Dynamic distribution and dosimetric evaluation of human non-specific immunoglobulin G labelled with 111In or 99Tcm

This study presents data on the dynamic distribution and dosimetry of 111In- and 99Tcm-labelled human non-specific immunoglobulin G (IgG), two recently developed radiopharmaceuticals for the detection of infection and inflammation. Five healthy volunteers were injected with 20-75 MBq 111In-IgG and seven patients were injected with 740 MBq 99Tcm-hydrazinonicotinamide derivative (HYNIC)-IgG. Blood samples, urine and feces were collected. Whole-body gamma camera imaging studies were performed. The activity in source organs was quantified using the conjugate view counting method and a partial background subtraction technique. Dosimetric calculations were performed using the MIRD technique. For 111In-IgG, the mean biological half-times in the blood were 0.90 and 46 h for the a- and b-phase, respectively. For 99Tcm-HYNIC-IgG, these half times were 0.46 and 45 h. For 111In-IgG, the mean cumulative urinary excretion in the first 48 h was 18% of the injected dose, while excretion in the feces was less than 2% of the injected dose. For 99Tcm-HYNIC-IgG, the whole-body retention was always 100% up to 24 h. The mean absorbed doses in the liver, spleen, kidneys, red marrow and testes from 111In-IgG were 0.8, 0.7, 1.2, 0.3 and 0.4 mGy MBq-1 respectively. The mean absorbed doses for 99Tcm-HYNIC-IgG to these organs were 16, 24, 15, 10 and 22 mu Gy MBq-1 respectively. The mean effective dose was 0.25 mSv MBq-1 and 8.4 mu Sv MBq-1 for 111In-IgG and 99Tcm-HYNIC-IgG respectively. In conclusion, the radiation absorbed doses for both 111In-IgG and 99Tcm-HYNIC-IgG are low and, therefore, these radiopharmaceuticals can be administered safely from a radiation risk perspective.     

Clinical pharmacology and tissue disposition studies of 131I-labeled anticolorectal carcinoma human monoclonal antibody LiCO 16.88

Antibody LiCO 16.88 is a human IgM recognizing a 30- to 45-kDa intracytoplasmic antigen present in human adenocarcinoma cells. An 8-mg sample of antibody labeled with 5 mCi 131I was co-administered i.v. with 120 mg (three patients), 240 mg (three patients) or 480 mg (four patients) unlabeled antibody as a 4-h infusion. The plasma half-life was 24 +/- 1.2 h and the immediate apparent volume of distribution was 5.2 +/- 0.2 l at the 28-mg dose level. The plasma half-lives and the cumulative urinary excretion of radiolabel did not seem to vary significantly with increasing doses of unlabeled antibody. However, both the volume of distribution and the clearance rate from plasma increased significantly with increasing antibody dose. Uptake of antibody into tumor tissues obtained during laparotomy 8-9 days after administration varied between 0.00002% ID/g and 0.00127% ID/g. In five of seven patients, the tumor content of antibody was higher than that in adjacent normal tissue. Tumor-to-normal tissue ratios ranged from 0.8 to 10 (mean = 3.8 +/- 1.0). In general, the higher radioactivity(cpm)/g tumor was confirmed by both immunoperoxidase and autoradiography. Antibody 16.88 localizes in tumors after administration and may be considered for use in radioimmunotherapy trials.     

