How to kill two "birds" with one medicine


Researchers from the Institute of Solution Chemistry have studied physicochemical properties of nadolol, a drug compound used to treat arterial hypertension, angina, tachycardia, as well as in symptomatic anxiety treatment and migraine prevention. The authors experimentally investigated the solubility of nadolol and its distribution in solvents modeling physiological media and its permeability through membranes imitating biological barriers. The researchers have found an interrelation between the partition coefficients of the drug compound and its permeability coefficients at a variety of temperatures. The obtained results will be used to predict permeability through intestinal epithelium membranes and bioavailability.

Most post-COVID-19 patients experience exacerbation of chronic cardiovascular diseases. The severity of the infection, vague recovery prospects, social isolation, and emotional stress accompanying COVID-19 often lead to depression. Besides, depressive symptoms are quite typical of patients with chronic cardiovascular diseases and may reduce treatment efficiency. Thus, patients often have to face two (rather than one) problems, which have to be treated with several preparations. However, administration of drugs for depression and cardiovascular diseases simultaneously may cause complications resulting associated with compatibility of the components and dosage. The risks of complications can be eliminated by taking one drug that can treat two diseases at once.

Of special interest in these terms is nadolol, a drug that slows down the heart rate, reduces the heart beat strength and dilates blood vessels, thus lowering blood pressure and improving heart blood supply. Besides, as a beta-blocker, nadolol can be used to relieve anxiety and depression symptoms, is well-tolerated by patients and does not have a strong effect on the cognitive abilities.

One of the properties antidepressant drugs are expected to have is permeability through the blood-brain barrier. Of equal relevance is the property of any orally administered drugs to permeate through intestinal epithelium membranes. However, there are currently insufficient literature data on the physicochemical properties of nadolol, which would indicate its ability to cross these barriers.

ISC RAS researchers have studied the distribution, solubility and permeability of nadolol at several temperature values. The experiment was made with solvents modeling biological media of the stomach, blood plasma and intestine. The authors used a Franz cell and an artificial membrane PermeaPad, whose composition is similar to that of real-life biological membranes of the intestinal epithelium, to study the drug permeability through the intestinal epithelium and blood-brain barrier.

In the partition experiment, the authors used a two-phase system of immiscible solvents (octanol/water or hexane/water), in which the nadolol got redistributed between the aqueous and organic phases. The authors also analysed the nadolol solubility by the isothermal saturation method at several temperatures, including the standard temperature of 25°C and the temperature close to the normal human value (37 °C).

The observations showed that as the temperature grew from 25 to 40 °C, the nadolol permeability increased more than twofold. The authors also found a linear dependence between the partition and permeability coefficients at different temperatures. The compound was also shown to distribute almost equally between the phases in the two-phase octanol/water system at a temperature of 25°C. And, vice versa, the distribution was shifted considerably to the organic phase in the hexane/water system. The solubility and distribution coefficient values of nadolol became higher as the temperature went up. The membrane permeability was shown to increase exponentially with temperature growth.

The obtained results will help find additives that will have to be introduced into the nadolol oral forms to create more effective delivery systems and can be applied to design combination drugs for treatment of cardiovascular diseases and relief of anxiety and depression symptoms.

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