Pharmaceutical Chemistry Journal (v.41, #11)

Bioavailability of boswellic acids: in vitro/in vivo correlation by M. V. Karlina; O. N. Pozharitskaya; V. M. Kosman; S. A. Ivanova (569-572).
Extract of Boswellia sacra (incense tree), the main active components of which are boswellic acids, is used for the treatment of rheumatoid arthritis and gout. Boswellic acids suppress leukotriene biosynthesis in neutrophilic granulocytes by non-redox, noncompetitive inhibition of 5-lipoxygenase. Representing pentacyclic triterpenoids, boswellic acids are characterized by poor solubility in water and are highly lipophilic (1og P = 7–10.3). Bioavailability of the B. sacra (BS) extract has been studied using a new method developed for estimating and predicting the possible absorption of medicinal substances in vivo, which is based on the establishment of a correlation between the data obtained in vivo and in vitro. The validity and applicability of the proposed method is demonstrated. Release of four individual boswellic acids from BS extract has been studied in vitro using a nonconventional two-phase system simulating conditions in the gastrointestinal tract. Based on these data, the dissolution rate constants of boswellic acids have been calculated. In addition, the parameters of pharmacokinetics of ketoacids in vivo have been determined and a correlation between these parameters and the rate of release in vitro has been studied. It is established that there is a strong correlation between the results obtained in vivo and the dissolution of boswellic acids in the model two-phase medium in vitro, which makes possible prediction of the pharmacokinetic profiles of individual acids upon per os administration of BS extract.

Distribution of sodium perrenate in intact mice by V. M. Petriev; O. A. Smoryzanova; V. G. Skvortsov (573-576).
The distribution of sodium perrenate (Na188ReO4) in the organism of intact mice has been studied. It is shown that the behavior of Na188ReO4 in the organism depends on the method of administration. In particular, the level of drug accumulation in the majority of organs and tissues is lower upon intraperitoneal administration than after intravenous introduction. The elimination of the preparation from the organs and tissues proceeds at a higher rate upon intraperitoneal administration than after intravenous injections. Selective accumulation of Na188ReO4 at higher concentrations takes place in the thyroid gland and stomach. These results can be useful in determining the pharmacokinetic characteristics of osteotropic radiopharmaceuticals for the estimation of their functional value for intratissue radionuclide therapy of bone metastases.

Modified prostaglandins: New possibilities for the pharmacological control of immunodeficient states by G. S. Lyubin; B. B. Kuz’mitskii; M. B. Golubeva; N. A. Konoplya; E. V. Koroleva; T. V. Chernikhova; F. S. Pashkovskii; I. P. Antonevich; F. A. Lakhvich (577-584).
The role of exogenous prostaglandins (PGs) as immune response and allergic inflammation regulators and the existing notions of the interaction between synthetic PGs or their modified analogs with prostanoid receptors are considered. Based on the principles of structural complementarity, the immunotropic effects of new synthetic 11-deoxyprostanoids of the E1, E2, and F series, modified at the α-and ω-chains and containing pharmacophores at various positions of the prostanoid skeleton, were studied as dependent on the dose and the chemical structure. It is established that prostanoids of the E series, which are deprived of oxo and hydroxy groups at the cyclopentane ring but contain a complete or nearly complete α-chain and a malonic ether fragment at the ω-chain, exhibit no immunotropic activity. On the other hand, the PG analogs containing 9-keto groups enhance both the cellular and humoral immunogenesis in mice immunized (sensitized) with sheep red blood cells. The presence of an oxo group at position 7 is also important for the immunopositive response and the pharmacological activity. The enhancement of the ligand — receptor interaction is retained upon replacing the cyclopentane fragment by the bicycloheptane moiety. The ω-chain modification by incorporating a sulfur heteroatom at position 13 caused no substantial changes in the immunomodulating activity, whereas the ω-chain modification resulting in the formation of 1-amino-3-oxo-oct-1-enyl fragment can be considered as an important condition for obtaining immunopositive prostanoids. As a rule, the ability to enhance the humoral immunity was increased on going from the E to F series of prostanoids. The pharmacodynamic parameters of the immune response evidenced a high affinity of F-prostanoids to EP receptors. It can be suggested that F-prostanoids may act as agonists of these receptors. From this standpoint, a decrease in the immunoactivity of compounds having too bulky fragments in the ω-chain is quite reasonable. Thus, some of the ligands affine to prostanoid receptors are worthy of attention as prototypes of safe and efficient low-molecular immunoregulators of a new generation.