Large, compressive goiters treated with radioiodine

OBJECTIVE: To evaluate the effectiveness of radioiodine therapy as an alternative for surgery in elderly patients with a large, compressive goiter using objective methods for measuring thyroid volume and tracheal compression. DESIGN: Prospective study. SETTING: University hospital in the Netherlands. PATIENTS: 19 patients (mean age +/- SD, 66 +/- 14 years) with a large, compressive multinodular goiter who had a high operative risk or refused to have thyroid surgery. INTERVENTION: A single intravenous dose of 131I at 2.6 +/- 1.0 GBq (70 +/- 28 mCi) (3.7 MBq or 100 microCi/g of thyroid tissue), followed by daily administration of L-thyroxine in doses that did not suppress thyroid-stimulating hormone. MEASUREMENTS: Clinical evaluation and measurements of thyroid volume, maximal tracheal deviation, and the smallest cross-sectional area of the tracheal lumen with magnetic resonance imaging before and 1 year after 131I treatment. RESULTS: No exacerbation of compressive symptoms after 131I therapy was observed. Thyroid volume was 269 +/- 153 mL before treatment and 154 +/- 73 mL 1 year after treatment (P < 0.001). Thyroid volume was reduced 40% +/- 15% (range, 19% to 68%). Maximal tracheal deviation (1.9 +/- 0.8 cm before and 1.5 +/- 0.7 cm 1 year after therapy) had decreased by 20% +/- 20% (range, -4% to 73%; P < 0.001), and the smallest cross-sectional area of tracheal lumen (0.78 +/- 0.38 cm2 before and 1.04 +/- 0.48 cm2 1 year after therapy) had increased by 36% +/- 38% (range, -3% to 125%; P < 0.001). Clinical signs and symptoms improved in 8 of 12 patients with dyspnea and inspiratory stridor and in both patients with compression of the superior vena cava. CONCLUSIONS: Therapy with 131I is an effective alternative to surgery for elderly patients with a large, compressive multinodular goiter.     

Vasopressin modulation of peritoneal, lymphatic, and plasma drug exposure following intraperitoneal administration

i.p. administration of cytotoxic drugs for the treatment of regionally confined cancers results in a greater total drug exposure [area under the concentration x time curve (AUC)] for the peritoneal fluid and regional lymphatics than for plasma. We sought to augment the relative advantage of i.p. administration further through modulation of peritoneal clearance by reduction in splanchnic blood flow. Pigs were treated with 5-fluorouracil, etoposide (VP-16), and carboplatin (CBDCA) alone by the i.p. route or with the same drugs in combination with i.v. lypressin, a synthetic vasopressin analogue, which reduces splanchnic blood flow. Drug concentrations in peritoneal fluid, plasma, and thoracic duct lymph were monitored over the ensuing 6 h. The pharmacokinetics of 5-fluorouracil were not altered by vasopressin; however, vasopressin increased the peritoneal fluid:plasma AUC ratio for CBDCA from 30.6 +/- 5.6 to 70. 6 +/- 7.4 (P < 0.01) and increased the lymph:plasma AUC ratio from 1.1 +/- 0.4 to 2.6 +/- 0.22 (P < 0.05). In the case of VP-16, vasopressin increased the peritoneal fluid:plasma AUC ratio from 129 +/- 35 to 350 +/- 76 (P < 0.05) and the lymph:plasma AUC ratio from 2.1 +/- 0.6 to 10.6 +/- 3.5 (P < 0.05). Concurrent i.v. administration of vasopressin can increase the pharmacokinetic advantage of the i.p. route of administration of CBDCA and VP-16 markedly in the pig model. These data suggest that the strategy of concurrent i.p. administration of CBDCA or VP-16 plus an agent that reduces splanchnic blood flow may increase the dose intensity in the abdominal cavity and intraabdominal lymphatic tissue substantially without increasing systemic toxicity.     

Maximum-tolerated dose, toxicity, and efficacy of (131)I-Lym-1 antibody for fractionated radioimmunotherapy of non-Hodgkin's lymphoma

