[Acute mesenteric ischemia complicated by intestinal necrosis: choice of strategies of treatment]. / Hostra mezenterial'na ishemiia, uskladnena nekrozov kyshky: vybir taktyky likuvannia.

Treatment of intestinal necrosis, caused by an acute mesenterial ischemia, represents the most complex field of surgery. Results of surgical treatment of 74 patients with various forms of mesenterial ischemia, complicated by intestinal infarction, were analyzed. Revascularization ought to be conducted if the ischemia may be eliminated. High frequency of anastomotic sutures insufficiency is noted in performance of primary resection of intestine. Syndrome of the polyorgan dysfunction constitutes the main cause of death in patients after the operation.

Prodrugs of butyric acid. Novel derivatives possessing increased aqueous solubility and potential for treating cancer and blood diseases.

The synthesis and biological activities of acidic, basic and neutral types of butyric acid (BA) prodrugs possessing increased aqueous solubility are described. The compounds are butyroyloxyalkyl derivatives of carboxylic acids, which possess functionalities suitable for aqueous solubilization. The anticancer activity of the prodrugs in vitro was evaluated by examining their effect on the growth of human colon, breast and pancreatic carcinoma cell lines, and their solubility in aqueous media was determined. The most promising compounds, with respect to activity and solubility, were found to be the butyroyloxymethyl esters of glutaric 2a and nicotinic acids 4a and phosphoric acid as its diethyl ester 10a, which displayed IC(50) values of 100 microM or lower. These prodrugs are expected to release formaldehyde upon metabolic hydrolysis. The corresponding butyroyloxyethyl esters (2b, 4b and 10b) that release acetaldehyde upon metabolism were significantly less potent. A similar correlation was observed for growth inhibition of the human prostate carcinoma cell lines PC-3 and LnCap and for induction of differentiation and apoptosis in the human myeloid leukemia cell line HL-60. The higher biological activity of the formaldehyde-releasing prodrugs 2a and 10a was further confirmed when induction of hemoglobin (Hb) synthesis in the human erythroleukemic cell line K562 was measured. Moreover, a therapeutic index (IC(50)/ED(50)) of ca. 5 was observed. The acute i.p. toxicity LD(50) in mice for 2a, 2b, 10a and 10b was similar and in the range of 400-600 mg kg(-1). The results obtained support the potential use of the butyric acid prodrugs for the treatment of neoplastic diseases and beta-globin disorders.

Self-assembly and lyomesophases formed by long-chain alkoxymethyl-nucleobase derivatives.

Amphiphilic complementary nucleobase derivatives, containing n-octadecyloxymethyl substituents at the N1 position of pyrimidine and N9 of purine, dissolved in chloroform form non-specific lyotropic mesophases, which were analyzed by optical polarizing microscopy. Molecular modeling studies visualize hypothetical horizontal and vertical nucleobase hydrogen-bonding and stacking arrangements, as well as aliphatic long-chain interstrand interaction.

Biomesogenic matrix systems.

The bifunctionally reactive nucleoside and distant nucleoside analogs adenosine (Ado), S-[(adenine-9-yl)methoxyethyl]-L-cysteine (Na-salt) (cysA) and 9-vinyladenine (vA) in aqueous solutions assemble on complementary polyuridylic acid templates to form complex lyomesophases. The systems are investigated by polarizing microscopy, differential scanning calorimetry (DSC) and 1H- and 31P-nmr spectroscopies, assisted by molecular modeling studies. The results indicate the importance of biomesogenic (pre)ordering in nucleic acid native and artificial matrix reactions.

Uptake of pivaloyloxymethyl butyrate into leukemic cells and its intracellular esterase-catalyzed hydrolysis.

UNLABELLED: Pivaloyloxymethyl butyrate (AN-9), a butyric acid (BA) prodrug, exhibited low toxicity and significant anticancer activity in vitro and in vivo. The purpose of this study was to elucidate the basis for AN-9 increased anticancer activity compared to BA, by studying the uptake of BA and AN-9 into the cells. METHODS: The uptake rate and level of [14C]-AN-9 and [14C]-BA, labeled on the carboxylic moiety of BA, into HL-60 and MEL leukemic cell lines was measured. The cells were filtered and the retained radioactivity was determined. The dependence of the uptake on the activity of cellular esterases and membrane fluidity was investigated. RESULTS: The uptake level in cells incubated with [14C]-AN-9 increased rapidly, peaked after 30 min in MEL and 1 h in HL-60 cells, and declined thereafter. This decline could be attributed to the hydrolysis of AN-9 by cellular esterases and catabolism of the released BA to CO2. In cells pretreated with an esterase inhibitor and incubated with [14C]-AN-9, the reduction of radioactivity was less precipitous. In cells exposed to [14C]-BA, the intracellular radioactivity level was low and unaffected by treatment with an esterase inhibitor. The uptake of [14C]-AN-9 decreased significantly at 4 degrees C compared to that at 37 degrees C. CONCLUSION: The higher potency of AN-9 compared to BA could be at least partially attributed to the more rapid uptake of the lipophilic AN-9 and the release of BA in the cells.

Immunoregulatory effects of N9-benzyl- and N7-benzyl-8-bromoguanines.

