DGMP guideline for medical physical aspects of intravascular brachytherapy. Part I: Guideline.
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Blood Vessels↗
Biomedical subjects
U Quast
Publications and source records attributed to U Quast.
[Suspected diphtheria. Immediately start therapy!].
Only those strains of corynebacteria that carry the gene for diphtheria toxin may cause diphtheria. The only known reservoir of C. diphtheriae is man. The past decade has seen a return of diphtheria in the newly independent states of the former Soviet Union. Owing to a lack of immunization of the population, more than 150,000 people went down with the disease. In Germany, too, contact resulted in a number of cases and two deaths. The sole effective protection is immunization. Although more than 90% of children and adolescents are protected, only 40% to 60% of adults are.
Adolescent↗
Chromanol 293B, a blocker of the slow delayed rectifier K+ current (IKs), inhibits the CFTR Cl- current.
The cystic fibrosis transmembrane conductance regulator (CFTR) and the sulphonylurea receptor subunit (SUR) of the KATP channel are both members of the ATP-binding cassette (ABC) protein superfamily. Many compounds that open or block the KATP channel by binding to SUR also inhibit the CFTR Cl- current (ICFTR); an example in point is the chromanol-type KATP channel opener, cromakalim. The structurally related chromanol 293B (trans-6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethyl-chromane), a blocker of the slow component of the delayed rectifier K+ current (IKs) in the heart, is also a weak inhibitor of KATP. This suggests that 293B may affect also ICFTR- We have addressed this question with human CFTR expressed in Xenopus oocytes. In two-electrode voltage-clamp experiments, 293B inhibited ICFTR with an IC50-value of 19 microM and Hill coefficient of 1.0; the inhibition was weakened by increasing concentrations of isobutyl-methylxanthine (IBMX). Patch-clamp recordings gave an IC50-value of 30 microM but showed a unusual variability in the sensitivity to 293B. The data show that 293B inhibits ICFTR and suggest that the mechanism of inhibition may depend on the phosphorylation state of the CFTR protein. The concentrations required for inhibition of ICFTR are three- to fivefold higher than those reported for inhibition of KvLQT1 + minK expressed in Xenopus oocytes. Since CFTR is expressed also in cardiac myocytes, the effects of 293B in these cells must be analysed with caution.
Animals↗
Synthesis and characterization of a novel tritiated KATP channel opener with a benzopyran structure.
The synthesis of a tritiated benzopyran-type opener of the ATP-dependent K+ channel (KATP channel), [3H]-PKF217 - 744 (3S,4R)-N-[3,4-dihydro-2,2-dimethyl-3-hydroxy-6-(2-methyl-4-pyridinyl)-2H-1-benzopyran-4-yl]-3-[2,6-3H]pyridinecarboxamide with a specific activity of 50 Ci mmol(-1) is described. Binding of the ligand was studied in membranes from human embryonic kidney cells transfected with the sulphonylurea receptor isoforms, SUR2B and SUR2A, respectively. PKF217 - 744 was confirmed as being a KATP channel opener by its ability to open the Kir6.1/SUR2B channel, the recombinant form of the vascular KATP channel, and to inhibit binding of the pinacidil analogue, [3H]-P1075, to SUR2B (Ki=26 nM). The kinetics of [3H]-PKF217 - 744 binding to SUR2B was described by rate constants of association and dissociation of 6.9x10(6) M(-1) min(-1) and 0.09 min(-1), respectively. Binding of [3H]-PKF217 - 744 to SUR2B/2A was activated by MgATP (EC50 approximately 3 microM) and inhibited (SUR2B) or enhanced (SUR2A) by MGADP: Binding of [3H]-PKF217 - 744 to SUR2B was inhibited by representatives of the different structural classes of openers and sulphonylureas. Ki values were identical with those obtained using the opener [3H]-P1075 as the radioligand. Glibenclamide accelerated dissociation of the SUR2B-[3H]-PKF217 - 744 complex. The data show that the affinity of [3H]-PKF217 - 744 binding to SUR2B is approximately 6 times lower than that of [3H]-P1075. This is due to a surprisingly slow association rate of the benzopyran-type ligand, suggesting a complex mechanism of opener binding to SUR. The other pharmacological properties of the two opener radioligands are identical.
ATP-Binding Cassette Transporters↗
Characterization of a mutant sulfonylurea receptor SUR2B with high affinity for sulfonylureas and openers: differences in the coupling to Kir6.x subtypes.