PURPOSE: Lym-1, a monoclonal antibody that preferentially targets malignant lymphocytes, has induced remissions in patients with non-Hodgkin's lymphoma (NHL) when labeled with iodine 131 ((131)I). Based on the strategy of fractionating the total dose, this study was designed to define the maximum-tolerated dose (MTD) and efficacy of the first two, of a maximum of four, doses of (131)I-Lym-1 given 4 weeks apart. Additionally, toxicity and radiation dosimetry were assessed. MATERIALS AND METHODS: Twenty patients with advanced NHL entered the study a total of 21 times. Thirteen (62%) of the 21 entries had diffuse large-cell histologies. All patients had disease resistant to standard therapy and had received a mean of four chemotherapy regimens. (131)I-Lym-1 was given after Lym-1 and (131)I was escalated in cohorts of patients from 40 to 100 mCi (1.5 to 3.7 GBq)/m2 body surface area. RESULTS: Mean radiation dose to the bone marrow from body and blood (131)I was 0.34 (range, 0. 1 6 to 0.63) rad/mCi (0.09 mGy/MBq; range, 0.04 to 0.17 mGy/ MBq). Dose-limiting toxicity was grade 3 to 4 thrombocytopenia with an MTD of 100 mCi/m2 (3.7 GBq/m2) for each of the first two doses of (131)I-Lym-1 given 4 weeks apart. Nonhematologic toxicities did not exceed grade 2 except for one instance of grade 3 hypotension. Ten (71 %) of 14 entries who received at least two doses of (131)I-Lym-1 therapy and 11 (52%) of 21 total entries responded. Seven of the responses were complete, with a mean duration of 14 months. All three entries in the 100 mCi/m2 (3.7 MBq/m2) cohort had complete remissions (CRs). All responders had at least a partial remission (PR) after the first therapy dose of (131)I-Lym-1. CONCLUSION: (131)I-Lym-1 induced durable remissions in patients with NHL resistant to chemotherapy and was associated with acceptable toxicity. The nonmyeloablative MTD for each of the first two doses of (131)I-Lym-1 was 100 mCi/m2 (total, 200 mCi/m2) (3.7 GBq/m2; total, 7.4 GBq/m2).     

Sensitivity and specificity of transferrin saturation and serum ferritin as markers of iron status after intravenous iron dextran in hemodialysis patients

This study was designed to investigate the effect of intravenous (i.v.) iron dextran (i.d.) on hematocrit (Hct), transferrin saturation (TS), and serum ferritin (SF) in hemodialysis patients treated with a constant dose of erythropoietin (EPO). The sensitivity, specificity, and predictive values of SF and TS for monitoring i.d. therapy were also assessed. All hemodialysis patients with baseline SF < 100 ng/mL or TS < 20%, with EPO dose unchanged 6 weeks before and 4 weeks after dosing with i.d. were included. I.d. (500 mg-1 g) was given as an infusion over 1 h. Patients receiving packed RBC or with active bleeding were excluded. Hct, TS, and SF were measured 2 weeks before and 4 weeks after i.d. Linear correlation coefficients between dose of i.d., changes in Hct, TS, and SF were calculated. The sensitivity, specificity, and predictive values of TS and SF were compared. A positive Hct response was defined as a > 5% increase from baseline 4 weeks after administration of i.d. Thirty-three patients (17 females) received a total of 51 doses of i.d. Mean +/- SD i.d. dose was 770 +/- 278 mg. Hct increased by a mean +/- SD of 4.8% +/- 9.9% (33.4% +/- 3.0% to 34.9% +/- 4.1% [p = 0.028]); SF rose by a median of 208.65% (mean +/- SD of 126.8 +/- 132.1 ng/mL to 325.3 +/- 222.0 ng/mL [p < 0.0001]; TS increased by a median of 53.8% (19.4% +/- 9.4% to 29.3% +/- 11.3% [p < 0.0001]) from baseline values. The correlations between dose of ID and percent changes in SF, TS, and Hct were poor (r2 < 0.02). The sensitivities and specificities were 74% and 36% (TS < 20% alone); 60% and 30% (SF < 100 ng/mL alone); and 33% and 67% (TS < 20% and SF < 100 ng/mL), respectively. The predictive values for positive responses were 48% for TS and 45% for SF when used alone, and 47% when both indices were used together. The predictive value increased to 65% when either SF < 100 ng/mL or TS < 20% were used. At a constant EPO dose, there was a statistically significant increase in Hct 4 weeks after i.d. administration in patients who were diagnosed with iron deficiency by using TS < 20% or SF < 100 ng/mL. The dose of i.d. administered was poorly correlated to changes in Hct, TS, and SF. Both TS and SF are non-specific and insensitive indicators for accurate diagnosis of iron deficiency in hemodialysis patients in EPO.     

