Polymorphic and Quantum Chemistry Characterization of Candesartan Cilexetil: Importance for the Correct Drug Classification According to Biopharmaceutics Classification System.

The recommended method for the biopharmaceutical evaluation of drug solubility is the shake flask; however, there are discrepancies reported about the solubility of certain compounds measured with this method, one of them is candesartan cilexetil. The present work aimed to elucidate the solubility of candesartan cilexetil by associating others assays such as stability determination, polymorphic characterization and in silico calculations of intrinsic solubility, ionized species, and electronic structures using quantum chemistry descriptors (frontier molecular orbitals and Fukui functions). For the complete biopharmaceutical classification, we also reviewed the permeability data available. The polymorphic form used was previously identified as the form I of candesartan cilexetil. The solubility was evaluated in biorelevant media in the pH range of 1.2-6.8 at 37.0°C according to the stability previously assessed. The solubility of candesartan cilexetil is pH dependent and the dose/solubility ratios obtained demonstrated the low solubility of the prodrug. The in silico calculations supported the found results and evidenced the main groups involved in the solvation, benzimidazole, and tetrazol-biphenyl. The human absolute bioavailability reported demonstrates that candesartan cilexetil has low permeability and when associated with the low solubility allows to classify it as class 4 of the Biopharmaceutics Classification System.

The changing face of oral anticoagulants.

Warfarin has been the established oral anticoagulant for the last 50 years, being effective in the prevention and treatment of venous and arterial thromboembolic disorders. However, the frequent requirement for INR monitoring, multiple drug and food interactions have fuelled the need for development of new oral anticoagulants. Dabigatran is the first of a series of new oral anticoagulants that are emerging as the successors to warfarin. This new group of anticoagulants is rapidly gaining FDA and NICE approval and has proven non-inferiority to warfarin and viable alternatives to warfarin in the coming years. Given the obvious impact of this on dental treatment in the primary care and hospital setting this article aims to increase familiarisation with this new medicine group.

Evaluation of the membrane permeability (PAMPA and skin) of benzimidazoles with potential cannabinoid activity and their relation with the Biopharmaceutics Classification System (BCS).

The permeability of five benzimidazole derivates with potential cannabinoid activity was determined in two models of membranes, parallel artificial membrane permeability assay (PAMPA) and skin, in order to study the relationship of the physicochemical properties of the molecules and characteristics of the membranes with the permeability defined by the Biopharmaceutics Classification System. It was established that the PAMPA intestinal absorption method is a good predictor for classifying these molecules as very permeable, independent of their thermodynamic solubility, if and only if these have a Log P(oct) value <3.0. In contrast, transdermal permeability is conditioned on the solubility of the molecule so that it can only serve as a model for classifying the permeability of molecules that possess high solubility (class I: high solubility, high permeability; class III: high solubility, low permeability).

Synthesis and in vitro activity of dicationic bis-benzimidazoles as a new class of anti-MRSA and anti-VRE agents.

A new class of novel bis-benzimidazole diamidine compounds have been synthesized and evaluated for in vitro antibacterial activities, including drug-resistant bacterial strains. Anti-MRSA and anti-VRE activities of the most potent compound 1 were more active than Vancomycin. The mechanism of action for this class of compounds appears to be different from existing antibiotics. Bis-benzimidazole diamidine compounds have potential for further investigation as a new class of potent anti-MRSA and anti-VRE agents.

Synthesis and antioxidant properties of novel N-methyl-1,3,4-thiadiazol-2-amine and 4-methyl-2H-1,2,4-triazole-3(4H)-thione derivatives of benzimidazole class.

Some novel 1-methyl-4-(2-(2-substitutedphenyl-1H-benzimidazol-1-yl)acetyl)thiosemicarbazides (16a-20a), 5-[(2-(substitutedphenyl)-1H-benzimidazol-1-yl)methyl]-N-methyl-1,3,4-thiadiazol-2-amines (17b-20b), and 5-[(2-(substitutedphenyl)-1H-benzimidazol-1-yl)methyl-4-methyl-2H-1,2,4-triazole-3(4H)-thiones (16c-20c) were synthesized and tested for antioxidant properties by using various in vitro systems. Compounds 16a-20a were found to be a good scavenger of DPPH radical (IC(50), 26 microM; IC(50), 30 microM; IC(50), 43 microM; IC(50), 55 microM; IC(50), 74 microM, respectively) when compared to BHT (IC(50), 54 microM). Noteworthy results could not be found on superoxide radical. Compound 19b, which is the most active derivative inhibited slightly lipid peroxidation (28%) at 10(-3)M concentration. Compound 17c inhibited the microsomal ethoxyresorufin O-deethylase (EROD) activity with an IC(50)=4.5 x 10(-4)M which is similarly better than the specific inhibitor caffeine IC(50)=5.2 x 10(-4)M.

