Benzotriazole: An overview on its versatile biological behavior.

Discovered in late 1960, azoles are heterocyclic compounds class which constitute the largest group of available antifungal drugs. Particularly, the imidazole ring is the chemical component that confers activity to azoles. Triazoles are obtained by a slight modification of this ring and similar or improved activities as well as less adverse effects are reported for triazole derivatives. Consequently, it is not surprising that benzimidazole/benzotriazole derivatives have been found to be biologically active. Since benzimidazole has been widely investigated, this review is focused on defining the place of benzotriazole derivatives in biomedical research, highlighting their versatile biological properties, the mode of action and Structure Activity Relationship (SAR) studies for a variety of antimicrobial, antiparasitic, and even antitumor, choleretic, cholesterol-lowering agents.

Encapsulation and modified-release of thymol from oral microparticles as adjuvant or substitute to current medications.

The aim of this study was to encapsulate, thymol, in natural polymers in order to obtain (i) taste masking effect and, then, enhancing its palatability and (ii) two formulations for systemic and local delivery of herbal drug as adjuvants or substitutes to current medications to prevent and treat several human and animal diseases. Microspheres based on methylcellulose or hydroxypropyl methylcellulose phthalate (HPMCP) were prepared by spray drying technique. Microparticles were in vitro characterized in terms of yield of production, drug content and encapsulation efficiency, particle size, morphology and drug release. Both formulations were in vivo orally administered and pharmacokinetic analysis was carried out. The polymers used affect the release and, then, the pharmacokinetic profile of thymol. Encapsulation into methylcellulose microspheres leads to short half/life but bioavailability remarkably increases compared to the free thymol. In contrast, enteric formulation based on HPMCP shows very limited systemic absorption. These formulations could be proposed as alternative or adjuvants for controlling pathogen infections in human or animal. In particular, methylcellulose microspheres can be used for thymol systemic administration at low doses and HPMCP particles for local treatment of intestinal infections.

Nasal administration of carbamazepine using chitosan microspheres: in vitro/in vivo studies.

The nasal route is used both for local therapies and, more recently, for the systemic administration of drugs, as well as for the delivery of peptides and vaccines. In this study the nasal administration of Carbamazepine (CBZ) has been studied using microspheres constituted by chitosan hydrochloride (CH) or chitosan glutamate (CG). Blank microspheres were also prepared as a comparison. The microspheres were produced using a spray-drying technique and characterized in terms of morphology (scanning electron microscopy, SEM), drug content, particle size (laser diffraction method) and thermal behaviour (differential scanning calorimetry, DSC). In vitro drug release studies were performed in phosphate buffer (pH 7.0). In vivo tests were carried out in sheep using the microparticles containing chitosan glutamate, chosen on the basis of the results of in vitro studies. The results were compared to those obtained after the nasal administration of CBZ (raw material) alone. For the evaluation of in vivo data statistical analysis was carried out using the unpaired t-test. Spray-drying was a good technique of preparation of CBZ-loaded microspheres. The loading of the drug into the polymeric network always led to an increase in the dissolution rate compared to CBZ raw material. The microspheres obtained using chitosan glutamate had the best behaviour both in vitro and in vivo. They increased the drug concentration in the serum when compared to the nasal administration of the pure drug (Cmax 800 and 25 ng/ml for microspheres and pure drug, respectively). The results obtained indicate that the loading of CBZ in chitosan glutamate microspheres increases the amount of the drug absorbed through the nose.

Tabletted microspheres containing Cynara scolymus (var. Spinoso sardo) extract for the preparation of controlled release nutraceutical matrices.