Biodistribution of (111)indium-labeled engineered human antibody CTMO1 in ovarian cancer patients: influence of protein dose

Thirty-one patients suspected of having ovarian cancer received a single i.v. injection of radiolabeled (100 MBq (111)In) engineered human CTMO1 (hCTMO1) to investigate its potential as an internalizing drug carrier. hCTMO1 is a complementary-determining region-grafted human IgG4 monoclonal antibody recognizing an ovarian carcinoma-associated antigen, the MUC-1-gene product. The amount of radioactivity was determined in tumor tissue, various normal tissues, including liver biopsies, and blood samples obtained at laparotomy, 6 days after injection of either 0.1 or 1.0 mg hCTMO1/kg of body weight. Circulating antigen-15-3 was measurable in all patients before injection, and immune complex formation was already present at the end of infusion. In the 0.1 mg/kg group, most of the radioactivity was bound to immune complexes, whereas in the 1.0 mg/kg group, most was bound to IgG monomers. Increasing the hCTMO1 dose 10-fold did not influence the overall disappearance of (111)In from the blood, but the elimination half-life of (111)indium bound to immune complexes was increased 2-fold. Uptake in tumor tissue 6 days postinjection at the 0.1 mg/kg dose was 7.6 times higher (P = 0.0009) than in normal tissue and 2.5 times higher (P = 0.03) than in blood. At the 1.0 mg/kg dose, the uptake in tumor tissue was 14.0 times higher (P = 0.0003) than in normal tissue and 8.1 times higher (P = 0.0007) than in blood. Liver activity was substantial (23.7 +/- 10.5 and 18.3 +/- 6.7% of the injected dose/kg for the 0.1 and 1.0 mg/kg dose group, respectively). These results are superior to those found with other clinically tested anti-MUC-1 gene product antibodies. hCTMO1 seems to be a suitable carrier for cytotoxic agents in ovarian carcinoma patients; the better uptake results and tumor-to-blood ratios are obtained at the higher dose of 1.0 mg hCTMO1/kg body weight.     

Radioimmunoimaging assay of ovarian tumor with 99mTc labeled anti-carcinoembryonic antigen monoclonal antibody

Radioimmunoimaging (RI I) assay with 99mTc labeled anti-CEA monoclonal antibody was performed in 31 patients with suspected primary or recurrent malignant ovarian tumor. The radiation dose raging from 920MBq to 110MBq(1mgIgG) was administered i.v. for each patient. Anterior-posterior views of the pelvis and abdomen were obtained routinely with gamma-camera during 18-24 hour after the application of antibody. The results of RII were compared with the findings in operation or CT examination. Sensitivity in diagnosis was 100% (13/13), specificity was 94%(16/17) and metastatic foci sensitivity was 63%(10/16). The serum CA125 in this study appeared to be correlated with the results of RII. However, in 2 patients with normal serum CA125 titers RII revealed true positive. The preliminary clinical results of RII with 99mTc-MAb showed that RII is a promising method for the detection of malignant ovarian tumors.     

Yttrium-90-DOTA-peptide-chimeric L6 radioimmunoconjugate: efficacy and toxicity in mice bearing p53 mutant human breast cancer xenografts

