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Biomedical subjects

M Sovak

Publications and source records attributed to M Sovak.

At least 19 recordsLinked to original sources
PubMed2001

A new prodrug of paclitaxel: synthesis of Protaxel.

2' and 7 Polyol carbonates of paclitaxel were synthesized and screened as potential paclitaxel prodrugs. Paclitaxel is released from 7-(2",3"-dihydroxypropylcarbonato) paclitaxel (Protaxel) at rates inversely proportional to pH, by an intramolecular cyclization. Compared to paclitaxel, maximum tolerated i.v. or i.p. doses (MTD) of Protaxel are about 2.5- to 3-fold higher; its efficacy is substantially higher in human cancer line xenografts in athymic mice, especially in prostate PC-3, breast MDA-MB 468 and ovary OVCAR-1.

Animals↗
PubMed1992

Role of Lys 558 and Lys 869 in substrate and inhibitor binding to the murine band 3 protein: a study of the effects of site-directed mutagenesis of the band 3 protein expressed in the oocytes of Xenopus laevis.

The effect of mutation of either Lys 558 or Lys 869 or both on mouse erythroid band 3 protein (AE1)-mediated 36Cl- efflux and its inhibition by pyridoxal 5-phosphate (P5-P), DNDS and H2DIDS were studied. Regardless of the mutation, band 3 was always capable of executing Cl- self-exchange. P5-P (5 mM, pH 7.6) produced irreversible inhibition in the wild type (KK) and in the mutant in which Lys 558 (NK) or Lys 869 (KM) had been replaced by asparagine (N) or methionine (M), respectively. However, when both residues were replaced, mutant (NM), irreversible inhibition could no longer be achieved. This shows that P5-P is capable of producing inhibition with either one of the lysine residues, 558 or 869. Inhibition by DNDS changed dramatically upon mutation. The Ki app increased from 6.0 microM in the wild type (KK) to 23 microM in the mutant NK, to 73 microM in the mutant KM and to 474 microM in the double mutant NM. The Km value for activation of the transport system by varying the substrate concentration by isosmotic substitution of Cl- with SO4(2-) decreased from 42 mM in the wild type (KK) to 11.3 mM in the mutant NM. The results show that both Lys 558 and Lys 869 are involved in the maintenance of the structure of the overlapping binding sites for stilbene disulfonates and the substrate Cl-. In the double mutant NM, H2DIDS is no longer able to produce irreversible inhibition at pH 7.6. This is evidently related to the replacement of Lys 558 (pK 8.2) by Asn 558 in this mutant (see Bartel, D., Lepke, S., Layh-Schmitt, G., Legrum, B., Passow, H., 1989. EMBO J. 8:3601-3609). However, at pH 9.5, some irreversible inhibition could still be observed. This suggests that the other lysine residue (pK 10.8) that is known to be involved in covalent binding with the second isothiocyanate group of H2DIDS is still present, and hence, not identical to Lys 869, which had been substituted by a methionine residue. However, this result remains inconclusive since after mutagenesis, the H2DIDS may produce inhibition at a site that is not normally involved in H2DIDS binding.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1992

Neuroendocrine regulation of immunity: the effects of noradrenaline in Xenopus laevis, the South African clawed toad.

A functional association between the peripheral nervous and the immune system in Xenopus laevis, the South African clawed toad, is demonstrated. This association involves the neurotransmitter noradrenaline (NA), produced and released by the sympathetic nerves of the spleen. Chemical sympathectomy prior to immunization reduces splenic NA, and decreases thymus-dependent (TD), but increases thymus-independent (TI), antibody responses. Immune challenge with representatives of the three antigen classes affects splenic NA levels differentially. Thus, the modulatory effect of NA on immunity will depend on the immunogen used. Carrier-priming of helper function in TD responses stimulates a transitory NA release in the spleen, while subsequent immunization activates a more prolonged release. The two types of challenge differ in the antigenic dose given. The effects of NA also depend on the time when it is applied. If used early in the in vivo TD response, antibody production is increased, but if given later, suppressor function is stimulated, thus decreasing antibody production. NA increases both amplifying and suppressing T cell functions in TD responses through stimulation of the alpha 2 adrenoceptor. Alpha 2 adrenoceptor stimulation decreases, and beta adrenoceptor stimulation increases, anti-TNP reactivity. Since an alpha 2 receptor agonist does not affect lectin-stimulated T cell mitogenesis, while a beta receptor agonist depresses it, NA appears to up-regulate T cell functions by affecting their maturation, rather than their clonal expansion.

