125I radioactive seed localization (RSL) in surgery of cervical metastasis of thyroid cancer. / Localización con semillas radioactivas 125I (RSL) en cirugía de metástasis cervical de cáncer de tiroides.

INTRODUCTION: The aim of this work is the evaluation of usefulness of radioactive seed localization (RSL) for the detection of cervical recurrence of thyroid cancer in order to improve the surgical outcome. MATERIAL AND METHOD: Ten patients with thyroid cancer and lymph node involvement (4 naive and 6 with cervical recurrence) evidenced by ultrasound, cytology/Tg-FNAB (reoperated group) were selected for this procedure. A 125I seed was placed in the metastatic lesion using a needle guided by ultrasound. During surgery, a handheld gamma probe/portable gammacamera were used for lesion localization and excision. After removing the target tissue, it was verified that the seed was included in the excised tissue. Surgical intervention duration, lesion location, seed activity, thyroglobulin level, effective radiation dose, complications and the degree of surgical resection were analyzed. RESULTS: All the marked nodes were positive in histology. The mean duration of the ultrasound procedure was 11.4±3.4minutes. Seed was kept inside the patient, in average, during 4days (1-7) and the average surgical time was 44.7±29.1minutes. We found 21 metastatic specimens with an average diameter 13.9±6.3mm. The mean activity of the implanted seed was 71.27±21.6MBq (42.8-105) In the reoperated group, thyroglobulin level was 2.08±1.56ng/dl and decreased after surgery to 0.13±0.12ng/dl, P<.01. Only one case of transient hypoparathyroidism was found in the total group. CONCLUSIONS: The introduction of RSL in our unit has shown benefits for the patient and medical team, being a safe and effective procedure that also improves surgical programming.

10-MV SBRT FFF IRRADIATION TECHNIQUE IS ASSOCIATED TO THE LOWEST PERIPHERAL DOSE: THE OUTCOME OF 142 TREATMENT PLANS FOR THE 10 MOST COMMON TUMOUR LOCATIONS.

There is a growing interest in the combined use of Stereotactic Body Radiation Therapy (SBRT) with Flattening Filter Free (FFF) due to the high local control rates and reduced treatment times, compared to conventionally fractionated treatments. It has been suggested that they may also provide a better radiation protection to radiotherapy patients as a consequence of the expected decrease in peripheral doses. This work aims to determine this reduction in unattended out-of-field regions, where no CT information is available but an important percentage of second primary cancers occur. For that purpose, ten different cases suitable for SBRT were chosen. Thus, 142 different treatment plans including SBRT, as well as 3D-CRT, IMRT and VMAT (with standard fractionation) in low and high energies for Varian (FF and FFF), Siemens and Elekta machines were created. Then, photon and neutron peripheral dose in 14 organs were assessed and compared using two analytical models. For the prostate case, uncomplicated and cancer free control probability estimation was also carried out. As a general behavior, SBRT plans led to the lowest peripheral doses followed by 3D-CRT, VMAT and IMRT, in this order. Unflattened beams proved to be the most effective in reducing peripheral doses, especially for 10 MV. The obtained results suggest that FFF beams for SBRT with 10 MV represent the best compromise between dose delivery efficiency and peripheral dose reduction.

External photon radiation treatment for prostate cancer: Uncomplicated and cancer-free control probability assessment of 36 plans.

PURPOSE: To perform a systematic and thorough assessment, using the Uncomplicated and Cancer-Free Control Probability (UCFCP) function, of a broad range of photon prostate cancer RT treatments, on the same scenario (a unique pelvic CT set). UCFCP considers, together with the probabilities of local tumour control (TCP) and deterministic (late) sequelae (NTCP), the second primary cancer risk (SPCR) due to photon and neutron peripheral doses. METHODS AND MATERIALS: Thirty-six radiotherapy plans were produced for the same CT. 6, 10, 15 and 18 MV 3DCRT, IMRT and VMAT (77.4 Gy in 43 fractions) and 6 and 10 MV SBRT (36.25 Gy in 5 fractions with flattened and FFF beams) for Elekta, Siemens and Varian Linacs plans were included. DVH and peripheral organ dosimetry were used to compute TCP, NTCP, and SPCR (the competition and LNT models) for further plan ranking. RESULTS: Biological models (and parameters) used predicted an outcome which is in agreement with epidemiological findings. SBRT plans showed the lowest SPCR and a below average NTCPrectal. High energy plans did not rank worse than the low energy ones. Intensity modulated plans were ranked above the 3D conformal techniques. CONCLUSIONS: According to UCFCP, the best plans were the10 MV SBRTs. SPCR rates were low and did not show a substantial impact on plan ranking. High energy intensity-modulated plans did not increase in excess the average of SPCR. Even more, they ranked among the best, provided that MU were efficiently managed.

