HPLC-MS Method for Simultaneous Quantitative Determination of an Innovative Russian Gestagen and its Metabolites in Rat and Rabbit Blood Sera

Pharmaceutical Chemistry Journal - An HPLC-MS method for simultaneous quantitative determination of a novel gestagenic pharmaceutical and two of its metabolites in rat and rabbit blood sera was...     

Comparative analysis of the effect of gestagens,antiestrogencytostatics, and androstenes on the viability of tumor and normal cells

The hormonal compound with the highest cytostatic activity against MCF-7 tumor cells (human breast cancer, BC) and the lowest activity against normal cells (rat skin fibroblasts) was sought among gestagens, androstenes, and antiestrogencytostatics. It was found that antiestrogencytostatics and androstenes had the highest cytostatic activity against tumor cells whereas gestagens and antiestrogencytostatics were least active against fibroblasts. Studies of the activity of the hormonal compounds in combination with doxorubicin on the viability of MCF-7 and rat skin fibroblasts found that all investigated compounds with the exception of dehydroepiandrosterone (DHEA) intensify the cytostatic activity of doxorubicin against tumor cells, the greatest effect seen for antiestrogencytostatics. A chemoprotective effect of androstenes on normal cells was noted. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 41, No. 7, pp. 3–7, July, 2007.     

6alpha-Methyl-16alpha,17alpha-cyclohexane progesterone and progesterone inhibit growth of doxorubicin-sensitive MCF-7 and HeLa tumor cells

Temporal and concentration dependencies of the effects of gestagens (6-methylpentarane and progesterone) and cytostatic doxorubicin on proliferation of MCF-7 and HeLa tumor cells was studied using ³H-thymidine test. Gestagens produced the maximum inhibitory effect of on cell proliferation in a concentration of 10^-5 M; the effect developed on day 6 of incubation. 6 -Methylpentarane in a concentration of 10^-8 inhibited proliferation of HeLa cells more effectively than progesterone (p<0.05). In experiments with combined treatment of doxorubicin-sensitive MCF-7 and HeLa cells, progesterone in a concentration of 10^-7 M attenuated the cytostatic effect of doxorubicin (p<0.05), while 6-methylpentarane in the studied concentrations did not modulate it.     

Inhibitors of Sortases of Gram-Positive Bacteria and their Role in the Treatment of Infectious Diseases (Review)

Pharmaceutical Chemistry Journal - The functions of sortase bacterial enzymes and their surface-protein substrates are reviewed. Their role in the pathogenesis of infectious diseases such as...     

Preparation of a Horse Chestnut Extract with a 50% Content of Escin and its Actions on Tumor Cell Proliferation and Isolated Mitochondria

Pharmaceutical Chemistry Journal - Escin-containing horse chestnut extracts and various medicinal formulations are widely used as venotonic agents whose mechanisms of action and intracellular...     

A new Russian gestagen with anticancer activity

The authors present results obtained in a complex study of 17alpha-acetoxy-3beta-butanoyloxy-6-methyl-pregna-4,6-dien-20-on (ABMP). ABMP was shown to differ from existing analogues by high gestagen activity and prolonged action. The substance does not possess androgenic or mineralocorticoid activity, is not toxic when used in high doses, and possesses significant cytostatic and chemiosensitizing activity. These properties of ABMP demonstrate that the substance should be studied in clinical setting as a gestagen with anticancer and chemiosensitizing activity for further application to therapy of hyperplastic processes in the female genital system and tumors that are sensitive to female sex hormones.     

