction between electron donors and acceptors. Commonly proposed mechanisms are those in which the acceptor interacts with the aromatic pi-systems in the donor molecule or the acceptor forms a weak interaction of the Lewis acid with Lewis base type. In this study, the above mechanisms were examined as well as other possible mechanisms. Promethazine was chosen as the model drug containing aromatic systems capable of pi-pi interaction as well as N-methyl group capable of forming a complex with the weak Lewis acid, p-chloranil. Our modelling studies revealed that the situation where the p-chloranil interacts with a protonated N-methyl group is the most significant mechanism of interaction, based on the calculated energies for the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), the Tripos force field energy terms and also the stability of the complexes during molecular dynamics simulations.

Evaluation of the physico-chemical properties of a new polysaccharide gum from Prosopis africana.

The gum obtained from the ripe seeds of Prosopis africana was processed to compendial standard for plant gums and characterised. Toxicological studies of the polysaccharide on mice showed the material to be safe. The material hydrates slowly in aqueous media to form a colloidal dispersion. Swelling studies on the gum shows that the gum has a higher swelling capacity than methylcellulose. Rheological studies showed that the material is more viscous than tragacanth gum at equivalent concentrations. Acid hydrolysis and thin layer chromatography of the resulting hydrolysates showed that the gum contains glucose, fructose, galactose and xylose as the monosaccharide components. Microbial tests showed the gum to contain 8.26 x 10(4) viable cells per gram when freshly prepared. Other properties of the gum evaluated includes; melting or charring temperature, optical properties, true density, ash values, element content as well as its reactions with lead subacetate solution and 0.02 M iodine.

Evaluation of Prosopis africana gum in the formulation of gels.

Prosopis africana gum was evaluated for use in the formulation of gels. The rate of release of salicylic acid from gels prepared from prosoopis gum was investigated. The rate of permeation of the drug through the gel was also evaluated. Surfactants were incorporated into the gels and the effect on the release and permeation was also investigated. Tragacanth gum gel was also prepared and used as the standard. The release and permeation of the drug from the gel was low. Incorporation of surfactants did not enhance the release of the drug. However the low release and permeation rates may be due to the poor water solubility of the incorporated drug. Correlation of the quantity of drug released with viscosity shows that drug release was dependent on the viscosity of the gels; the highly viscous gels showed slower release rates.