Peripheral equivalent neutron dose model implementation for radiotherapy patients.

PURPOSE: Neutron peripheral contamination in high-energy radiotherapy implies an increase of secondary radiation-induced cancer risk. Although peripheral neutron dose (PND) has been evaluated in organs, few studies have been performed regarding patient size. This work aims to improve an existing methodology for adult patient PND estimations to generalize it to young and children, for its implementation in treatment planning systems (TPS). METHODS: As a first step, we aimed to generalize the previous model to be usable with any thermal neutron detector. Then, taking into account total neutron spectra and dose-to-point thermal neutron fluence measurements for three phantom sizes (adult, teen and child) and two common treatment locations (H&N and abdomen), the new model was proposed. It represents an upgraded parameterization and extension of the existing one, including patient anatomy. Finally, comparison between estimations and measurements, as well as validation against the original model, was carried out for 510 measured patients. RESULTS: Concordance found between experimental and theoretical estimations makes us confident about later implementation in treatment planning systems. Comparison among the previous and upgraded models shows no significant differences for the adult case. However, an important underestimation (34.1% on average) can be observed regarding child case for the original one. CONCLUSIONS: An improved generalization of an existing PND model, considering patient anatomy has been validated and used in real patients. The final methodology is easily implementable in clinical routine and TPS thanks to the ready availability of input parameters (patient height and weight, high-energy MU and facility characterization).

Neutron measurements in radiotherapy: A method to correct neutron sensitive devices for parasitic photon response.

One of the major causes of secondary malignancies after radiotherapy treatments are peripheral doses, known to increase for some newer techniques (such as IMRT or VMAT). For accelerators operating above 10MV, neutrons can represent important contribution to peripheral doses. This neutron contamination can be measured using different passive or active techniques, available in the literature. As far as active (or direct-reading) procedures are concerned, a major issue is represented by their parasitic photon sensitivity, which can significantly affect the measurement when the point of test is located near to the field-edge. This work proposes a simple method to estimate the unwanted photon contribution to these neutrons. As a relevant case study, the use of a recently neutron sensor for "in-phantom" measurements in high-energy machines was considered. The method, called "Dual Energy Photon Subtraction" (DEPS), requires pairs of measurements performed for the same treatment, in low-energy (6MV) and high energy (e.g. 15MV) fields. It assumes that the peripheral photon dose (PPD) at a fixed point in a phantom, normalized to the unit photon dose at the isocenter, does not depend on the treatment energy. Measurements with ionization chamber and Monte Carlo simulations were used to evaluate the validity of this hypothesis. DEPS method was compared to already published correction methods, such as the use of neutron absorber materials. In addition to its simplicity, an advantage of DEPs procedure is that it can be applied to any radiotherapy machine.

Monte Carlo correction factors for a Farmer 0.6 cm3 ion chamber dose measurement in the build-up region of the 6 MV clinical beam.

Reference dosimetry of photon fields is a well-established subject and currently available protocols (such as the IAEA TRS-398 and AAPM TG-51) provide methods for converting the ionization chamber (IC) reading into dose to water, provided reference conditions of charged particle equilibrium (CPE) are fulfilled. But these protocols cannot deal with the build-up region, where the lack of CPE limits the applicability of the cavity theorems and so the chamber correction factors become depth dependent. By explicitly including the IC geometry in the Monte Carlo simulations, depth-dependent dose correction factors are calculated for a PTW 30001 0.6 cm(3) ion chamber in the build-up region of the 6 MV photon beam. The corrected percentage depth dose (PDD) agrees within 2% with that measured using the NACP 02 plane-parallel ion chamber in the build-up region at depths greater than 0.4 cm, where the Farmer chamber wall reaches the phantom surface.

Improving the neutron-to-photon discrimination capability of detectors used for neutron dosimetry in high energy photon beam radiotherapy.