Antitumor activity of the new gestagen 17alpha-acetoxy-3beta-butanoyloxy-6-methyl-pregna-4,6-dien-20-one

Antitumor activity of a new highly active promising gestagen 17alpha-acetoxy-3beta-butanoyloxy-6-methyl-pregna-4,6-dien-20-one (butagest) was studied in mice with model cervical carcinoma (RShM-5). The reference drug was medroxyprogesteron acetate (MPA, Depo Provera) used in clinics. The new preparation introduced perorally in a dose of 1 mg per mice inhibited the model tumor growth by 73%, which was 18% (p < 0.01) more effective than the action of the reference drug MPA. The effect of the new gestagen was also studied in vitro with respect to human breast carcinoma of the MCF-7 line and human cervical carcinoma HeLa. The viability of the tumor cells was studied during a 6-day incubation with the drug at a concentration of 10(-7)-10(-5) M (MTT test). The reference compounds were progesterone and MPA. These drugs suppressed the growth of both MCF-7 and, in higher concentrations, of HeLa. Butagest inhibited the growth of HeLa in all concentrations. Thus, the new gestagen 17alpha-acetoxy-3beta-butanoyloxy-6-methyl-pregna-4,6-dien-20-one is capable of suppressing the viability of human breast carcinoma and human cervical carcinoma, being comparable or even more effective than the reference drugs.     

Toxic effects of microbial phenolic acids on the functions of mitochondria

Low-molecular-weight phenolic acids (PhAs) phenylacetate, phenyllactate, phenylpropionsmall a, Cyrillicte, small er, Cyrillic-hydroxyphenyllactate, and p-hydroxyphenylacetate are essentially the products of the degradation of aromatic amino acids and polyphenols by the intestinal microflora. In sepsis, the concentrations of some of these acids in the blood increase tens of times. Assuming that these compounds can cause the mitochondrial dysfunction in sepsis, we examined their effects on respiration, the induction of pore opening, and the production of reactive oxygen species (ROS) in mitochondria. It was found that phenylpropionsmall a, Cyrillicte and phenylacetate produce a more toxic effect on mitochondria than the other phenolic acids. At concentrations 0.01-0.1mM they decreased the rate of oxidation of NAD-dependent substrates and activated the Ca(2+)- and menadione-induced opening of the cyclosporin A-sensitive pore and the production of ROS. The disturbances caused by these PhAs are similar to those observed in mitochondria in sepsis, and hence the rise in their level may be one of the causes of mitochondrial dysfunctions. Phenyllactate, small er, Cyrillic-hydroxyphenyllactate, and p-hydroxyphenylacetate inhibited the production of ROS and pore opening, acting as antioxidants. Thus, the ability of PhAs to affect the mitochondrial functions, as well as an increase in their concentrations in sepsis (the total concentration of these PhAs in the blood is close to 0.1mM), suggests that PhAs can be directly involved in the development of mitochondrial failure.     

Development of New Dosage forms of Niclosamide with Increased Solubility and Cytotoxic Activity

Pharmaceutical Chemistry Journal - The work was devoted to increasing the solubility of the anthelmintic agent niclosamide (NS). Methods for increasing the solubility of NS were described....     

Effect of progesterone and its synthetic analogues on the activity of mitochondrial permeability transition pore in isolated rat liver mitochondria

The influence of progesterone and its synthetic analogues on the induction of the Ca²⁺-dependent mitochondrial permeability transition pore (MPTP) has been studied. The novel synthetic analogue of progesterone 17a-acetoxy-3b-butanoyloxy-6-methyl-pregna-4,6-diene-20-on (buterol) was compared with progesterone and medroxyprogesterone acetate (MPA). It was found that progesterone and buterol have opposite effects on the induction of MPTP opening by calcium ions. By contrast to progesterone, which decreased the calcium ion concentration necessary for pore opening, and MPA, which also, although at a lesser extent, activated the pore induction, buterol at a concentration of 20-100 μM blocked the pore opening and increased the calcium retention capacity of mitochondria more than twofold. The action of buterol is specific to the pore since it did not affect the respiration, whereas progesterone completely inhibited NAD-dependent respiration. MPA acted similar to progesterone but less effectively. The inhibitory effect of buterol was eliminated in the presence of carboxyatractyloside, which selectively binds the thiol groups of adenylate translocase and prevents the adenine nucleotide binding. These data indicate that buterol interacts with thiol groups, which explains its inhibitory effect not only on the mitochondrial pore but also on the transport system of xenobiotics in tumor cells in which buterol reduces the multidrug resistance.