Controlled release dosage forms based on tabletted microspheres containing fresh artichoke Cynara scolymus extract were performed for the oral administration of a nutritional supplement. Microspheres were prepared using a spray-drying technique; lactose or hypromellose have been chosen as excipients. Microspheres were characterized in terms of encapsulated extract content, size and morphology. Qualitative and quantitative composition of the extract before and after the spray process was determined. Compressed matrices (tablets) were prepared by direct compression of the spray-dried microspheres. In vitro release tests of microparticles and tablets prepared were carried out in both acidic and neutral media. Spray-drying is a good method to prepare microspheres containing the artichoke extract. The microspheres encapsulate an amount of extract close to the theoretical value. Particle size analyses indicate that the microparticles have dvs of approximately 6-7 microm. Electronic microscopy observations reveal that particles based on lactose have spherical shape and particles containing hypromellose are almost collapsed. The hydroalcoholic extract is stable to the microsphere production process: its polyphenolic composition (qualitative and quantitative) did not change after spraying. In vitro release studies show that microparticles characterized by a quick polyphenolic release both in acidic and neutral media due to the high water solubility of the carrier lactose. On the contrary, microspheres based hypromellose release only 20% of the loaded extract at pH 1.2 in 2 h and the total amount of polyphenols is released only after about further 6 h at pH 6.8. Matrices prepared tabletting lactose microspheres and hypromellose microparticles in the weight ratio 1:1 show a slow release rate, that lasts approximately 24 h. This one-a-day sustained release formulation containing Cynara scolymus extract could be proposed as a nutraceutical controlled release dosage form for oral administration.

Carboplatin sustained delivery system using injectable microspheres.

A controlled carboplatin delivery system using biodegradable polymer has been used in this study. The purpose was to evaluate the local and systemic effects of injectable, biodegradable microspheres containing carboplatin when injected as aqueous suspension subcutaneously in rats. Biocompatibility and toxicity of empty microspheres and microspheres loaded with carboplatin were evaluated by clinical and histological examination. The diffusion of carboplatin in tissues and time of drug release were evaluated by platinum determination in plasma and tissues over the time. The results of the study suggest that microspheres provide a sustained slow release of carboplatin and that multiple inoculations of microspheres containing drug and no evidence of local or systemic toxicity is found. This device may be useful in the treatment of solid tumours.

Compressed biodegradable matrices of spray-dried PLGA microspheres for the modified release of ketoprofen.

A spray-drying technique was used to prepare poly(lactide-co-glycolide) (PLGA) drug loaded microspheres. Ketoprofen was chosen as a model NSAID drug. The microspheres were characterized in terms of morphology, drug content and release behaviour. The spray-dried particles were subject to a direct compression process for the preparation of biodegradable matrix tablets. The spray-dried powders were found to have good compaction properties. Tablets were also prepared from a mixture of microspheres and microcrystalline cellulose, mannitol and hydroxypropylmethylcellulose or sodium alginate. The release of ketoprofen in phosphate buffer (pH 7.4) was significantly sustained, indicating the suitability of using tabletted spray-dried PLGA microspheres for controlled drug delivery. The results show that spray-dried PLGA particles have promising properties as direct compression and release controlling excipients in matrix tablets for oral administration.

Spray-dried microspheres containing ketoprofen formulated into capsules and tablets.

In this study, microspheres were prepared by a spray-drying technique using solutions of ketoprofen and two polymers, cellulose acetate butyrate (CAB) and hydroypropylmethylcellulose phthalate (HPMCP), in different weight ratios. Different total concentrations were used in the feed solutions: 3, 6 and 9% w/v. The spray-dried microparticles were characterized in terms of shape (SEM), size (light scattering method), production yield and encapsulation efficiency. They were formulated into capsules; tablets were prepared by direct compression of the microparticles mixed with maltose and, in some cases, hydroypropylmethylcellulose (HPMC). In vitro release studies were performed both at acidic and neutral pHs. The spray-drying process of solutions of ketoprofen with polymeric blends of cellulose derivatives leads to microparticles which, depending on their final formulation (capsules or tablets), can give a rapid or prolonged drug release. The formulations here described can be proposed for the oral administration of NSAIDs.

Synthesis and analgesic-antiinflammatory activities of novel acylarylhydrazones with a 5-phenyl-4-R-3-pyrrolyl-acyl moiety.