The increasing interest of the medical community to radioinduced second malignancies due to photoneutrons in patients undergoing high-energy radiotherapy, has stimulated in recent years the study of peripheral doses, including the development of some dedicated active detectors. Although these devices are designed to respond to neutrons only, their parasitic photon response is usually not identically zero and anisotropic. The impact of these facts on measurement accuracy can be important, especially in points close to the photon field-edge. A simple method to estimate the photon contribution to detector readings is to cover it with a thermal neutron absorber with reduced secondary photon emission, such as a borated rubber. This technique was applied to the TNRD (Thermal Neutron Rate Detector), recently validated for thermal neutron measurements in high-energy photon radiotherapy. The positive results, together with the accessibility of the method, encourage its application to other detectors and different clinical scenarios.

Using a Tandem Pelletron accelerator to produce a thermal neutron beam for detector testing purposes.

Active thermal neutron detectors are used in a wide range of measuring devices in medicine, industry and research. For many applications, the long-term stability of these devices is crucial, so that very well controlled neutron fields are needed to perform calibrations and repeatability tests. A way to achieve such reference neutron fields, relying on a 3 MV Tandem Pelletron accelerator available at the CNA (Seville, Spain), is reported here. This paper shows thermal neutron field production and reproducibility characteristics over few days.

Radiation doses in the surroundings of patients undergoing nuclear medicine diagnostic studies.

Dose rate measurements were performed at 0, 0.5, and 1 m from the external surface of 79 patients corresponding to the most frequent studies: 99mTc-cardiac with reinjection, 99mTc-cardiac single injection, 99mTc-bone scan, 99mTc-lung studies, and cardiac studies using 201Tl. Doses to staff, nearby patients, and the collective effective doses were estimated for the different working shifts and hospital areas. The estimated dose for nurses for 1 y was 518 microSv in the cardiology section and 338 microSv in the short stay section. For patients, the mean dose per stay was calculated to be 8.5 microSv in the cardiology section. The maximum dose that a patient could receive from a radioactive patient is 499 microSv for a double injection cardiac patient study. The maximum collective effective dose for the whole hospital was calculated to be 0.063 person-Sv. The probability of staff receiving doses higher than the limits for a working day is negligible. Maximum doses for staff and patients are far below dose limits for the public and therefore no additional radiological protection is needed.

Commissioning the neutron production of a Linac: development of a simple tool for second cancer risk estimation.

PURPOSE: Knowing the contribution of neutron to collateral effects in treatments is both a complex and a mandatory task. This work aims to present an operative procedure for neutron estimates in any facility using a neutron digital detector. METHODS: The authors' previous work established a linear relationship between the total second cancer risk due to neutrons (TR(n)) and the number of MU of the treatment. Given that the digital detector also presents linearity with MU, its response can be used to determine the TR(n) per unit MU, denoted as m, normally associated to a generic Linac model and radiotherapy facility. Thus, from the number of MU of each patient treatment, the associated risk can be estimated. The feasibility of the procedure was tested by applying it in eight facilities; patients were evaluated as well. RESULTS: From the reading of the detector under selected irradiation conditions, m values were obtained for different machines, ranging from 0.25 × 10(-4)% per MU for an Elekta Axesse at 10 MV to 6.5 × 10(-4)% per MU for a Varian Clinac at 18 MV. Using these values, TR(n) of patients was estimated in each facility and compared to that from the individual evaluation. Differences were within the range of uncertainty of the authors' methodology of equivalent dose and risk estimations. CONCLUSIONS: The procedure presented here allows an easy estimation of the second cancer risk due to neutrons for any patient, given the number of MU of the treatment. It will enable the consideration of this information when selecting the optimal treatment for a patient by its implementation in the treatment planning system.

Peripheral administration of an angiotensin II AT(1) receptor antagonist decreases the hypothalamic-pituitary-adrenal response to isolation Stress.

Angiotensin II, which stimulates AT(1) receptors, is a brain and peripheral stress hormone. We pretreated rats with the AT(1) receptor antagonist candesartan for 13 d via sc-implanted osmotic minipumps, followed by 24-h isolation in individual metabolic cages. We measured angiotensin II receptor-type binding and mRNAs and tyrosine hydroxylase mRNA by quantitative autoradiography and in situ hybridization, catecholamines by HPLC, and hormones by RIA. Isolation increased AT(1) receptor binding in hypothalamic paraventricular nucleus as well as anterior pituitary ACTH, and decreased posterior pituitary AVP. Isolation stress also increased AT(1) receptor binding and AT(1B) mRNA in zona glomerulosa and AT(2) binding in adrenal medulla, adrenal catecholamines, tyrosine hydroxylase mRNA, aldosterone, and corticosterone. Candesartan blocked AT(1) binding in paraventricular nucleus and adrenal gland; prevented the isolation-induced alterations in pituitary ACTH and AVP and in adrenal corticosterone, aldosterone, and catecholamines; abolished the increase in AT(2) binding in adrenal medulla; and substantially decreased urinary AVP, corticosterone, aldosterone, and catecholamines during isolation. Peripheral pretreatment with an AT(1) receptor antagonist blocks brain and peripheral AT(1) receptors and inhibits the hypothalamic-pituitary-adrenal response to stress, suggesting a physiological role for peripheral and brain AT(1) receptors during stress and a possible beneficial effect of AT(1) antagonism in stress-related disorders.