ATP-dependent K(+) channels are composed of pore-forming subunits of the Kir6.x family and of sulfonylurea receptors (SURs). SUR1, expressed in pancreatic beta-cells, has a higher affinity for sulfonylureas, such as glibenclamide, than SUR2B, expressed in smooth muscle. This difference is mainly caused by serine 1237 in SUR1 corresponding to tyrosine 1206 in SUR2B. To increase the affinity of SUR2B for glibenclamide, the mutant SUR2B(Y1206S) was constructed. In whole-cell patch-clamp experiments, glibenclamide inhibited the channel formed by coexpression of mutant SUR2B with Kir6.1 or 6.2 in human embryonic kidney cells with IC(50) values of 2.7 and 13 nM, respectively (wild-type, 43 and 167 nM). In intact cells, [(3)H]glibenclamide bound to mutant SUR2B with a K(D) value of 4.7 nM (wild-type, 32 nM); coexpression with Kir6.1 or 6.2 increased affinity by 4- and 8-fold, respectively. Binding of the opener [(3)H]P1075 to SUR2B(Y1206S) was the same as to wild-type and was unaffected by coexpression. In cells, the ratio of glibenclamide:P1075 sites was approximately 1:1; in membranes, it varied with the MgATP concentration. Heterologous competition curves were generally biphasic; the shape of the curve depended on the Kir-subtype. The effects of coexpression were weakened or abolished when binding assays were conducted in membranes. It is concluded that the mutation Y1206S increases the affinity of SUR2B for and the channel sensitivity toward glibenclamide by 7- to 15-fold. The interaction of glibenclamide (but not opener) with mutant SUR2B is modified by coexpression with Kir6.x in a manner depending on the Kir subtype and on the integrity of the cell.
ATP-Binding Cassette Transporters↗
Interaction of the sulfonylthiourea HMR 1833 with sulfonylurea receptors and recombinant ATP-sensitive K(+) channels: comparison with glibenclamide.
The novel sulfonylthiourea 1-[[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea (HMR 1883), a blocker of ATP-sensitive K(+) channels (K(ATP) channels), has potential against ischemia-induced arrhythmias. Here, the interaction of HMR 1883 with sulfonylurea receptor (SUR) subtypes and recombinant K(ATP) channels is compared with that of the standard sulfonylurea, glibenclamide, in radioligand receptor binding and electrophysiological experiments. HMR 1883 and glibenclamide inhibited [(3)H]glibenclamide binding to SUR1 with K(i) values of 63 microM and 1.5 nM, and [(3)H]opener binding to SUR2A/2B with K(i) values of 14/44 microM and 0.5/2.8 microM, respectively (values at 1 mM MgATP). The interaction of HMR 1883 with the SUR2 subtypes was more sensitive to inhibition by MgATP and MgADP than that of glibenclamide. In inside-out patches and in the absence of nucleotides, HMR 1883 inhibited the recombinant K(ATP) channels from heart (Kir6.2/SUR2A) and nonvascular smooth muscle (Kir6.2/SUR2B) with IC(50) values of 0.38 and 1.2 microM, respectively; glibenclamide did not discriminate between these channels (IC(50) approximately 0.026 microM). In whole cells, the recombinant vascular K(ATP) channel, Kir6.1/SUR2B, was inhibited by HMR 1883 and glibenclamide with IC(50) values of 5.3 and 0.043 microM, respectively. The data show that the sulfonylthiourea exhibits a selectivity profile quite different from that of glibenclamide with a major loss of affinity toward SUR1 and slight preference for SUR2A. The stronger inhibition by nucleotides of HMR 1883 binding to SUR2 (as compared with glibenclamide) makes the sulfonylthiourea an interesting tool for further investigation.
ATP-Binding Cassette Transporters↗
[Vaccination record. Patient data series].
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Adolescent↗
Atypical effect of minoxidil sulphate on guinea pig airways.
