Experience and prospects for the use of off-label drugs in oncology.

According to the World Health Organization, half of all drugs available on the global pharmaceutical market are sometimes used for indications that are not included in the instruction for use. This method of therapy has the term "off-label use" which means the use "out of instruction". Today, off-label drugs are also prescribed for cancer treatment. For example, a drug developed to treat one type of tumor can sometimes be used to treat other types of cancer. The treatment of certain types of pain with tricyclic antidepressants is also an example of the off-label drugs used in oncology. An example of an off-label prescription is anxiolytic medicine lorazepam, which can be used off-label as an antiemetic in cancer patients. Low doses of naltrexone are applied to treat cancer and autoimmune diseases. A retrospective analysis of modern oncotherapy indicates that oncologists often use off-label drugs in combination therapy, especially in the treatment of patients with concomitant diseases, in case of progressive development of the tumor, or to reduce the toxicity and cost of treatment components. American oncologists are of the opinion that if all the drugs prescribed by the International Recommendations failed in the treatment of cancer, doctors can prescribe off-label medications, but only if their effectiveness and safety are clearly established. The problem of the off-label use of drugs in oncology has not yet been studied in detail, however, this direction has certain promising prospects.

[The mechanism of the pulmoprotective action of carboxytherapy]. / Mekhanizm pul'moprotektornogo deistviia karboksiterapii.

The problem of finding new ways for pharmacological prophylaxis and treatment of respiratory tract diseases is very relevant in public health. To eliminate hypoxia, many European and American clinics use carboxytherapy as an additional or alternative treatment. Carbon dioxide administration eliminates the sequels of oxygen starvation, by producing artificial tissue hypercapnia, which causes an increase in oxygen delivery and carbon dioxide removal from the tissues and then from the body. The main mechanism of action of carboxytherapy is associated with enhanced tissue oxygenation and is due to the Verigo-Bohr effect: the effect of CO2 concentration and pH on the binding of hemoglobin to oxygen and release of the latter from hemoglobin. By affecting the chemoreceptors of the respiratory center, carboxytherapy contributes to increased pulmonary ventilation and reduces bronchial smooth muscle tone and bronchial mucous secretion, as well as inflammation; all this improves breathing. By exerting a direct and reflex effect on the respiratory center, carboxytherapy induces hurried and deeper breathing, which increases pulmonary ventilation, speeds up perfusion and gas exchange in the lung, eliminates dyspnea and bronchospasm; therefore, it is widely used for lung diseases (asthma, pneumosclerosis, and silicosis). Carboxytherapy improves lung function in case of bronchopulmonary diseases, performance, and quality of life and it is used as an additional method in the pharmacotherapy of many diseases in pulmonology.

[Carboxytherapy - an innovative trend in resort medicine]. / Karboksiterapiia - odno iz innovatsionnykh napravlenii v kurortologii.

Carboxytherapy (the treatment based on carbon dioxide injections) is a multipurpose and widely used medical technology. The use of CO2 injections (intracutaneous, subcutaneous, and pneumopuncture) have substantially supplemented and increased the practical relevance of carboxytherapy as a method for the treatment of many diseases. Thanks to it physiological properties, CO2 has antihypoxic, antioxidant, vasodilatory, anti-inflammatory, analgesic, and spasmolytic activities; moreover, it improves blood viscosity, stimulates neoangiogenesis, and regenerative processes. Carbon dioxide is a sort of biochemical 'peacemaker' in tissue oxygenation: when blood cells are exposed to high CO2 concentrations (Bohr effect), the rate of gas exchange (CO2 and O2) increases. The human organism interprets carboxytherapy (local hypercapnia) as oxygen deficiency and responses to it by boosting not only the blood flow, but also the vascular endothelial growth factor which stimulates neoangiogenesis and in the long run improves blood supply and tissue trophism. The multiple mechanisms of action, polymodal efficacy, a tool kit with a wide range of detectors and various modes of treatment make carboxytherapy a popular medical technology all over the world, namely in cosmetology, dermatology, aesthetic medicine, angiology, orthopaedics, cardiology, neurology, pulmonology, gynaecology, urology, proctology, plastic and general surgery, and other areas. Carboxytherapy provides a perfect example of the off-label usage in medicine that made it one of the most extensively applied medical technology for the treatment of various diseases despite the lack of the preclinical data and scarce relevant information available in textbooks, reference books and booklets.

Chronopharmacological Characteristics of the Effect of Hepatoprotectors in Experiment?

We studied circadian rhythms of activity of hepatoprotectors (Antral, Carsil, and glutargin) under conditions of acute paracetamol-induced hepatitis simulated in the morning, afternoon, evening, and at night (09.00, 15.00, 21.00, and 03.00). Antral and Carsil exhibited similar chronoprofiles with the maximum hepatoprotective activity at 09.00 and 21.00, while glutargin exhibited circadian pattern opposite and its activity was maximum at 15.00 and 03.00.