Role of 5-ht7 receptors in the long-lasting hypotensive response induced by 5-hydroxytryptamine in the rat.

1. The receptor mediating the long-lasting hypotensive effect of intravenous (i.v.) 5-hydroxytryptamine (5-HT) in the rat was originally classified as 5-HT1-like. Since some pharmacological properties of this receptor are closely similar to those for the cloned 5-ht7 receptor, the present study investigated the effects of several 5-HT receptor agonists and antagonists showing high affinity for the cloned 5-ht7 receptor in pithed rats with artificially raised blood pressure. 2. I.v. bolus administration of 5-HT, 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine, lisuride and sumatriptan to bilaterally vagotomized pithed rats pretreated with ketanserin (0.18 mumol kg-1, i.v.), the diastolic blood pressure of which had been raised by a continuous i.v. infusion of methoxamine (60-80 nmol kg-1 min-1), produced dose-dependent hypotensive responses; only 5-HT and 5-CT displayed similar maximum effects. In addition to mimicking the hypotensive action of 5-HT with a lower maximum effect, lisuride strongly antagonized the 5-CT-induced hypotensive responses thus suggesting a partial agonist effect. The rank order of hypotensive agonist potency was 5-CT > > 5-HT > or = 5-methoxytryptamine > or = lisuride > > sumatriptan. 3. In experiments with antagonists, i.v. treatment with metergoline (2.48 mumol kg-1), mesulergine (2.76 mumol kg-1), methysergide (2.13 mumol kg-1), lisuride (0.22 mumol kg-1), methiothepin (0.68 mumol kg-1), mianserin (10.6 mumol kg-1), or the atypical antipsychotic drugs, clozapine (11.0 mumol kg-1) or risperidone (78.0 nmol kg-1), produced significant rightward displacements of the dose-response curve for 5-CT in methoxamine-infused pithed animals pretreated with ketanserin (0.18 mumol kg-1, i.v.); lisuride, methiothepin and risperidone behaved as non-competitive antagonists as they elicited a significant reduction of the maximum effect to 5-CT. In contrast, blockade of 5-HT1, 5-HT3 and 5-HT4 receptors with i.v. propranolol (3.38 mumol kg-1), MDL-72222 (1.59 mumol kg-1) and GR125487 (1.91 mumol kg-1), respectively, did not alter 5-CT-induced hypotensive responses; ketanserin (0.18 mumol kg-1, i.v.) failed to modify the dose-response curve for 5-CT in saline-pretreated animals. Lastly, inhibition of the prostaglandin-forming cyclo-oxygenase and nitric oxide synthase with indomethacin (14 mumol kg-1, i.v.) and NG-nitro-L-arginine methyl ester (L-NAME, 120 mumol kg-1, i.v.), respectively, had no significant effects on 5-CT-induced hypotensive effects. 4. Taken together, the present pharmacological data suggest that the long-lasting vasodepressor action of 5-HT in the rat involves activation of receptors closely similar to the cloned 5-ht7 subtype. Since no evidence for an indirect mechanism could be obtained, these receptors may be primarily located in the vascular smooth muscle of the systemic resistance vessels. These findings represent further evidence favouring the functional role of the 5-ht7 receptor.

The relaxant 5-HT receptor in the dog coronary artery smooth muscle: pharmacological resemblance to the cloned 5-ht7 receptor subtype.