The novel radioimmunoconjugate, 90Y-DOTA-peptide-chimeric L6 (ChL6), was designed to reduce radiation to critical normal tissues with an exceptionally stable 90Y chelate moiety and a biodegradable linker. Human breast cancer tumors (HBT 3477) in mice were treated with 90Y-DOTA-peptide-ChL6 to examine the effects of increasing dose on the therapeutic efficacy and toxicity of this new agent. METHODS: Groups of athymic mice bearing HBT 3477 xenografts received 4.1- to 14.1-MBq doses of 90Y-DOTA-peptide-ChL6 intravenously. The lethal dose (LD)(50/30), general well-being (weight loss), hematotoxicity and therapeutic efficacy were studied. RESULTS: The LD(50/30) was 12.8 MBq, which corresponded to doses of 17.9 and 50.9 Gy to the total body and tumor (200 mm3), respectively. Deaths were associated with hematotoxicity; no deaths occurred at doses of 9.6 MBq or less. At sublethal doses, the rate of tumor response (cures +/- complete responses + partial responses) increased with increasing dose: 4.1 MBq, 27%; 5.9 MBq, 41%; 8.5 MBq, 69%; and 9.6 MBq, 79% (maximum tolerated dose, MTD). In mice receiving doses of 4.1-9.6 MBq, 6 of 74 (8%) of tumors were cured. Increasing the 90Y dose led to smaller tumor size at nadir and longer tumor regrowth delay but no increase in cure. Although the HBT 3477 p53 gene was found to be mutant resulting in p53 protein not binding DNA breaks, tumors at MTD demonstrated evidence of apoptosis. CONCLUSION: In the human breast cancer athymic mouse model, 90Y-DOTA-peptide-ChL6 had a high therapeutic index and LD(50/30) leading to a 79% response rate at the MTD. The evidence of apoptosis as a mechanism for this tumor response in p53 mutant breast cancer warrants further studies because these observations are relevant to the treatment of lethal breast cancer.     

Substance P in the ventral pallidum: projection from the ventral striatum, and electrophysiological and behavioral consequences of pallidal substance P

1. Piroximone was administered orally (p.o.) and intravenously (i.v.) to male Beagle dog. In vitro, piroximone was incubated with dog liver microsomes. 2. Piroximone was metabolized in vivo to five metabolites (1-5) representing approximately 20% of the total administered dose. 3. The parent drug and its metabolites were totally eliminated in urine. 4. Reduced piroximone (piroximole), representing approximately 10% of the administered dose, was identified as the major metabolic product in vivo. 5. In vitro, piroximone was metabolized by dog liver microsomes to isonicotinic acid (1) and piroximole (4), with the same ratio as in vivo (1:4 = 0.2). The Michaelis-Menten parameters were determined for piroximole formation and were: Kmapp = 733 microM and Vmax app = 232 pmol/mg protein/min. 6. Comparison of the pharmacokinetics of piroximone and piroximole revealed that both compounds were very well absorbed (F = 93 +/- 7 and 89 +/- 8% respectively), slightly distributed (Vd app = 0.78 +/- 0.04 and 1.02 +/- 0.09 l/kg p.o., and 0.95 +/- 0.05 and 0.76 +/- 0.13 1/kg i.v. respectively) and excreted into urine to the same extent (UEx = 54.7 +/- 1.2 and 53.2 +/- 12.6% p.o., and 59.1 +/- 5.3 and 51.2 +/- 5.7% i.v. respectively), except that the clearance of piroximone was two-fold higher than that observed for piroximole (ClT = 7.77 +/- 1.35 and 4.12 +/- 0.44 ml/min/kg p.o., and 7.68 +/- 1.25 and 4.06 +/- 0.51 ml/min/kg i.v. respectively).     

Human biodistribution and dosimetry of iodine-123-fluoroalkyl analogs of beta-CIT

Two new N-omega-fluoroalkyl analogs of [123I]2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([123I]beta-CIT), the fluoroethyl and fluoropropyl compounds ([123I]FE-CIT and [123I]FP-CIT, respectively), have been shown to have faster kinetics and better selectivity for the dopamine transporter than [123I]beta-CIT. We examined the organ biodistribution and radiation safety of these two compounds in six healthy volunteers who received an injection with each of the two compounds 2 weeks apart. Data were obtained on the Strichman 860 whole-body scanner. Transmission scans were obtained in all subjects prior to the injection of the radiotracer with a line source and used to derive organ-specific attenuation correction factors. Whole-body planar images were acquired every hour for the first 6 h, and at 24 h. Attenuation-corrected regional conjugate counts were converted into units of activity using a calibration factor obtained for each subject by dividing whole-body conjugate decay-corrected counts from the first acquisition by the injected activity. Radiation dose estimates were on average higher for [123I]CIT-FE than for [123I]CIT-FP, with the lower large intestine receiving the highest exposure: 0.15+/-13% mGy/MBq (mean +/-COV) and 0.12+/-14% mGy/MBq for [123I]FE-CIT and [123I]FP-CIT, respectively, followed by the upper large intestine and the spleen.     

