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Biomedical subjects

A P Mazurek

Publications and source records attributed to A P Mazurek.

At least 19 recordsLinked to original sources
PubMed2001

A nicked duplex decamer DNA with a PEG(6) tether.

A dumbbell double-stranded DNA decamer tethered with a hexaethylene glycol linker moiety (DDSDPEG), with a nick in the centre of one strand, has been synthesised. The standard NMR methods, E.COSY, TOCSY, NOESY and HMQC, were used to measure (1)H, (31)P and T:(1) spectral parameters. Molecular modelling using rMD-simulated annealing was used to compute the structure. Scalar couplings and dipolar contacts show that the molecule adopts a right-handed B-DNA helix in 38 mM phosphate buffer at pH 7. Its high melting temperature confirms the good base stacking and stability of the duplex. This is partly attributed to the presence of the PEG(6) linker at both ends of the duplex that restricts the dynamics of the stem pentamers and thus stabilises the oligonucleotide. The inspection of the global parameters shows that the linker does not distort the B-DNA geometry. The computed structure suggests that the presence of the nick is not disturbing the overall tertiary structure, base pair geometry or duplex base pairing to a substantial extent. The nick has, however, a noticeable impact on the local geometry at the nick site, indicated clearly by NMR analysis and reflected in the conformational parameters of the computed structure. The (1)H spectra also show much sharper resonances in the presence of K(+) indicating that conformational heterogeneity of DDSDPEG is reduced in the presence of potassium as compared to sodium or caesium ions. At the same time the (1)H resonances have longer T:(1) times. This parameter is suggested as a sensitive gauge of stabilisation.

Cations↗
PubMed2000

Evaluation of radioiodinated histamine as isotope carrier in vivo.

The iodo derivative of histamine labelled with 125I has been used for many years to prepare tracers used in RIA systems. The aim of this study was to evaluate radioiodinated histamine as a potential isotope carrier for in vivo applications. The biological behaviour of radioiodinated histamine has been investigated in rodents. The observed absence of any specific iodohistamine uptake by a critical organ or tissue promises a very quick distribution of the iodohistamine in soft tissues, and a rapid rate of whole-body clearance via the urinary tract (e.g. over 50% of the injected dose (ID) during the first hour after administration). In spite of moderately low in vitro stability of iodohistamine in serum, biodistribution studies in rodents have not shown any significant release of iodine from the parent molecule in the whole animal. Low uptake was observed in the thyroid (e.g. 0.22 and 0.11% ID at 1 and 2 h after administration to rats), and not more than 3% of injected activity was detected in the stomach in all of the biodistribution experiments. Moreover, our results refute any possibility of competition between histamine and iodohistamine for receptor binding sites, and suggest that radioactive mono-iodohistamine may be used successfully to develop some new radiolabelled bioactive molecules with potential application in vivo.

Animals↗
PubMed2000

Identification of transplanted pancreatic islet cells by radioactive dithizone-[131I]-histamine conjugate. Preliminary report.

BACKGROUND: The unique mechanism of dithizone action in the interior of the viable pancreatic islet suggests the possible development of a specific radiopharmaceutical that may have a potential clinical application in the diagnosis of the pancreatic organ allografts or islets rejection. The radiodiagnostic properties of the newly developed radioactive analogue of dithizone, i.e. Dithizone-[(131)I]-Histamine conjugate have been evaluated in the present study. METHODS: The four islet cells transplantation models were chosen for this purpose. The most important feature of the Dithizone-[(131)I]-Histamine conjugate is its possessed ability of zinc chelation. As was presented in the recent study, the conjugate stains pink-reddish the isolated pancreatic islets in vitro. Among the studied transplantation models, only the islets grafting under testis capsule enabled determination of the pancreatic islets in rats by radioactive Dithizone-[(131)I]-Histamine conjugate. The level of the radioactivity in the recipient testis (right) was almost two times higher compared to the controls (0.24 vs. 0.13% ID/g, respectively). CONCLUSIONS: These preliminary data demonstrate the ability of the developed radioactive analogue of dithizone for in vivo identification of transplanted pancreatic islets, and suggests a potential clinical application of the radiodithizone in the diagnosis of the pancreatic islet rejection.

Journal Article↗
PubMed1998

The synthesis, radioiodination and preliminary biological study of the new carboxylic derivatives of dithizone.

Synthesis, characteristics and radioiodination of the new carboxylic derivatives of dithizone are described in this paper. We have applied the carboxy dithizones for preparation of radioactive compounds by coupling with [131I]-histamine. Preliminary biological studies of the new radiodithizone were done in rats after two different application routs: peripheral i.v. injection and direct injection to splenic artery. Biodistribution of the carboxy dithizone-[131I]-histamine conjugate (i.v. injection) was quite different than that for free [131I]-histamine. However, uptake of activity in pancreas was low (0.81% g-1 of tissue). Direct application of the conjugate to splenic artery resulted in high activity retention in pancreas after 30 and 45 min post injection (respectively 8.8 and 12.4% g-1 of tissue) indicating potential usefulness of the new radiodithizone for in vivo monitoring of pancreas.

Animals↗
PubMed1998

Monitoring of rat islet allografts with dithizone after induction of donor specific transplant tolerance by intrathymic administration of soluble alloantigens.