1. The relaxant effect of 5-hydroxytryptamine (5-HT) in the dog isolated coronary artery deprived of endothelium is mediated by a receptor unrelated to the 5-HT1, 5-HT2, 5-HT3 or 5-HT4 types. Based upon the pharmacological characteristics of this relaxant 5-HT receptor and those reported for the new members of the 5-HT receptor family, the present study explored the possibility that the relaxant 5-HT receptor referred to above, corresponds to the cloned 5-ht7 subtype. Thus, the relaxing and/or blocking effects of several 5-HT receptor drugs as well as some typical and atypical antipsychotic drugs with high affinity for the cloned 5-ht7 receptor in precontracted ring segments were analyzed. 2. 5-HT, 5-carboxamidotryptamine (5-CT) and 5-methoxytryptamine, but not 8-OH-DPAT or sumatriptan, produced concentration-dependent relaxations in endothelium-denuded canine coronary artery rings precontracted with prostaglandin F2a (2 microM). Clozapine (1 microM) produced in some cases a small relaxing effect and antagonized 5-HT- and 5-CT-induced relaxation suggesting a partial agonist effect. In the presence of the 5-HT1D receptor antagonist, GR127935 (100 nM), the rank order of agonist potency was 5-CT > 5-HT > clozapine > or = 5-methoxytryptamine. 8-OH-DPAT and sumatriptan remained inactive as agonists. 3. In GR127935-treated preparations, methiothepin (3 nM) and mianserin (1 microM), as well as the antipsychotics, clozapine (1 microM), pimozide (300 nM), risperidone (3 nM) and spiperone (1 microM), failed to induce a significant relaxation in prostaglandin F2x-precontracted vessels, but produced significant rightward displacements of the concentration-response curves to 5-HT and 5-CT without significantly reducing the Emax. In a final set of experiments with 5-CT, metergoline (100 nM) and mesulergine (300 nM) behaved as competitive antagonists. In contrast, lisuride (3 nM) noncompetitively antagonized 5-CT-induced relaxation. The estimated affinity (apparent pKa values) of the above antagonist drugs for the relaxant 5-HT receptor significantly correlated with their reported affinity at the cloned 5-ht7 receptor. 4. Taken together, the above pharmacological data may suggest that the relaxant 5-HT receptor in the smooth muscle of the canine coronary artery is similar to the cloned 5-ht7 receptor subtype.

The 5-HT1-like receptor mediating the increase in canine external carotid blood flow: close resemblance to the 5-HT1D subtype.

1. It has recently been shown that the increase in external carotid blood flow induced by 5-hydroxy-tryptamine (5-HT) in the anaesthetized dog, being mimicked by 5-carboxamidotryptamine (5-CT), inhibited by methiothepin, vagosympathectomy and sympatho-inhibitory drugs, and resistant to blockade by ritanserin and MDL 72222, is mediated by stimulation of prejunctional 5-HT1-like receptors leading to an inhibitory action on carotid sympathetic nerves; these 5-HT1-like receptors are unrelated to either the 5-HT1A, 5-HT1B or 5-HT1C (now 5-HT2C) receptor subtypes. Inasmuch as 5-CT, 5-methoxytryptamine, sumatriptan and metergoline display high affinity, amongst other 5-HT binding sites, for the 5-HT1D subtype, in the present study we have used these drugs in an attempt to determine whether the above inhibitory prejunctional 5-HT1-like receptors correlate with the 5-HT1D subtype. 2. One-minute intracarotid (i.c.) infusions of 5-HT (0.3, 1, 3 and 10 micrograms), 5-CT (0.01, 0.03, 0.1 and 0.3 micrograms), 5-methoxytryptamine (1, 3, 10 and 30 micrograms) and sumatriptan (1, 3, 10, 30 and 100 micrograms) resulted in dose-dependent increases in external carotid blood flow (without changes in mean arterial blood pressure or heart rate) with the following rank order of agonist potency: 5-CT >> 5-HT > 5-methoxytryptamine > or = sumatriptan. Interestingly, sumatriptan-induced vasodilatation was followed by a more pronounced vasoconstriction. 3. The external carotid vasodilator effects of 5-HT, 5-CT, 5-methoxytryptamine and sumatriptan were dose-dependently and specifically antagonized by metergoline (10, 30 and/or 100 micrograms kg-1, i.v.). In addition, 5-methoxytryptamine- and sumatriptan-induced vasodilator effects were, respectively, markedly inhibited or abolished after vagosympathectomy, as previously shown for 5-CT and 5-HT.4. Sumatriptan showed tachyphylaxis in its vasodilator component and antagonized 5-HT-induced external carotid vasodilatation in a specific manner, suggesting that a common site of action may be involved.5. Taken together, the above results support our contention that 5-HT, 5-CT, 5-methoxytryptamine and sumatriptan produce external carotid vasodilatation in the dog by an action that might primarily involve a prejunctional inhibition on carotid sympathetic nerves; a secondary component of this vasodilator response may be postsynaptic (endothelium-dependent and/or even directly on the vasculature).Based on the rank order of agonist potency, inhibition by vagosympathectomy and blockade by metergoline, we suggest that the inhibitory prejunctional 5-HT1-like receptors mediating external carotid vasodilatation in the dog closely resemble the 5-HTID receptor subtype. The pharmacological profile of these receptors is similar (sympathetic nerves of the rat kidney and human saphenous vein, as well as porcine coronary endothelium) to other putative 5-HTID receptors mediating vascular responses.