The effects of minoxidil sulphate, an "atypical" K(ATP) channel opener, and bimakalim, a benzopyran-type classical K(ATP) channel opener, on guinea pig airways in vitro and in vivo and on isolated portal veins from rats and guinea pigs were compared. Minoxidil sulphate inhibited the spontaneous activity of isolated guinea pig and rat portal vein preparations with pD2 values of 7.83+/-0.08 and 7.14+/-0.03, respectively (Emax=100% in both preparations). Bimakalim caused a more potent inhibition with pD2 values of 8.80+/-0.05 and 8.20+/-0.04, respectively (Emax=100% in both preparations). Minoxidil sulphate reduced the spontaneous tone of isolated guinea pig tracheal rings with a pIC50 value of 3.92+/-0.02 and the same efficacy as isoprenaline. Bimakalim was more potent (pIC50=7.25+/-0.02) but less efficacious (Emax=75% of the Emax of isoprenaline). The airway relaxant effect of bimakalim, but not minoxidil sulphate, was antagonised by glibenclamide (pA2=7.50) at concentrations above 0.1 microM. Bombesin-induced bronchoconstriction in anaesthetised, ventilated, normoreactive guinea pigs (measured as increase in total lung resistance) was dose-dependently reversed by intratracheally (i.t.) administered bimakalim (ED50=4 microg/kg; Emax=92% of maximally possible inhibition), but not by minoxidil sulphate, at doses up to 1 mg/kg i.t. In the same animals, following i.t. administration of higher doses, both minoxidil sulphate and bimakalim reduced blood pressure. Airways hyperreactivity to histamine induced by acute treatment of guinea pigs with immune complex was dose-dependently reversed by bimakalim (ED50=0.5 microg/kg i.t., Emax=100%). This effect was antagonised by glibenclamide (30 mg/kg i.v.). Minoxidil sulphate had a biphasic effect on airways hyperreactivity: at 1 microg/kg i.t., airways hyperreactivity was augmented, whereas at doses above 3.2 microg/kg i.t. it caused reversal of airways hyperreactivity. Both of the effects of minoxidil sulphate were insensitive to glibenclamide (30 mg/kg i.v.). It is concluded that the pharmacological profile of minoxidil sulphate in guinea pig airways is completely different from that of classical K(ATP) channel openers such as bimakalim. Minoxidil sulphate is either only weakly active or even inactive at K(ATP) channels in guinea pig airways or interacts with these channels in a different manner. The current results are consistent with there being differences between the K(ATP) channels in airways and blood vessels.
Adenosine Triphosphate↗
Potent stimulation and inhibition of the CFTR Cl(-) current by phloxine B.
The effects of the fluoresceine derivative, phloxine B, on the Cl(-) current through the cystic fibrosis transmembrane conductance regulator (CFTR) were examined in Xenopus oocytes expressing human CFTR. In whole oocytes, the CFTR Cl(-) current (I(CFTR)) was activated by superfusion with isobutylmethylxanthine and forskolin. I(CFTR) was stable during activation and deactivated rapidly upon washout of the activation solution. Phloxine B slowed deactivation and, at high concentrations, inhibited I(CFTR) weakly. In excised inside-out macropatches, I(CFTR) was activated by the catalytic subunit of protein kinase A (cPKA) and MgATP. Phloxine B (0.01 - 3 microM), applied after activation, increased I(CFTR) within 30 s followed by a slow decrease which became dominant at high concentrations. Slowing of deactivation of the CFTR was observed at all concentrations. The effect of phloxine B after 30 s had a bell-shaped concentration-dependence with midpoints at 45 and 1600 nM for the stimulatory and the inhibitory limb, respectively; maximum stimulation was about 1.8 times. The slow inhibitory component, measured after 6 min, occurred with an IC(50) value of approximately 1 microM. In the absence of cPKA, phloxine B did not stimulate I(CFTR). In the presence of cPKA and MgATP, the effects of phloxine B were more prominent at low (0.02 mM) than at high ATP (2 mM). The data show that phloxine B modulates I(CFTR) by increasing channel activity and slowing channel deactivation; at high concentrations inhibition dominates. The effects may be mediated by direct interactions with CFTR from the inside of the cell.
ATP-Binding Cassette Transporters↗
A high-precision, high-resolution and fast dosimetry system for beta sources applied in cardiovascular brachytherapy.
A fast dosimetry system based on plastic scintillator detectors has been developed which allows three-dimensional measurement of the radiation field in water of beta-sources appropriate for application in cardiovascular brachytherapy. This system fulfills the AAPM Task Group 60 recommendations for dosimetry of cardiovascular brachytherapy sources. To demonstrate the use of the system, measurements have been performed with an 90Y-wire source. The dose distribution was determined with a spatial resolution of better than 0.2 mm, with only a few minutes needed per scan. The scintillator dosemeter was absolutely calibrated in terms of absorbed dose to water with a precision of +/-7.5%. The relative precision achievable is +/-2.5%. The response of the system is linear within +/-2% for dose rates from 0.5 mGy s(-1) to 500 mGy s(-1).