A new series of arylidene 5-phenyl-4-R-pyrrole-3-carbohydrazides 1a-j were prepared and evaluated for their analgesic-antiinflammatory activities. All synthesized compounds showed a significant analgesic action in mice after intraperitoneal administration at a dose of 100 microM/kg. Two of these, 1b, (4'-methylbenzylidene)-5-phenyl-1H-pyrrole-3-carbohydrazide, and 1d, (4'-chlorobenzylidene)-5-phenyl-1H-pyrrole-3-carbohydrazide, were found to be more potent as antinociceptive agents respect to dipyrone and indometacin, used as reference drugs. Among compounds 1, only 1b showed a moderate antiinflammatory effect in rats while 1d proved to be a potent non antiinflammatory analgesic.

Pyridazine N-oxides. III. Synthesis and "in vitro" antimicrobial properties of N-oxide derivatives based on tricyclic indeno[2,1-c]pyridazine and benzo[f]cinnoline systems.

A number of 9H-indeno[2,1-c]pyridazine N-oxides (3a-c) and benzo[f]cinnoline N-oxides (4,5a-c) have been synthesized and tested for antimicrobial activity. All new products were inactive against Gram negative bacteria and fungi. In contrast, among the compounds synthesized, 3b, 4b and 5b showed a moderate activity against Gram positive Staphylococcus aureus and Staphylococcus epidermidis. Of the present series, the 9-nitro-benzo[f]cinnoline N-oxide 5b possessed the highest activity especially against Trichomonas vaginalis (MIC = 3.9 micrograms/ml).

Tabletted polylactide microspheres prepared by a w/o emulsion-spray drying method.

An emulsification-spray drying technique is used to prepare poly(D,L-lactic acid) (PDLLA) microparticles loaded with a water soluble, non-steroidal anti-inflammatory drug (NSAID), sodium naproxen (NaNPX). The method involves the preparation of a w/o emulsion in which the water soluble drug is dissolved in the aqueous dispersed phase, while the polymer is dissolved in the organic continuous phase. As a comparison, microparticles were prepared by spraying a suspension of the drug into an organic solution of the polymer. The spray-dried particles were characterized using SEM, DSC, XRD and in vitro release tests. The spray-dried product was then compressed (direct compression) to obtain controlled release matrix tablets. All microparticles release NaNPX within 30 min. The matrix tablets release the drug in 8-10 h; the matrix tablets characterized by the presence of surfactant (due to the emulsion used to obtain the microparticles) have the highest release rate.

In vitro release and antiinflammatory activity of topical formulations of ketoprofen.

Ketoprofen (KP) is a potent nonsteroidal anti-inflammatory drug (NSAID) widely used in clinical practice for the control of acute and chronic pain of soft tissues and skeletal muscle system. The importance of KP in the therapeutic field, has stimulated the development of topical dosage forms to improve its percutaneous absorption through the application site. Moreover they could provide relatively consistent drug levels for prolonged periods and avoid gastric irritation, typical side effect of NSAID oral administration. Since the topical formulation efficiency depends on vehicle characteristics, some different ointments, at 1% and 5% concentrations of KP, were evaluated by in vitro and in vivo studies. Among tested ointments, 1% Carbopol cream and 5% Carbopol gel showed the best fluxes of drug through regenerated cellulose membrane. The in vivo percutaneous absorption of KP, evaluated by carrageenan-induced paw edema in rats, showed a good correlation with the in vitro results about considered creams, but the gels in vivo activity was not in according to their in vitro behaviour. The extemporaneous Carbopol cream was able to produce a better edema inhibition than the commercial one, taken as a reference and widely utilized as a topical therapeutic item. About gels, the obtained results were nearly the maximum response considered possible for a topical antiinflammatory drug.

Polylactide microspheres for the modified release of corticosteroids.

A steroidal drug, prednisolone 21-acetate, has been incorporated into polylactide (PDLLA) microspheres using a single emulsion/evaporation technique. This paper describes the method used and the characterization of the microspheres obtained: morphology, particle size distribution, drug content, yield of production and in vitro drug release behaviour.

Evaluation of alginate compressed matrices as prolonged drug delivery systems.