Pharmacological evidence for the 5-HT7 receptor mediating smooth muscle relaxation in canine cerebral arteries.

1. We investigated in the present study whether 5-HT is able to exert direct relaxant responses in canine basilar and middle cerebral arteries via the 5-HT7 receptor. 2. In arterial rings deprived of endothelium and pre-contracted with prostaglandin F2 alpha (2 microM), 5-HT, 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine, sumatriptan or alpha-methyl-5-HT produced further increase in tone and/or slight relaxation. Blockade of 5-HT1B 1D and 5-HT2A receptors with GR127935 (1 microM) and ketanserin (0.1 microM), respectively, antagonized the vasoconstrictor component of the response and unmasked a concentration-dependent relaxation to 5-HT, 5-CT and 5-methoxytryptamine; sumatriptan and alpha-methyl-5-HT remained inactive as relaxant agonists. The rank order of agonist potency in both arteries was 5-CT > 5-HT > 5-methoxytryptamine >> sumatriptan > or = alpha-methyl-5-HT. 3. In dog basilar artery, pre-incubated with GR127935 (1 microM) and ketanserin (0.1 microM) and precontracted with prostaglandin F2 alpha (2 microM), the 5-HT7 ligands, clozapine (1 microM), mesulergine (0.3 microM), methiothepin (3 nM), risperidone (3 nM), spiperone (1 microM) and LY215840 (10-100 nM), produced significant rightward shifts of the concentration-response curves for 5-HT and 5-CT. Only methiothepin and risperidone reduced significantly the maximum relaxant response (Emax), whilst the other drugs behaved as competitive antagonists with affinity values (pKB) that significantly correlated with their binding affinity (pKi) at recombinant 5-HT7 receptors. 4. These data disclosing the involvement of the 5-HT7 receptor in cerebrovascular relaxation may be strongly relevant in the light of: (1) the involvement of 5-HT in migraine; (2) the putative linkage between cephalovascular vasodilatation and migraine headache; and (3) the relatively high 5-HT7 receptor affinity of migraine prophylactic 5-HT antagonists.

Mediation of 5-HT-induced external carotid vasodilatation in GR 127935-pretreated vagosympathectomized dogs by the putative 5-HT7 receptor.

1. The vasodilator effects of 5-hydroxytryptamine (5-HT) in the external carotid bed of anaesthetized dogs with intact sympathetic tone are mediated by prejunctional sympatho-inhibitory 5-HT1B/1D receptors and postjunctional 5-HT receptors. The prejunctional vasodilator mechanism is abolished after vagosympathectomy which results in the reversal of the vasodilator effect to vasoconstriction. The blockade of this vasoconstrictor effect of 5-HT with the 5-HT1B/1D receptor antagonist, GR 127935, unmasks a dose-dependent vasodilator effect of 5-HT, but not of sumatriptan. Therefore, the present study set out to analyse the pharmacological profile of this postjunctional vasodilator 5-HT receptor in the external carotid bed of vagosympathectomized dogs pretreated with GR 127935 (20 micrograms kg-1, i.v.). 2. One-minute intracarotid (i.c.) infusions of 5-HT (0.3-30 micrograms min-1), 5-carboxamidotryptamine (5-CT; 0.01-0.3 microgram min-1), 5-methoxytryptamine (1-100 micrograms min-1) and lisuride (3-1000 micrograms min-1) resulted in dose-dependent increases in external carotid blood flow (without changes in blood pressure or heart rate) with a rank order of agonist potency of 5-CT > > 5-HT > or = 5-methoxytryptamine > lisuride, whereas cisapride (100-1000 micrograms min-1, i.c.) was practically inactive. Interestingly, lisuride (mean dose of 85 +/- 7 micrograms kg-1, i.c.), but not cisapride (mean dose of 67 +/- 7 micrograms kg-1, i.c.), specifically abolished the responses induced by 5-HT, 5-CT and 5-methoxytryptamine, suggesting that a common site of action may be involved. In contrast, 1 min i.c. infusions of 8-OH-DPAT (3-3000 micrograms min-1) produced dose-dependent decreases, not increases, in external carotid blood flow and failed to antagonize (mean dose of 200 +/- 33 micrograms kg-1, i.c.) the agonist-induced vasodilator responses. 3. The external carotid vasodilator responses to 5-HT, 5-CT and 5-methoxytryptamine were not modified by intravenous (i.v.) pretreatment with either saline, (+/-)-pindolol (4 mg kg-1) or ritanserin (100 micrograms kg-1) plus granisetron (300 micrograms kg-1), but were dose-dependently blocked by i.v. administration of methiothepin (10 and 30 micrograms kg-1, given after ritanserin plus granisetron), mesulergine (10 and 30 micrograms kg-1), metergoline (1 and 3 mg kg-1), methysergide (1 and 3 mg kg-1) or clozapine (0.3 and 1 mg kg-1). Nevertheless, the blockade of the above responses, not significant after treatment with the lower of the two doses of metergoline and mesulergine, was nonspecific after administration of the higher of the two doses of methysergide and clozapine. 4. Based upon the above rank order of agonist potencies and the antagonism produced by a series of drugs showing high affinity for the cloned 5-ht7 receptor, our results indicate that the 5-HT receptor mediating external carotid vasodilatation in GR 127935-pretreated vagosympathectomized dogs is operationally similar to the putative 5-HT7 receptor mediating relaxation of vascular and non-vascular smooth muscles (e.g. rabbit femoral vein, canine coronary artery, rat systemic vasculature and guinea-pig ileum) as well as tachycardia in the cat.

