About 10% of the drugs in the preclinical stage are poorly soluble, 40% of the drugs in the pipeline have poor solubility, and even 60% of drugs coming directly from synthesis have aqueous solubility below 0.1 mg/ml. Out of the research around, 40% of lipophilic drug candidates fail to reach the market despite having potential pharmacodynamic activities. Microtubule-modulating chemotherapeutics is an important class of cancer chemotherapy. Most chemotherapeutics that belong to this category are plant-derived active constituents, such as vincristine, vinblastine, colchicine, docetaxel, paclitaxel, and noscapinoids. The pKa of a drug considerably affects its solubility in physiological fluids and consequently bioavailability. It usually ranges from 5 to 12 for microtubule-modulating drugs. Hence, the solubility of these drugs in physiological fluids is considerably affected by a change in pH. However, because of unpredictable parameters involved in poor solubility and the low oral bioavailability of these chemotherapeutics during the early phases of drug development, they often have an unusual pharmacokinetic profile. This makes the development process of novel chemotherapeutics slow, inefficient, patient-unfriendly, and very costly, emphasizing a need for more rational approaches on the basis of preclinical concepts. Nanosolvation is a process of increasing the polarity of a hydrophobic molecule either by solvation or cavitization in a hydrophilic macrocycle. The present review therefore focuses on the techniques applied in nanosolvation of microtubule-modulating chemotherapeutics to enhance solubility and bioavailability. The methodologies described will be highly beneficial for anticancer researchers to follow a trend of rational drug development.
Objective:The present study investigates acute toxicity and leukotriene inhibitory property of Nicotiana tabacum. Materials and Methods: Leaves of N. tabacum were extracted with aqueous ethanol (1:1) by cold percolation method. The extract was administered orally at the limit dose of 2000 mg/kg to evaluate the toxic potential of the plant. In vitro leukotriene inhibitory property of extract was examined on isolated lung strips of guinea pigs contracted with leukotriene D4 (10 µMol). The relaxation response was observed at six cumulative concentrations (6.25, 12.5, 25, 50, 100, and 200 mg/ml) of extract and standard, Montelukast, (0.15, 0.3, 0.45, 0.6, 0.75, and 0.9 mM). One-way ANOVA followed by Tukey's test was used for statistical analysis of data using GraphPad Prism 7. Results: Crude extract of N. tabacum administered orally at the dose of 2000 mg/kg did not cause any mortality indicating safety of the plant. The LD 50 of the plant was found to be >2000 mg/kg. Increasing concentrations of N. tabacum showed a decrease in muscle tone induced by LTD 4 in a dose-dependent manner (105.12 ± 1.03% at 200 mg/kg and EC 50 = 22.22 mg/ml). However, the relaxant effect of extract at highest concentration was nonsignificant (P > 0.05) compared to Montelukast. The relaxant effects of all concentrations of montelukast were significantly higher (P < 0.001) than saline. On the other hand, at the lowest concentration, the relaxant effect of N. tabacum was not significant (P > 0.05) compared to saline. Montelukast showed maximum relaxation of 112.82 ± 2.16 % at highest concentration (EC 50 = 0.20 mM).
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