This research investigated the use of sodium alginate for the preparation of hydrophylic matrix tablets intended for prolonged drug release using ketoprofen as a model drug. The matrix tablets were prepared by direct compression using sodium alginate, calcium gluconate, and hydroxypropylmethylcellulose (HPMC) in different combinations and ratios. In vitro release tests and erosion studies of the matrix tablets were carried out in USP phosphate buffer (pH 7.4). Matrices consisting of sodium alginate alone or in combination with 10% and 20% of HPMC give a prolonged drug release at a fairly constant rate. Incorporation of different ratios of calcium gluconate leads to an enhancement of the release rate from the matrices and to the loss of the constant release rate of the drug. Only the matrices containing the highest quantity of HPMC (20%) maintained their capacity to release ketoprofen for a prolonged time.

Synthesis and pharmacological evaluation of 4a-methyl-4,4a,5,6-tetrahydrothieno[2,3-h]cinnolin-3(2H)-ones.

A number of 4a-methyl-4,4a,5,6-tetrahydrothieno[2,3-h]cinnolin-3(2H)-one s (3-5) have been synthesized and tested for their pharmacological profile. These were compared with the 8-acetylamino-4, 4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)one 1 which we reported to be a potent antihypertensive agent. In vivo tests indicated that 3 displayed lower even if still significant levels of antihypertensive activity in respect to the lead compound, while all the new derivatives exhibited lower hypotensive activity. Tricyclic thienocinnolinones 3-5 demonstrated fairly potent plateled antiaggregatory activity.

Pyridazine N-oxides. II. Synthesis and in vitro antimicrobial evaluation of 3-chloro-4-carbamoyl-5-aryl-6-methyl-pyridazine N-oxides.

As a part of a research project on antimicrobial agents, various novel carbamoyl derivatives of pyridazine-N-oxides 7a-j were prepared in moderate to good yields from 3-chloro-4-ethoxycarbonyl-5-aryl-6-methyl-3-pyridazine. All compounds synthesized were ineffective against Gram+, Gram- bacteria and fungi while 7e and 7j exhibited a fairly good activity against Trichomonas vaginalis.

Synthesis and pharmacological evaluation of 5,6-dihydrobenzo[f] cinnolin-2(3H)ones analogues of antihypertensive and antiaggregating benzo[h]cinnolinones.

Two new dihydrobenzo[f]cinnolin-2(3H)ones (4a,b) have been synthesized and tested for their hypotensive, antihypertensive and antiaggregating activities in comparison with the lead 8-acetylamino-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one 1. In vivo tests indicated that 4a,b displayed hypotensive and antihypertensive properties weaker than the model compound. On the contrary both compounds were more potent than 1 in inhibiting collagen-induced platelet aggregation.

Synthesis and pharmacological activity of 4-carbamoyl-6-beta-thienyl-4,5-dihydropyridazin-3-(2H)ones.

A new series of 4-carbamoyl-6-beta-thienyl-4,5-dihydropyridazin-3-(2H)ones 4a-g have been synthesized and tested for their anti-inflammatory and analgesic properties. Among the tested compounds, only 4f at 1 mmole/Kg showed antiinflammatory activity that was comparable with that of indomethacin (5 mg/Kg) though of shorter duration. Compounds 4a, 4e and especially 4g at 0.2 mmoles/Kg displayed relevant analgesic activity, 4g being the most potent derivative in the writhing test. Compounds 4c and 4g were found to possess analgesic activity also in the hot plate test.

In vitro antibacterial activity of antiseptics against vaginal lactobacilli.

The results of investigations carried out to evaluate the inhibitory activity in vitro of seven vaginal antiseptic douche solutions against several strains of vaginal lactobacilli isolated from asymptomatic women are reported. Some of the products examined showed marked antibacterial activity even at high dilutions and for short exposure times. The post-antibiotic effect of two of these antiseptics on vaginal lactobacilli was also evaluated. The results of these investigations suggest that uncontrolled use of antiseptic products could cause changes in the normal vaginal flora.