Characterization of prejunctional 5-HT receptors mediating inhibition of sympathetic vasopressor responses in the pithed rat.

1. It has recently been shown that continuous infusions of 5-hydroxytryptamine (5-HT) are able to inhibit, in a dose-dependent manner, the pressor responses induced by preganglionic (T7-T9) sympathetic stimulation in pithed rats pretreated with desipramine (50 micrograms kg-1, i.v.). This inhibitory effect, besides being significantly more pronounced at lower frequencies of stimulation (0.03-I Hz) and devoid of tachyphylaxis, is reversible after interrupting the infusions of 5-HT (up to 5.6 micrograms kg-1 min-1). In the present study we have characterized the pharmacological profile of the receptors mediating the above inhibitory effect of 5-HT. 2. The inhibition induced by 5.6 micrograms kg-1 min-1 of 5-HT on sympathetically-induced pressor responses was not blocked after i.v. treatment with physiological saline (1 ml kg-1), ritanserin (0.1 mg kg-1), MDL 72222 (0.15 mg kg-1) or tropisetron (3 mg kg-1), which did not modify the sympathetically-induced pressor responses per se, but was significantly antagonized by the 5-HT1-like and 5-HT2 receptor antagonist, methysergide (0.3 mg kg-1), which also produced a slight attenuation of the pressor responses to 0.03 and 0.1 Hz per se. 3. Unexpectedly and contrasting with methysergide, the 5-HT1-like and 5-HT2 receptor antagonists, methiothepin (0.01, 0.03 and 0.1 mg kg-1) and metergoline (1 and 3 mg kg-1), apparently failed to block the above 5-HT-induced inhibition. Nevertheless, it is noteworthy that these antagonists also blocked the electrically-induced pressor responses per se, presumably by blockade of vascular alpha 1-adrenoceptors and, indeed, this property might have masked their potential antagonism at the inhibitory 5-HT1-like receptors. 4. Consistent with the above findings, 5-carboxamidotryptamine (5-CT, a potent 5-HT1-like receptor agonist), metergoline and methysergide mimicked the inhibitory action of 5-HT with the following rank order of agonist potency: 5CT > > 5-HT > metergoline > or = methysergide. 5. Taken together, the above results suggest that the inhibitory action of 5-HT on the electrically-induced pressor responses is primarily mediated by an action on inhibitory prejunctional 5-HT1-like receptors leading to a decrease in the sympathetic nerve discharge. Interestingly, 5-HT-induced excitatory mechanisms could be made manifest once the inhibitory action of 5-HT had been antagonized.

Pharmacological profile of the receptors that mediate external carotid vasoconstriction by 5-HT in vagosympathectomized dogs.