Beta Particles↗
In-phantom response of LiF TLD-100 for dosimetry of 192Ir HDR source.
An experiment was carried out to reevaluate the response of LiF TLD-100 rods (1 mmx1 mmx6 mm) at different depths in a water substituting phantom to provide an answer to a prevailing controversy about the over-response of LiF to the softened photon spectra of 192Ir HDR source at depths in phantom due to its photon energy dependence. Claims of some authors that LiF TLDs over-responds by 8.5% at 10 cm depth in phantom, necessitating depth-dependent correction factors even for an 192Ir source and of some others for no over-response were evaluated. The over-response of LiF TLD-100 rods, against a calibrated ion chamber having a photon energy-independent response within 2%, was found to be not exceeding 2.5% at a depth of 10 cm in the phantom as compared to a depth at 1 cm, for a precision of the order of +/- 1% (1sigma) in the TLD measurements. By using ISO equivalent photon beams, photon energy dependence of the dosimeters was evaluated and for LiF TLD-100 rods it was found to be in close agreement (within 3%) with the ratios of mass energy absorption coefficients of LiF and water in the range of effective photon energy from 26 keV to 1.25 MeV. Parameters that could contribute to the discrepancy in the reported values of experimental results have been discussed.
Biophysical Phenomena↗
[Structure of ATP-dependent potassium channels: SUR/Kir6 molecular complex].
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ATP-Binding Cassette Transporters↗
Vasorelaxation by new hybrid compounds containing dihydropyridine and pinacidil-like moieties.
The synthesis and pharmacological properties of a novel type of vasorelaxant hybrid compounds are described. The investigated compounds originate from fluorinated 4-aryl-1,4-dihydropyridines, which are known calcium channel blockers, and/or from fluorinated analogues of pinacidil, which is an opener of ATP-sensitive potassium channels. In particular, we studied the most potent hybrid, 2,6-dimethyl-3,5-dicarbomethoxy-4-(2-difluoromethoxy-5-N-(N' '-cyano-N'-1,2,2-trimethyl-propylguanidyl)-phenyl)-1, 4-dihydropyridine (4a), together with its parent compounds, the dihydropyridine 1b and the pinacidil analogue 3. In isolated rat mesenteric arteries, micromolar concentrations of 4a relaxed contractions exerted by K(+)-depolarization or by norepinephrine. The latter effect was sensitive to the potassium channel blocker glibenclamide. Micromolar 4a also inhibited [(3)H](+)-isradipine and [(3)H]P1075 binding to rat cardiac membranes, and it blocked L-type calcium channels expressed in a mammalian cell line. The respective parent compounds 1b and 3 were always more potent and more selective regarding calcium channel or potassium channel interaction, respectively. In contrast, 4a combined both effects within the same concentration range, indicating that it may represent a lead structure for a novel class of pharmacological hybrid compounds.
Animals↗
Pharmacological evidence for a KATP channel in renin-secreting cells from rat kidney.
1. Openers of the ATP-sensitive potassium channel (KATP channel) increase and blockers decrease renin secretion. Here we report the effects of levcromakalim (LCRK, a channel opener) and glibenclamide (GBC, a blocker) on membrane potential, whole-cell current and the cytoplasmic Ca2+ concentration of renin-secreting cells (RSC). Studies were performed on afferent arterioles from the kidney of Na+-depleted rats. 2. As monitored with the fluorescent oxonol dye DiBAC4(3), LCRK (0.3 and 1 microM) induced a hyperpolarization of approximately 15 mV which was abolished by GBC (1 microM). 3. Whole-cell current-clamp experiments showed that RSC had a membrane potential of -61 +/- 1 mV (n = 16). LCRK (1 microM) induced a hyperpolarization of 9.9 +/- 0.2 mV (n = 16) which, in the majority of cells, decreased slowly with time. 4. Capacitance measurements showed a strong electrical coupling of the cells in the preparation. 5. At -60 mV, LCRK induced a hyperpolarizing current in a concentration-dependent manner with an EC50 of 152 +/- 31 nM and a maximum current of about 200 pA. 6. Application of GBC (1 microM) produced no effect; however, when applied after LCRK (300 nM), GBC inhibited the opener-induced hyperpolarizing current with an IC50 of 103 +/- 36 nM. 7. LCRK (0.3 and 1 microM) did not significantly affect the cytoplasmic Ca2+ concentration either at rest or after stimulation by angiotensin II. 8. The data show that LCRK induces a GBC-sensitive hyperpolarizing current in rat RSC. This current presumably originates from the activation of KATP channels which pharmacologically resemble those in vascular smooth muscle cells. The stimulatory effect of KATP channel opening on renin secretion is not mediated by a decrease in intracellular Ca2+ concentration.