Synthesis and antiarrhythmic activity of n-(1-methyl-2-phenylethyl)aminoethanesulfonic acid isopropylamide hydrochloride by N. S. Sapronov; L. K. Gavrovskaya; I. B. Krylova; S. V. Kulikov; N. R. Evdokimova; N. I. Kudryashova (585-587).
The synthesis and pharmacological properties of a new taurine amide derivative, N-(l-methyl-2-phenylethyl) aminoethanesulfonic acid isopropylamide hydrochloride (I), are described. Pronounced antiarrhythmic effect of compound I was observed in animals with experimental ventricular arrhythmias (early postocclusive and calcium chloride models). The drug significantly decreased the frequency and intensity of paroxysmal tachycardia attacks and ventricular fibrillation after coronary artery occlusion. Simultaneous administration of calcium chloride and compound I increased the arrhythmogenic dose of calcium chloride, inducing lethal heartbeat disorder and asystolia, and decreased the frequency of ventricular flutter and fibrillation. The antiarrhythmic effect of the drug was similar to that of lidocaine. The antifibrillatory activity is the most important manifestation of the antiarrhythmic action of the taurine derivative studied. These data suggest that compound I is a potential drug for urgent aid in myocardial infarction.

New methods for the synthesis of 4-substituted 6,7-dihydro-7,7-dimethyl-5-oxo-9H-pyrano-[4′,3′: 4,5]-thieno[3,2-e]imidazo[1,2-a]pyrimidines and their hydrochlorides are developed. The anticonvulsant and tranquilizer properties of newly synthesized compounds have been studied.

Synthesis and conversions of polyhedral compounds: 28. Synthesis and psychotropic activity of some 1,3-diazaadamantane derivatives by G. L. Arutyunyan; I. A. Dzhagatspanyan; I. M. Nazaryan; A. G. Akopyan; A. D. Arutyunyan (591-593).
The anticonvulsant and tranquilizer properties of some new derivatives of 1,3-diazaadamantane have been investigated. It is established that some of the synthesized compounds prevent corazole-induced convulsions in mice in a dose range of 18–75 mg-kg. The study of the influence of these compounds on the behavior of rats under open-field test conditions revealed a pronounced tranquilizer action.

Synthesis and antibacterial and antifungal activity of 2-thiocyanato-2-methyl-3-arylpropionic acid allyl esters by B. D. Grishchuk; S. I. Klimnyuk; R. V. Simchak; O. V. Pokryshko; V. S. Baranovskii; P. M. Gorbovoi (594-595).
Allyl esters of 2-thiocyanato-2-methyl-3-arylpropionic acids exhibit pronounced antibacterial activity with respect to various test strains of staphylococci, colon bacilli, aerobic bacilli, and yeast fungi. The maximum activity is observed for compounds containing chlorine or bromine atoms at the aromatic nucleus.

Synthesis and antimicrobial activity of sulfanylamide-containing copper(II) and nickel(II) salicylidenethiosemicarbazidates by A. P. Gulya; V. I. Prisacar’; V. I. Tsapkov; S. A. Buracheva; S. N. Spynu; N. P. Bezhenar’; D. Poirier; J. Roy (596-599).
A series of streptocide-, sulfacyl-, norsulfazole-, ethazole-, sulfadimezine-, and sulfapyridazine-containing copper(II) and nickel(II) salicylidenethiosemicarbazidates and salicylidene-4-phenilthiosemicarbazidates possessing high antimicrobial activity has been synthesized. The composition and probable structures of the obtained coordination compounds are proposed based on elemental analysis and magnetochemical, IR spectroscopy, and thermogravimetric data. The dependence of the antimicrobial activity of compounds on the nature of the central atom, sulfanilamide, and phenyl radicals in the thiosemicarbazide fragment of azomethine has been studied with respect to ten species of staphylococcus, streptococcus, and intestine bacillus strains. The maximum activity was exhibited by norsulfazole-and sulfacyl-containing Cu(II) salicylidenethiosemicarbazidate and Cu(II) salicylidene-4-phenilthiosemicarbazidate.

