Cyclodextrins: an overview of the complexation of pharmaceutical proteins.

Cyclodextrins are oligosaccharides, specifically cyclic alpha-1,4-D-glucose oligomers, that possess a cone-like shape resulting in a hydrophobic inner cavity capable of forming complexes with several guest molecules in a hydrophilic matrix. This capability has led to an extensive investigation into cyclodextrin applications in several different substrates with the purpose of overcoming limitations, such as solubility issues, physical degradation and sensitivity to solvents, in guest substances. Researchers have recently described successful interactions between cyclodextrins and proteins, such as enzymes, peptides and amino acids. These complex biomolecules consist of potent active ingredients and are employed in several industrial biocatalyst processes. However, this group in particular tends to have limited usage in pharmaceuticals due to its natural processes of degradation and instability in unusual environments, frequently requiring accurate procedures and stabilization methods in all stages of production. In several cases, the final product still has a short shelf-life and often requires a controlled environment for storage. The formation of a cyclodextrin supramolecular complex could not only prevent such problems, but also enhance the intrinsic characteristics of guest substances, thus allowing for an expansion in their industrial production and application. This work focuses on cyclodextrin interactions with protein-like structures in order to describe their possible applications in the formulation of pharmaceutical proteins.

Desenvolvimento de formulações de comprimidos tamponados mastigáveis de didanosina com perfil de dissolução e capacidade neutralizante ácida otimizados / Development of didanosine chewable buffered tablets with optimized dissolution profile and acid neutralizing capacity.

Neste estudo buscou-se desenvolver formulações de comprimidos tamponados mastigáveis (CTM) de didanosina com eficiência de dissolução (ED%) e capacidade neutralizante ácida (CNA) otimizados, tendo como base o medicamento referência e especialidades farmacêuticas disponíveis no mercado nacional. Cinco formulações de CTM foram produzidas e avaliadas quanto a ED% e CNA, por meio de ensaio de dissolução e titulação ácido-base, respectivamente. Os resultados iniciais de CNA foram próximos aos encontrados para as especialidades farmacêuticas, aproximadamente 12 mEq HCl, porém distantes do medicamento referência (especialidade A, CNA = 17,93 mEq HCl). Já as formulações derivadas de CTM-4 conduziram à obtenção de comprimidos tamponados com CNA otimizada de aproximadamente 17,5 mEq HCl, o mesmo ocorrendo para ED%, (61,33% e 62,00%, CTM-4-2-1 e3, respectivamente). Esse resultado mostra-se próximo ao valor de 59,33% da especialidade A, quando utilizado o mesmo método de dissolução, indicando haver equivalência entre estas formulações e o medicamento referência para estes parâmetros.

The aim in this study was to develop chewable buffered tablets (CBT) of didanosine with optimized dissolution efficiency (DE) and acid-neutralizing capacity (ANC), using the reference medicine and other pharmaceutical didanosine products available in Brazil as models. Five CBT formulations were prepared and assessed for DE and ANC, through the dissolution test and acid-base titration, respectively. The initial ANC results fell short of those for the reference medicine (product A, ANC= 17.93 mEq HCl), but were close to those obtained for other pharmaceutical products (approximately 12 mEq HCl). The formulations derived from CBT-4 resulted in buffered tablets with an optimized ANC of 17.5 mEq HCl, approximately. The same was found for DE (61.33% and 62.00%, CBT-4-2-1 and CBT 3, respectively). This result proved to be close to that of product A (59.33%), when the same method was used for the dissolution test, indicating that both formulations and the reference medicine were equivalent with respect to these properties.

Antibothropic action of Casearia sylvestris Sw. (Flacourtiaceae) extracts.

Casearia sylvestris Sw., popularly known in Brazil as 'guaçatonga', has been used as antitumor, antiseptic, antiulcer, local anaesthetic and healer in folk medicine. Snakebite envenomation by Bothrops jararacussu (Bjssu) constitutes a relevant public health hazard capable of inducing serious local damage in victims. This study examined the pharmacological action of apolar and polar C. sylvestris leaf extracts in reverting the neuromuscular blockade and myonecrosis, which is induced by Bjssu venom and its major toxin bothropstoxin-I on the mouse phrenic nerve-diaphragm preparations. The polar methanol extract (ME) was by far the most efficacious. ME not only prevented myonecrosis and abolished the blockade, but also increased ACh release. Such facilitation in neuromuscular transmission was observed with ME alone, but was accentuated in preparations incubated with ME plus venom or toxin. This established synergy opens an interesting point of investigation because the venom or toxin in contact with ME changes from a blocking to a facilitating effect. It is suggested that rutin, known to have potent antioxidant properties, and one of the components present in the ME, could have a role in the observed effects. Since commercial rutin did not reproduce the ME effects, it is likely that a rutin-containing phytocomplex is neutralizing the bothropic envenoming effects.

Neutralization of the neuromuscular activity of bothropstoxin-I, a myotoxin from Bothrops jararacussu snake venom, by a hydroalcoholic extract of Casearia sylvestris Sw. (Guaçatonga

Numerous plants are used as snakebite antidotes in Brazilian folk medicine, including Casearia sylvestris Swartz, popularly known as guaçatonga. In this study, we examined the action of a hydroalcoholic extract from C. sylvestris on the neuromuscular blockade caused by bothropstoxin-I (BthTX-I), a myotoxin from Bothrops jararacussu venom, in mouse isolated phrenic nerve-diaphragm (PND) preparations. Aqueous (8 and 12 mg/ml, n=4 and 5, respectively) and hydroalcoholic (12 mg/ml, n=12) extracts of the leaves of C. sylvestris caused facilitation in PND preparations followed by partial neuromuscular blockade. BthTX-I (20 mg/ml, n=4) caused 50% paralysis after 65±15 min (mean ± S.E.M). Preincubation (30 min at 37°C) of BthTX-I (20 mg/ml, n=4) with a concentration of the hydroalcoholic extract (4 mg/ml) that had no neuromuscular activity, such as the control (n=5), prevented the neuromuscular blockade caused by the toxin. This protection may be mediated by compounds such as flavonoids and phenols identified by thin-layer chromatography and colorimetric assays

Neutralization of the neuromuscular activity of bothropstoxin-i, a myotoxin from Bothrops jararacussu snake venom, by a hydroalcoholic extract of Casearia sylvestris Sw. (guaçatonga)

Numerous plants are used as snakebite antidotes in Brazilian folk medicine, including Casearia sylvestris Swartz, popularly known as guaçatonga. In this study, we examined the action of a hydroalcoholic extract from C. sylvestris on the neuromuscular blockade caused by bothropstoxin-I (BthTX-I), a myotoxin from Bothrops jararacussu venom, in mouse isolated phrenic nerve-diaphragm (PND) preparations. Aqueous (8 and 12 mg/ml, n=4 and 5, respectively) and hydroalcoholic (12 mg/ml, n=12) extracts of the leaves of C. sylvestris caused facilitation in PND preparations followed by partial neuromuscular blockade. BthTX-I (20 µg/ml, n=4) caused 50% paralysis after 65±15 min (mean ± S.E.M). Preincubation (30 min at 37° C) of BthTX-I (20 µg/ml, n=4) with a concentration of the hydroalcoholic extract (4 mg/ml) that had no neuromuscular activity, such as the control (n=5), prevented the neuromuscular blockade caused by the toxin. This protection may be mediated by compounds such as flavonoids and phenols identified by thin-layer chromatography and colorimetric assays.