Adrenergic alpha-Agonists↗
PubMed1990

Ioxilan, a third generation low osmolality nonionic contrast medium. Systemic and renal hemodynamic effects.

The choice between high cost, low toxicity nonionic contrast media (CM) and low cost ionic CM poses a dilemma for radiologists. Ioxilan, a third generation nonionic CM, is obtained by simple conversion from an ionic CM. To examine how this economically promising, low osmolality CM (570 mOsm at 300 mgI/ml) affects canine systemic and renal hemodynamics, IV bolus injections of 350 mgI/ml at 2 ml/kg of Iohexol and Ioxilan were compared. Satisfactory nephrograms and pyelograms were produced by both agents, without significant differences. The effects on systemic and renal hemodynamics were minimal and statistically equal for both CM. The acute systemic and renal responses and radiographic image quality of Ioxilan and Iohexol confirm that the two compounds are biologically equivalent, and that the novel molecular design employed in Ioxilan to achieve very low osmolality also provides good biological tolerance.

Animals↗
PubMed1988

The need for improved contrast media. Ioxilan: updating design theory.

Because of computed tomography (CT) and digital subtraction angiography (DSA), other diagnostic procedures assisted by urovascular contrast media (CM) have decreased, but the annual total remains at 10 to 11 million procedures since 1980. This trend, expected to continue, suggests that CM will remain vital to medical imaging. The current nonionic CM are not universally affordable, and may elicit pain in peripheral angiography. The author and co-workers explored conversion of ionic into nonionic CM, and have arrived at Ioxilan, 5-(N-2,3-dihydroxypropylacetamido)-2,4,6-triiodo-N-(2-hydroxyethyl )-N'-(2,3- dihydroxypropyl)-isophthalamide; a stable, water-soluble and well-tolerated CM. Ioxilan has unexpectedly low osmolality (570 mOsm at 300 mgI/mL), attributable to the region of double-methylenes that, by hydrophobic bonding, transiently associates the Ioxilan molecules. The high overall hydrophilicity, and thus good biological tolerance, of Ioxilan is accomplished by masking the hydrophobic region with a hydrophilic group. The author suggests that improved urovascular nonionic CM can be designed using this principle.

Angiography↗
PubMed1988

Current contrast media and ioxilan. Comparative evaluation of vascular pain by aversion conditioning.

Vascular pain caused by contrast media (CM) cannot be quantified by subjective patient reports or manifest pain reactions in experimental animals. Therefore, conditioned taste aversion (CTA), a psychopharmacological method, was used in double-blind femoral arteriography in rats to compare a new nonionic monomeric CM, ioxilan, with iohexol, iopamidol (all at 350 mgI/mL) and 22% sorbitol. A chronically implanted femoral artery catheter was used to inject 0.2 mL/kg body weight. By measuring the intake of water laced with the flavor that thirsty rats had learned to associate with the injection, the degree of aversion, assumed proportional to pain, was determined. Ioxilan (690 mOsm) produced the least pain, followed by iopamidol (810 mOsm), iohexol (844 mOsm) and sorbitol (1410 mOsm). Since all test substances are highly and similarly hydrophilic and nonionic, the intensity of vascular pain must depend on solution osmolality, rather than on chemotoxicity or ionicity. Compounds of the lowest osmolality, ig, ioxilan, elicit the least vascular pain.

Animals↗
PubMed1988

Isomerism in iohexol and ioxilan. Analysis and implications.