Study (1991 to 2001) of drug-resistant Population B small strongyles in critical tests in horses in Kentucky at the termination of a 40-year investigation.

Population B, drug-resistant small strongyles have been studied in naturally infected horses in Kentucky for more than 40 years. These parasites first were found to be resistant to phenothiazine (PTZ) and thiabendazole (TBZ), later to other parasiticides. Studies have been on evaluation of antiparasitic efficacy of several compounds, especially the benzimidazoles, against Population B small strongyles in clinical (field) tests (1959-1983) on the commercial farm of origin and in clinical and critical tests (1966-2001) at the University of Kentucky (UK) research farm. Research on these nematodes through 1990 has been published. The current paper presents data on efficacies of various anthelmintics (mostly TBZ) against these and other internal parasites in critical tests done between 1991 and 2001. These were the last critical tests in the UK horses; the entire herd was terminated in 2005. Population B small strongyles were established in horses on a pasture at the UK research farm on Old Lot 4 in 1966, and a satellite of this group was relocated to Field 24 in 1987. The last treatment of any of the horses in clinical tests on pasture was 22 years for Old Lot 4 (mostly benzimidazoles) and 5 years for Field 24 (TBZ) before the last critical test in 2001. Antiparasitic compounds (all paste formulations) administered orally in critical tests (n = 36) reported in this paper were TBZ (@ 44 mg/kg), pyrantel pamoate (PRT @ 6.6 mg base/kg), PTZ (@ 55 mg/kg), fenbendazole (FBZ @ 5 mg/kg), oxfendazole (OFZ @ 10 mg/kg), and oxibendazole (OBZ @ 10 mg/kg). The drug given and number of horses treated from Old Lot 4 were TBZ (18), PRT (3), PTZ (2), FBZ (2), OFZ (1), and OBZ (1) and from Field 24 were OFZ (1) and TBZ (8). Removal of small strongyles in Old Lot 4 was excellent for PRT, OFZ, and OBZ but much less for TBZ, PTZ, and FBZ. For the 16 species present in this lot, removal by TBZ was lowest for seven species (Coronocyclus (Cor.) coronatus, Cyathostomum (Cya.) catinatum, Cylicocyclus (Cyc.) nassatus, Cylicostephanus (Cys.) calicatus, Cylicostephanus goldi, Cylicostephanus longibursatus, and Cylicostephanus minutus). Of these seven species, lowest activity was found for five by PTZ and FBZ. One of the five resistant species was different for each of these two drugs. In Field 24, efficacy against small strongyles was excellent for the one foal treated with OFZ early (1992) in the study. TBZ initially had higher activity than in later years. Of the 12 small strongyle species present in this field, TBZ activity throughout the study was, in general, low for Cor. coronatus, Cys. goldi, and Cys. longibursatus, but it declined more or less progressively for Cya. catinatum, Cylicocyclus leptostomus, Cyc. nassatus, and Cys. calicatus over the study period. Cys. minutus were not present in high enough numbers to evaluate drug efficacy. Overall activity of TBZ on the group of small strongyles did not change; that is, susceptibility did not increase over time in Old Lot 4 where these parasites were not exposed to a benzimidazole for many years. However, in Field 24, where additional TBZ pressure was put on these parasites, efficacy not only did not increase but it decreased. From the data for small strongyles in the two groups of foals, eight species were considered benzimidazole resistant in varying degrees (most research on TBZ). Data on prevalence and drug activity on other internal parasite species besides small strongyles also are given.

A criteria to classify biological activity of benzimidazoles from a model of structural similarity.

We have classified a set of 250 benzimidazoles using a criterion of structural similarity. This criterion has led us to several clusters, which keep a close relationship between the molecules belonging to each one of them and their pharmacological activity. To study the structural similarity we have built a mathematical space where chemical structures are pictured as vectors. A set of well-chosen descriptors was used as variables. These descriptors arise from graph theoretical studies and quantum mechanical calculations. Principal components analysis was employed to find the suitable dimension for the space. Finally, cluster analysis was performed to classify the set of molecules by similarity. A Euclidean metric was used as a similarity coefficient.