Angiotensin II↗
Potent inhibition of the CFTR chloride channel by suramin.
After phosphorylation by protein kinase A and in the presence of ATP, the cystic fibrosis transmembrane conductance regulator (CFTR) functions as a Cl- channel. In this study we have examined the effects of suramin on the CFTR Cl- current (I(CFTR)) in excised inside-out macropatches from Xenopus oocytes expressing human CFTR; glibenclamide, the standard inhibitor of I(CFTR), and some congeners were tested in comparison. I(CFTR) was activated by addition of the catalytic subunit of protein kinase A and MgATP to the bath. Suramin inhibited I(CFTR) with an IC50 value of 1 microM and a Hill coefficient close to 1; the inhibition showed little voltage dependence and was easily reversed upon washout of the drug. In comparison, glibenclamide inhibited I(CFTR) with an IC50 value of approximately 20 microM. When tested against I(CFTR) in whole oocytes, bath application of suramin was ineffective whereas glibenclamide was about four times weaker than in the inside-out patch configuration. The data show that suramin is the most potent inhibitor of CFTR yet described and suggest that the compound approaches its site of action from the cytosol.
Adenosine Triphosphate↗
Fluorescence 125I eye applicator.
A new approach to optimize curative eye plaque brachytherapy is presented. The application of ophthalmic plaques is a common therapy modality for small and medium sized intraocular tumors. At Essen University Hospital eye applicators with photon emitting 125I seeds are used for the treatment of tumors with a thickness from 5 to 10 mm. Our clinical experiences indicate that the dose distributions of these applicators-used so far worldwide-are not optimal. A steeper dose falloff would meet the radiobiological requirements better, to provide the eradication of all tumor cells as well as sufficient occlusion of tumor supplying blood vessels. Our investigations for eye plaque optimization are based both on measurements and Monte Carlo simulation. For fast dosimetric measurements we have built a computer controlled device which allows reading out, directly and simultaneously, 16 1 mm3 scintillators. For the numerical simulations of the dose distribution of 125I eye plaques we have adapted a Monte Carlo program originally developed to calculate the synchrotron radiation in particle physics. We have investigated the influence of geometrical as well as physical eye plaque parameters on the dose distribution: Shielding of the primary radiation, penumbra modification, and energy conversion by exploiting fluorescence x-radiation have been considered. New types of fluorescence eye applicators have been designed which are more suitable for the prevention of radiopathic effects on structures at risk.
Brachytherapy↗
ATP-Sensitive K+ channel modulator binding to sulfonylurea receptors SUR2A and SUR2B: opposite effects of MgADP.
KATP channels are heteromeric complexes of inwardly rectifying K+ channel subunits and sulfonylurea receptors (SURs). SUR2A and SUR2B, which differ within the carboxyl terminal exon 38, are characteristic for the cardiac and smooth muscle type channels, respectively. Here we compare binding of the tritiated KATP channel opener, [3H]P1075, to membranes from human embryonic kidney (HEK) cells transfected with murine SUR2A and 2B at 37 degrees C. Binding to both SURs required addition of Mg2+ and ATP in the low micromolar range. In the presence of MgATP, micromolar concentrations of MgADP, formed by the ATPase activity of the membrane preparation, increased binding to SUR2A but inhibited binding to SUR2B. Decreasing temperatures strongly reduced [3H]P1075 binding to SUR2A, whereas binding to SUR2B was increased in a bell-shaped manner. Kinetic experiments revealed a faster dissociation of the [3H]P1075-SUR2A complex, whereas the association rate constants for [3H]P1075 binding to SUR2A and 2B were similar. Openers inhibited [3H]P1075 binding to SUR2A with potencies approximately 4 times lower than to SUR2B; in contrast, glibenclamide inhibited [3H]P1075 binding to SUR2A approximately 8 times more potently than to SUR2B. The data suggest that SUR2A and 2B represent the opener receptors of cardiac and vascular smooth muscle KATP channels, respectively, and show that MgADP is an important modulator of opener binding to SUR. The different carboxyl termini of SUR2A and 2B lead to differences in the MgADP dependence and the thermodynamics of [3H]P1075 binding, as well as in the affinities for openers and glibenclamide, underlining the importance of this part of the molecule for KATP channel modulator binding.
ATP-Binding Cassette Transporters↗