Transplantation of whole pancreas or pancreatic islets remains a promising approach to treatment of diabetes mellitus. Since there is no efficient method presently known for in vivo detection of pancreatic islet rejection, we have utilized dithizone [DTZ] to monitor the survival of transplanted islet allografts following the induction of tolerance by a new strategy of deliberate introduction of donor antigens into the adult thymus. In this study, we examined the morphology of islet allografts in vivo and in vitro following pretreatment with intrathymic (IT) inoculation of 2 mg soluble Ag obtained from 3M KCl extracts of resting T-cells with or without ALS immunosuppression in the WF-to-Lewis combination. Fresh isolated rat islets stained pink 3-5 minutes following exposure to medium containing 0.12 mM DTZ solution in DMSO. Intravenous (i.v.) injection of DTZ solution into unmodified recipients of islet allografts that had rejected their grafts showed massive degranulation of islets which did not stain pink with DTZ. This was confirmed by microscopic finding of fibrosis and lymphocytic infiltration. In contrast, i.v. injection of DTZ solution into long-term recipients of islet allografts at 50, 100, and 150 days after transplantation showed viable islet cells which stained crimson red with DTZ and the findings were confirmed with microscopic sections. This study demonstrates that DTZ is an effective means of in vivo and in vitro identification of transplanted pancreatic islets and suggests that this strategy may have potential clinical application in the diagnosis of the pancreatic islet rejection.

Animals↗
PubMed1998

Mitochondrial activity after cold preservation of pancreatic islet cells treated with pefloxacin (PFX).

Mitochondrial energetic and oxidative dysfunctions caused by free radical production trigger release of proinflammatory cytokines involved in organ rejection. The aim of this study was to investigate the role of a fluoroquinolone drug, pefloxacin (PFX) and those of various cold preservation solutions on pancreatic beta cell viability. Our data clearly demonstrate that islet cell viability, as determined by glucose-stimulated insulin secretion, is directly correlated with reduced expression of microsomal cytochrome P-450IIIA. Moreover, IL-2, a known mediator of apoptosis was found to be downregulated, whereas TNF-alpha had been upregulated for the first 18 hours after pefloxacin administration. These results demonstrate that pefloxacin downregulates the expression of cytochrome P-450IIIA isozyme and regulates the production of TNF-alpha and IL-2. Thus, we postulate that the presence of pefloxacin in the pancreatic islet cells before organ preservation facilitates increased cell viability.

4-Quinolones↗
PubMed1996

The efficacy and potency of antiplatelet activity of ticlopidine is increased by aspirin.

Concomitant therapy with ticlopidine (T) and aspirin (ASA) profoundly increases spectrum of antiplatelet activities of both drugs. It was hypothesized that in addition to increased spectrum of activity (efficacy) each drug may potentiate the specific antiplatelet activity (potency) of the other. In 32 volunteers whole blood platelet aggregation (PA) in response to ADP, collagen, and arachidonic acid was evaluated ex vivo following 10-day treatments with normal or subthreshold doses of T or ASA with addition of second drug on the 5th day of administration of the first. PA was measured before, on day 5 and 10 of treatment. The results indicate that ASA increased spectrum of activity of T, i.e. T and ASA in combination, were significantly more effective against collagen-induced PA than either drug alone. This increased efficacy was retained when subthreshold dose of T (100 mg, qd) was used. T was without effect on AA-induced and ASA on ADP-induced PA. However, ASA potentiated effect of T on ADP-induced PA; the subthreshold dose of T (100 mg, qd) in presence of ASA (100 mg, qd) exerted powerful inhibition. Thus, combination therapy increases both efficacy and potency of T allowing for reduction of the dose.

Adenosine Diphosphate↗
PubMed1996

Pharmacodynamics of ticlopidine: relation between dose and time of administration to platelet inhibition.

In spite of long clinical experience with ticlopidine (T) knowledge of its pharmacodynamics is limited. In this study relation between dose and time of administration of T to platelet inhibition was investigated in 62 healthy volunteers ex vivo in whole blood and platelet rich plasma. Gender-related sensitivity of platelets to ticlopidine was also evaluated. Inhibition of ADP-induced platelet aggregation by T, 500 mg, daily, was almost identical in both sexes. 100 mg daily did not inhibit ADP-induced platelet aggregation even after 14 days of administration. 250 mg daily induced strong inhibition on day 5 of administration comparable to the inhibition obtained with 500 mg daily dose. The antiplatelet (ADP) effect of T (500 mg, daily) was present on day 2-3 and full inhibitory effect on day 4 of administration. T1/2 of antiplatelet (ADP) activity of T was 5.3 days and full recovery of platelets activity 11-13 days. No rebound phenomenon was present. T (regardless the dose) inhibited platelet aggregation induced by small but not high concentrations of collagen and was without effect on arachidonic acid-induced platelet aggregation. Therefore, T is not suitable for treatment of acute event, 250 mg daily dose should be used especially for combination with other drugs and 11 days washout interval seems necessary to change the treatment or to perform surgery.

Adenosine Diphosphate↗
PubMed1995

Clonidine hypotension in spontaneously hypertensive rats (SHR) depends on the functional state of GABAergic and glutamatergic systems.

The effect of gamma-aminobutyric acid (GABA)A receptors and of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor blockade on clonidine hypotension was studied. The experiments were performed on spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. We found that the blockade of GABAA receptors line significantly (P < 0.01) reduced hypotensive responses to clonidine. Similarly, the NMDA receptor antagonist dizocilpine (MK-801) completely abolished the blood pressure lowering effect of clonidine. Our findings support the conclusion that clonidine hypotension is closely related to the functional state of both inhibitory GABAergic and excitatory glutamatergic systems.

Animals↗