[CIRCADIAN DEPENDENCE OF PARACETAMOL HEPATOTOXICITY IN RATS.]

Results of chronopharmacological study of the circadian dependence of paracetamol toxicity and the extrapolation of obtained results to determine peculiarities in the daily activity of metabolic processes in rat liver are reported. The study was conducted on the model of acute paracetamol-induced hepatitis in both male and female rats in four diual periods: 03.00 a.m., 09.00 a.m., 15.00 p.m., and 21.00 p.m. The toxicity of paracetamol and the functional activity of liver were estimated by changes in markers of cytolytic activity of alanine aminotransferase (AIAT) and aspartate aminotransferase (AsAT) in blood serum, and the content of reduced glutathione (RG) in liver tissue. It is established that the degree of paracetamol toxicity and the level of hepatocyte RG are mutually dependent: the higher the content of RG in cells, the less pronounced toxic effect of xenobiotic is and vice versa, which is confirmed by correlation analysis (r = 0.43 - 0.94, depending on the circadian system of animals from control group). Extrapolation of results on the toxicity of paracetamol was used to reveal periods of the maximum and minimum functional activity of the liver. Acrophase of the functional activity of liver in rats corresponds to 15.00, and the antiphase of this activity in humans, to 01 - 03.

[An experimental study of suikrepan]. / Eksperimental'noe izuchenie suikrepana.

Acute, subacute, and chronic experiments were performed to examine the toxicity, specific action, analgetic, and physicochemical properties of suicrepan derived from the porcine duodenal mucosa and the hormone secretin contained in it. Suicrepan was found to be an effective pancreatic extrasecretory function stimulant, by showing therapeutical benefits in experimental pancreatitis and analgesic effects. The drug was demonstrated to display a low toxicity.

[The liver-protective properties of the pediatric drug form of propolis in animals of different age groups]. / Izuchenie gepatozashchitnykh svoistv detskoi lekarstvennoi formy propolisa u zhivotnykh raznykh vozrastnykh grupp.

The pharmacological activity of a pediatric formulation of the phenolic hydrophobic drug propolis was studied in the experiments on albino rats of various age with toxic liver damages of various duration and in acute hepatic ischemia. In all models of hepatic abnormalities, the drug was found to show antioxidative properties which were moderate (30-60%). In addition, there were improvements in hepatic secretion of bile, cholic acids, and cholesterol. On the other hand, the membrane-stabilizing effect of the drug was exerted in not all the tested models of hepatic damage.

[The tocolytic activity of melatonin]. / Issledovanie tokoliticheskoi aktivnosti melatonina.

Melatonin was shown to produce a tocolytic effect in experiments on the isolated uterine horn in different experimental animals and on the whole body. The ability of melatonin to inhibit uterine contractility was confirmed by the studies of the effects of melatonin on oxytocin-induced myometrial contractions. It may be suggested that the antagonism between melatonin and oxytocin is uncompetitive.

[The effect of the amino sugar glucosamine on the endogenous intoxication processes in pulmonary edema in rats]. / Vliianie aminosakhara gliukozamina na sostoianie protsessov éndotoksikoza pri oteke legkikh u krys.

The effects of glycosamine aminosugar on the processes of endotoxicosis and lipid peroxidation were thoroughly studied in rats with toxic pulmonary edema. There was a glycosamine-induced decrease in markers of endotoxicosis, such as medium-weight molecular peptides and malonic dialdehyde in serum and lung tissue. Administration of exogenous glucosamine resulted in its incorporation into the membranes of target organs, connective tissue and normalized the levels of endogenous N-acetyl-glucosamine, which finally determined antitoxic and antioxidative properties in this aminosugar.

[The efficacy of hydroxycinnamic acids in toxic lesions of the liver]. / Effektivnost' oksikorichnykh kislot pri toksicheskikh porazheniiakh pecheni.

The albino rat experiments studied the pharmacological action of oxycinnamic acid derivatives in acute tetrachloromethane-induced hepatic dystrophy and combined CCl4-ethanol-induced hepatic lesion. The tested agents were found to produce cholagogic, membrane-protective, and antioxidative effects in these hepatic abnormalities, thus improving the functional (cholate- and glycogen-synthetic) parameters of the liver.

[Antihypoxic effect of glucosamine in acute hypoxic states in mice]. / Antygipoksychnyi efect gliukozaminu pry gostrykh gipoksychnykh stanakh organizmu myshei.

The preventive glucosamine injection causes an increase in the survival of mice with acute hypobaric hypoxia. The injection of glucosamine, combined with sodium hydroxybutyrate greatly increased their antihypoxic activities.