1. 5-Hydroxytryptamine (5-HT) can produce vasodilatation or vasoconstriction of the canine external carotid bed depending upon the degree of carotid sympathetic tone. Hence, external carotid vasodilatation to 5-HT in dogs with intact sympathetic tone is primarily mediated by prejunctional 5-HT1-like receptors similar to the 5-HT1D subtype, which inhibit the carotid sympathetic outflow. The present investigation is devoted to the pharmacological analysis of the receptors mediating external carotid vasoconstriction by 5-HT in vagosympathectomized dogs. 2. Intracarotid (i.c.) infusions for 1 min of 5-HT (0.3, 1, 3, 10, 30 and 100 micrograms) resulted in dose-dependent decreases in both external carotid blood flow and the corresponding conductance; both mean arterial blood pressure and heart rate remained unchanged during the infusions of 5-HT. These responses to 5-HT were resistant to blockade by antagonists at 5-HT2 (ritanserin) and 5-HT3/5-HT4 (tropisetron) receptors, but were partly blocked by the 5-HT1-like and 5-HT2 receptor antagonist, methiothepin (0.3 mg kg-1); higher doses of methiothepin (1 and 3 mg kg-1) caused little, if any, further blockade. These methiothepin (3 mg kg-1)-resistant responses to 5-HT were not significantly antagonized by MDL 72222 (0.3 mg kg-1) or tropisetron (3 mg kg-1). 3. The external carotid vasoconstrictor effects of 5-HT were mimicked by the selective 5-HT1-like receptor agonist, sumatriptan (3, 10, 30 and 100 micrograms during 1 min, i.c.), which produced dose-dependent decreases in external carotid blood flow and the corresponding conductance; these effects of sumatriptan were dose-dependently antagonized by methiothepin (0.3, 1 and 3 mg kg-1), but not by 5-HT1D-like receptor blocking doses of metergoline (0.1 mg kg-1). 4. The above vasoconstrictor effects of 5-HT remained unaltered after administration of phentolamine, propranolol, atropine, hexamethonium, brompheniramine, cimetidine and haloperidol, thus excluding the involvement of alpha- and beta-adrenoceptors, muscarinic, nicotinic, histamine and dopamine receptors. Likewise, inhibition of either 5-HT-uptake (with fluoxetine) or cyclo-oxygenase (with indomethacin), depletion of biogenic amines (with reserpine) or blockade of calcium channels (with verapamil) did not modify the effects of 5-HT. 5. Taken together, the above results support our contention that the external carotid vasoconstrictor responses to 5-HT in vagosympathectomized dogs are mainly mediated by activation of sumatriptan-sensitive 5-HT1-like receptors. It must be emphasized, notwithstanding, that other mechanisms of 5-HT, including an interaction with a novel 5-HT receptor (sub)type and/or an indirect action that may lead to the release of a known (or even unknown) neurotransmitter substance cannot be categorically excluded.

A CT-aided PC-based physical treatment planning of TBI: a method for dose calculation.

BACKGROUND AND PURPOSE: As for conventional radiotherapy, one of the basic requirements in Total Body Irradiation (TBI) is to know accurately the dose delivered to the entire body. Both the dosimetry and the treatment planning need to be improved. Physical, technical and dosimetrical aspects of TBI have been widely discussed in the literature. However, to our knowledge, no planning systems specifically designed for TBI are commercially available. This article describes a CT-aided PC-based planning system (TBI-Plansys) and its dose calculation algorithm, which applies scatter and inhomogeneity corrections, developed for the TBI technique currently in use at our centre (AP/PA irradiation with patient positioned on his side). MATERIAL AND METHOD: A description of the material and method followed in the dosimetrical procedure is included as it constitutes the basis of the proposed dose calculation algorithm (more than 2D). A Windows programming environment has been used to develop the software. RESULTS: TBI-Plansys uses patient CT data and indicates absolute and relative dose distributions along midline (at reference points), the transversal axis at the specification point and on transverse sections. The system also calculates the appropriate thicknesses of bolus and shielding to modify undesired dose distributions. TBI-Plansys has been checked against two other well-established systems (beam-zone method and our in vivo semiconductor probe-based system). The checks showed good accuracy with dose differences less than 1% and 3% for homogeneous and inhomogeneous tissues, respectively. CONCLUSIONS: CT calculations by TBI-Plansys allow us to detect undesired distributions which may go unnoticed by calculations at only some specific points. The system has shown clear advantages for routine clinical use as it generates more detailed and accurate information than manual calculations and diminishes the time requirements.

Verification of an on line in vivo semiconductor dosimetry system for TBI with two TLD procedures.

This work presents the verification of an on line in vivo dosimetry system based on semiconductors. Software and hardware has been designed to convert the diode signal into absorbed dose. Final verification was made in the form of an intercomparison with two independent thermoluminiscent (TLD) dosimetry systems, under TBI conditions.