Pharmacologically useful contrast media (CM) must be highly water-soluble to form stable supersaturated solutions. Iohexol and ioxilan both contain centers of potential isomerism stemming from the D,L hydroxyalkyls, the carbamoyl substituents, the alkylated anilide nitrogen and the acetylated anilide. The D,L isomers are individual compounds, both highly water-soluble and equally highly hydrophilic. The carbamoyl rotamers result from steric restriction by the adjacent iodines, and are interconvertible at physiologic temperature ranges; only at low temperatures can high field nuclear magnetic resonance (NMR) identify them. The isomers resulting from the alkylated anilide are fixed, but since they can exist only by reference to fixed carbamoyls, they are not relevant at physiologic temperatures. The N-acetyl endo-/exo-isomers are crystallizable from alcoholic solvents and identifiable by high-pressure liquid chromatography (HPLC) and hydrogen-1 (1H) and 13C NMR. They interconvert rapidly in water, forming stable and highly soluble mixtures. All isomers of iohexol or ioxilan, based on HPLC, are similarly highly hydrophilic, and are expected to show low binding to biomacromolecules with a concomitantly high biological tolerance. Since these mixtures are unavoidable, they must be considered a pharmacologic entity.

Chromatography, High Pressure Liquid↗
PubMed1988

Selective transcervical fallopian tube catheterization: technique update.

A technique of transcervical fallopian tube catheterization involving use of a new vacuum hysterograph and coaxial catheter set is described. In 25 women, selective catheterization of the uterine cornua was accomplished with a 94% success rate. Ostial salpingography permitted visualization of 26% of the 46 tubes found to be obstructed or poorly visualized with conventional hysterosalpingography. Recanalization was successful in 96% of 28 proximal tubal obstructions and in 33% of six midisthmic obstructions unrelated to surgery. Recanalization attempts resulted in tubal perforations without apparent clinical effects in four tubes, one with proximal and three with midisthmic postsurgical obstructions. The new hysterograph with coaxial catheter set is more suitable for recanalization of the obstructed fallopian tubes than is the previously used balloon catheter set.

Adult↗
PubMed1982

Nonionic dimer: development and initial testing of an intrathecal contrast agent.

A nonionic dimer (DL-3-117) containing a novel substituent (D,L amino-threitol) was synthesized and tested as an intrathecal contrast medium. In the complement-mediated assay, the dimer was approximately half as inhibitory of hemolysis as metrizamide or iopamidol. The lethal dose (LD50) in protozoa was 320 mg I/ml for DL-3-117, 96 mg I/ml for metrizamide, and 101 mg I/ml for iopamidol. The intravenous LD50 of DL-3-117 in mice was 26 g/kg, and in rats it was 12.7 g/kg. The effective dose (ED50) of intradiencephalic injection in rats was 219 mg I/kg for DL-3-117, 61.9 mg I/kg for metrizamide, and 154.1 mg I/kg for iopamidol, which are significantly different. A dose of 300 mg I/kg injected into a permanently cannulated lateral ventricle produced neurofunctional deficits with all contrast media except DL-3-117, which scored equal to Ringer's solution. Metrizamide and iopamidol in the same model, adapted for aversion conditioning, induced aversion with 45 mg I/kg, while DL-3-117 did not condition the rats.

Animals↗
PubMed1982

Experience with metrizamide in patients with previous severe anaphylactoid reactions to ionic contrast agents.

Metrizamide was employed in six patients who, during angiography, had had severe anaphylactoid reactions to conventional ionic contrast media. Five of these patients had received corticoid premedication before injection of both conventional contrast medium and metrizamide; anaphylaxis occurred only after administration of conventional contrast media. Four patients had no detectable reaction whatsoever after metrizamide; a fifth had only transient tachycardia. In the sixth patient, delayed edema developed in the region of his cerebral arteriovenous malformation. These observations suggest a marked decrease in the incidence and severity of anaphylactoid reactions when metrizamide is substituted in patients who have reacted to ionic contrast media. Metrizamide, or a comparable nonionic contrast agent, should be strongly considered in patients who have had a severe reaction to conventional contrast medium.

Adolescent↗