[The effect of the new nonsteroidal anti-inflammatory agent glucamine on oxidative phosphorylation processes]. / Vliianie novogo nesteroidnogo protivovospalitel'nogo sredstva gliukamina na protsessy okislitel'nogo fosforilirovaniia.

A study was made of the action of the nonsteroidal antiinflammatory agent glucamin on the processes of oxidation and phosphorylation (OP) in isolated mitochondria of the liver. It has been established that glucamin does not exhibit the properties of a separator in the explored concentrations (10(-2)-10(-7) M). Unlike the standard drug voltaren that separates OP processes, it slightly enhances interaction of liver mitochondria which oxidize NAD-dependent substrates. The effect of voltaren is dose-dependent, being pronounced to a greater measure when succinate is applied as a substrate of mitochondria oxidation.

[The influence of glucosamine on the antiexudative effect of nonsteroidal anti-inflammatory agents]. / Vliianie gliukozamina na antiékssudativnyi éffekt nesteroidnykh protivovospalitel'nykh svoistv.

The study of the antiexudative activities of voltaren, indomethacin and piroxicam in combination with glucosamine on the model of carrageenan inflammation showed that the combination makes it possible to decrease the effective doses of nonsteroidal anti-inflammatory drugs by 2-2.7 times with the preservation of the pronounced antiexudative activity. A diverse influence of aminosugar on the anti-inflammatory effect of nonsteroidal anti-inflammatory drugs depending on the sequence and routes of administration is connected with their membrane mechanisms and metabolic features of amino sugar.

[The efficacy of glucosamine in treating complicated hyperreactive experimental myocardial infarct]. / Effektivnost' gliukozamina v lechenii oslozhnennogo giperreaktovnogo éksperimental'nogo infarkta miokarda.

The effect of glucosamine hydrochloride on the course of complicated hyperreactive myocardial infarction in dogs was studied. Glucosamine contributed to the restoration of reactivity in the animals. The reactivity became corresponding for normoreactive myocardial infarction. Glucosamine normalized carbohydrate and protein metabolism in the necrosis zone, cAMP and cGMP and also their ratio that led to healing by postinfarction scar, and in none of the cases the heart aneurysm developed. The optimizing healing of hyperreactive myocardial infarction under the influence of glucosamine is mediated through the mechanisms of reactivity and the regulation of metabolic processes.

[The liver-protective properties of D-glucosamine]. / Gepatozashchitnye svoistva D-gliukozamina.

The antioxidant and membrane-stabilizing activities of D-glucosamine were studied on two models of toxic liver damage. When administered in a dose of 50 mg/kg, D-glucosamine was found to prevent the development of the hepatocyte cytolysis syndrome, to normalize the cholate- and glycogen-synthetic functions of the liver. D-glucosamine exhibited a significant anabolic effect that also supplemented its hepatoprotective activity.

[Physiologic importance of glucosamine]. / Fiziologicheskoe znachenie glikozamina.

The paper reviews the present state of the problem on the physiological importance of D-(+)-glucosamine, an amino sugar. Glucosamine is shown to be a component of many biological important systems widely spread in nature. It is a part of the connective tissues, membranes, lipopolysaccharides and mucopolysaccharides and participates in detoxic function of the liver and kidneys. The data from literature reviewed permit concluding that glucosamine and its derivatives are potentially useful and possess antiinflammatory, liver-defending, antihypoxic and other pharmacological activities.

[The hepatotropic properties of nonsteroidal anti-inflammatory agents]. / O gepatotropnykh svoistvakh nesteroidnykh protivovospalitel'nykh sredstv.

The hepatotropic effect of nonsteroidal anti-inflammatory drugs (NSAID) such as indomethacin, voltaren, piroxicam, phenylbutazon, mefenamic acid was studied. It was found that according to their level of the pharmacological protection of the liver against tetrachlormethan these agents may be arranged in the following sequence: mefenamic acid, phenylbutazon, voltaren, piroxicam. The hepatoprotective effect of NSAID correlates with the antioxidant properties and fails to correlate with the antioxidant ones. The hepatotoxic effect of NSAID was determined by their ability to suppress synthesis of prostaglandins.

[Interrelation of the antialterative and antiproliferative effects of indomethacin, voltaren, piroxicam and D-glucosamine]. / Vzaimosviaz' antial'terativnogo i antiproliferativnogo éffektov indometatsina, vol'tarena, piroksikama i D-gliukozamina.

In experiments on rats it was shown that voltaren had a moderate degree and D-glucosamine a pronounced degree of antiproliferative and antialterative effects. On these models indomethacin and piroxicam also exerted a marked antiproliferative action and the ability to suppress tissue regeneration in alterative inflammation.