In this study we investigated the effects of two guanine derivatives, 9-benzyl- (I) and 7-benzyl-8-bromoguanines (II) on the proliferation of human T-cell leukemia and T-cell lymphoma, normal human peripheral blood mononuclear cells (PBMC), and mouse Th1 (pGL10) and Th2 (D10.G4.1) clones. We also assessed their effects on cytokine production (IL-3, IL-10 and IFN-gamma) in PBMC, T-cell lymphoma, HUT78 (IL-2), and murine Th1 (IL-2) and Th2 (IL-4 and IL-5) clones. These compounds were synthesize as analog of known inhibitors of purine nucleoside phosphorylase (PNP) 8-amino-9-benzylguanine. These compounds suppressed proliferation of human leukemia MOLT-4 cells, human cutaneous lymphoma HUT78 cells and normal PMBC. Compound II was a significantly more potent inhibitor than compound I. Exogenous recombinant human IL-2 reversed the anti-proliferative effects of both compounds on HUT78 cells. These compounds had low toxicity to human EBV-transformed B-lymphocytes. Both compounds suppressed the production of IL-2 by activated human HUT78 cells, IFN-gamma by PBMC and did not affect IL-3 and IL-10 production in PBMC. Compound I inhibited anti-CD3-activated IL-2 secretion from the murine Th1 clone. The murine Th2 clone was less sensitive to both compounds as compared with Thl. The production of IL-4 and IL-5 by this clone was not suppressed. Thus, it has been shown that not only 9-substituted guanines but also their 7-isomers selectively inhibit T-cell functions and both selectively inhibit Th1-related cytokines secretion.

Renal transplantation--choice of anesthesia.

The appropriate anesthesia for renal transplantation (RT) requires minimal toxicity for patient and transplant besides of sufficient pain relief and correction of vital functions. Since 1990 for this reason prolonged epidural anesthesia (PEA) was used for 42 RT. The catheterization of epidural space was performed on the spine level Th9-Th12. Lidocaine and Bupivacaine solutions were used for epidural block. Sedation during the operation was performed only with low doses of Diazepam and Sodium Oxybutyrate. After the operation epidural catheters were used for pain relief during 2-5 postoperative days. Less cardiodepressive effect, stable intraoperative hemodynamics and absence of serious post-operative pulmonary complications were observed in patients operated under PEA. Also less toxic action of PEA for recipient as well as for renal allograft was marked. Obtained results show that PEA might be the preferable method for RT due to its lower toxicity, significantly less number of postoperative complications.

[Purine nucleoside analogs. 5. Acycloguanosine derivatives containing O-alkoxyalkyl substituents in acyclic parts of the molecule]. / Analogi purinnukleozidov. 5. Proizvodnye atsikloguanozina, soderzhashchie O-alkoksialkil'nyi zamestitel' v atsiklicheskoi chasti molekuly.

A series of new acycloguanosine O-alkoxyalkyl derivatives have been obtained by the reaction of 9-(2-hydroxyethoxymethyl)- and 8-bromo-9-(2-hydroxyethoxymethyl)-N2-acetylguanines with cyclic and acyclic alpha-vinyl ethers. 9-[2-(Alkoxyalkyl)oxyethoxymethyl]-N2-acetylguanines are better soluble in water and low-polar organic solvents as compared with acycloguanosine. The compounds have the pronounced antiviral activity against HSV-I in the experiments in vivo and can be applied as acycloguanosine prodrugs.

Conformational aspects of antiviral activity of deoxyguanosine acyclic analogues.

Conformational possibilities of a series of deoxyguanosine analogues possessing or lacking antiviral activity were evaluated using methods of the molecular mechanics. Comparison of the spatial structures of acyclic analogues with one another and with the spatial structures of deoxyguanosine demonstrates restricted conformational mobility for compounds devoid of activity. The level of sterically allowed superposition of functional groups from the acyclic moieties of analogues and the corresponding atomic centres of deoxyribose could serve as a criterion of activity. The superposition could be performed in two different ways through either of the nonhydrogen substituents at the C1' atom in the five-membered ring.

Pyrimidine nucleoside analogues.X. 5-Substituted 1-(1,3-dihydroxypropyl-2) uracils.

A convenient method is suggested for synthesis of uracil-1-malonic acid diethyl ester by alkylating 2,4-bis(trimethylsilyl) uracil with bromo-malonic acid diethyl ester. This compound has been shown to hydrolyze with NaOH yielding either uracil or uracil-1-acetic acid, depending on reaction conditions. Similarly, thymine-1-malinic acid diethyl ester and 5-fluorouracil-1,3-dimalonic acid tetraethyl ester were obtained. 1-(1,3-Dihydroxypropyl)uracil has been obtained by reducing uracil-1-malonic acid diethyl ester with NaBH4.

[Clinical pharmacokinetics of 2-C14-ftorafur in patients with astrocytoma]. / Klinicheskaia farmakokinetika 2-C14-ftorafura u bol'nykh astrotsitomoi

Patients with dedifferentiated brain astrocytoma during an operation were injected intravenously 2-C14-fluorofur (3 muC/Kg). In different periods after the injection the level of radioactivity was determined in different sites of the tumor, brain tissue, as well as in blood plasma, cerebrospinal liquor and urine. Intracellular localization of the labeled substance in the tumor tissue was examined autohistoradiographically. 2-C14-fluorofur was found to readily penetrate the hemato-encephalic barrier and to be absorbed both by tissues of neuroectodermal tumor and adjacent brain tissues. In astrocytoma cells the labelled substance is localized mainly extranuclearly. Radioactive products are excreted from the organism slowly and their traces are observed in blood, cerebrospinal liquor and urine even on the third day postoperatively.