Chemical composition and biological activity of total bufadienolides from the Central-Asian Bufo viridis toad venom by A. B. Soliev; Sh. Ya. Mirzaakhmedov; M. S. Tashmukhamedov; F. G. Kamaev; Sh. I. Salikhov; N. I. Zakirova; A. Yu. Abramov; I. V. Usanova; V. N. Syrov; Z. A. Khushbaktova (600-604).
The chemical composition of bufadienolides isolated from the venom of Bufo viridis green toad occurring in Central Asia was determined and their biological properties were studied. Six individual bufadienolides were isolated by reverse-phase chromatography on a Lichrosorb RP-8 (10 µ) column in amounts sufficient for qualitative analysis. Two of these were previously identified as arenobufagin and gamabufotalin by NMR spectroscopy and x-ray diffraction methods. The chemical structures of four other bufadienolides are now established by NMR spectroscopy and HPLC. These compounds have been identified as telocinobufagin (3β,5β,14β-trihydroxybufa-20,22-dienolide), marinobufagin (3β, 5β-hydroxy-14,15β-epoxybufa-20,22-dienolide), bufarenogin (3β,12β,14β-hydroxybufa-20,22-dienolide), and bufalin (3β,14β-hydroxybufa-20,22-dienolide).

Chemical composition and pharmacological activity of anthraquinones from Rubia cordifolia cell culture by N. P. Mishchenko; S. A. Fedoreev; V. M. Bryukhanov; Ya. F. Zverev; V. V. Lampatov; O. V. Azarova; Yu. N. Shkryl’; G. K. Chernoded (605-609).
The results of qualitative and quantitative determination of anthraquinones in Indian madder (Rubia cordifolia L.) cell culture are presented. According to the 1H and 13C NMR, UV, IR, and mass-spectroscopic data, seven anthraquinones have been identified, in which munjistin and purpurin are predominant. The cell culture preparation exhibits antiinflammatory activity, which is manifested by an antiexudative effect and antiproliferative action during the rapid development of a model edema. Adecrease in the antioxidant state without significant suppression of enzymatic activity is demonstrated.

A new mixed plant preparation possessing antistressor properties by I. G. Nikolaeva; L. N. Shantanova; G. G. Nikolaeva; S. M. Nikolaev; K. V. Par’eva; I. K. Ivanova (610-613).
The optimum extraction conditions for obtaining a new mixed plant preparation (tanton) have been determined and its phytochemical composition has been studied. The antistressor activity of tanton has been established in experiments on white rats.

Colloidal-chemical properties of perfluorocarbon (PFC) emulsions, which are used as plasma substitutes when the transfer of normal blood is problematic or impossible, ere considered. Physicochemical properties of emulsions based on perfluorodecalin and perfluoromethylcyclohexylpiperidine stabilized by Proksanol 268 (Pluronic F68) at an average particle size of 50–80 nm are considered. According to the colloidal-chemical classification, PFC emulsions for biomedical applications represent direct, concentrated, highly and freely dispersed heterogeneous thermodynamically unstable colloidal systems possessing an excess of free energy and a very large gas-exchange surface, in which a dispersed phase of insoluble monodisperse PFC nanoparticles is coated with a surfactant (emulsifier) and occurs in the suspended state in a surrounding structured aqueous dispersion medium.

Synthesis and tuberculostatic activity of N-aminoacetic acid hydrazides and acylhydrazides based on ephedrine alkaloids by I. V. Kulakov; O. A. Nurkenov; M. A. Gazalieva; S. K. Zhaugasheva; Zh. O. Isakova (620-624).
N-Alkaloid acetic acid hydrazides have been obtained by the hydrazinolysis of morpholones, and the acylation reactions of these hydrazides have been carried out. Screening investigations of the synthesized derivatives in vitro and in vivo have revealed, for the first time among the ephedrine alkaloids, a promising compound (N-d-pseudoephedrinylacetic acid hydrazide) possessing pronounced antituberculosis activity comparable with that of isoniazid.