Role of the liver and gut in systemic diphenhydramine clearance in adult nonpregnant sheep

We investigated the contribution of the liver and gut to systemic diphenhydramine (DPHM) clearance in adult nonpregnant sheep in two separate studies. In the first study, a simultaneous 50-mg bolus each of DPHM and its deuterium-labeled analog ([2H10]DPHM) was administered to five sheep via the femoral (i.v.) and the portal venous (p.v.) routes in a randomized manner. Arterial plasma concentrations of DPHM, [2H10]DPHM, and their deaminated metabolites, DPMA (diphenylmethoxyacetic acid) and [2H10]DPMA, were measured using gas chromatography-mass spectrometry. The hepatic first-pass extraction of DPHM after p.v. administration was 94.2 +/- 3.7%. However, the area under the plasma concentration versus time profile of the metabolite after i.v. dosing was only 32.5 +/- 14.0% relative to that after p.v. administration. Thus, only approximately 32.5% of the i.v. dose is metabolized in the liver and a significant extrahepatic systemic clearance component is evident. Using the calculated total hepatic blood flow values, it was found that 98.6 +/- 9.2% of the i.v. dose eventually was delivered to the "hepatoportal" system. Because the drug delivered to the hepatoportal system is almost completely eliminated in a single pass (hepatic extraction approximately 94%), this indicates a lack of any significant pulmonary drug uptake. Also, because only approximately 32.5% of the i.v. dose is metabolized in liver, the gut is most likely responsible for the clearance of the remainder. This gut contribution to systemic DPHM clearance was confirmed in a separate direct study in four sheep where the steady-state DPHM gut extraction ratio was 49.0 +/- 3.0%. Thus, gut accounts for a significant proportion (>/=50%) of DPHM systemic clearance in sheep in spite of a very high hepatic drug extraction efficiency.     

Pharmacokinetics of gentamicin following single-dose parenteral administration to goats

The disposition kinetics of parenterally administered gentamicin (5 mg kg-1) has been studied in Gaddi goats. The serum concentration-time profile was described by bi-exponential and mono-exponential equations following intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administration with elimination half-life values of 0.96 +/- 0.09, 2.37 +/- 0.47 and 3.56 +/- 0.39 h, respectively. The apparent volume of distribution following i.v. administration (Vdarea: 0.26 +/- 0.041 kg-1) reflected limited extracellular distribution of the drug. The bioavailability was higher following i.m. administration (96.3%) compared to s.c. (76.9%). In view of the significantly longer biological half-life and larger area under the curve values, the s.c. route may be preferred. It is concluded that a suitable and practical dosage recommendation for gentamicin in goats would be 3.35 mg kg-1 body weight given s.c. at 12 h intervals.     

The renal effects of the water-soluble, non-folylpolyglutamate synthetase-dependent thymidylate synthase inhibitor ZD9331 in mice

ZD9331 is a novel, potent thymidylate synthase (TS) inhibitor which does not require polyglutamation by folylpolyglutamate synthetase (FPGS) for its activity. In contrast to Tomudex (ZD1694), ZD9331 may therefore be active against tumours with low FPGS activity. ZD9331 shows anti-tumour activity by both 24-h infusion and bolus administration in the murine thymidine kinase-deficient (TK -/-) lymphoma L5178Y. In view of the history of renal toxicity with some earlier TS inhibitors and the possible therapeutic use of bolus ZD9331, we have examined the effects of bolus ZD9331 dose and route of administration on plasma and kidney pharmacokinetics and renal function in mice. Renal function was assessed by measuring [14C]inulin clearance, and drug concentrations were assayed by reverse-phase high-performance liquid chromatography (HPLC). Renal function was unaffected by ZD9331 up to 150 mg kg(-1) either i.v. or i.p. However, at 200 mg kg(-1), glomerular filtration rate was significantly inhibited following i.v. but not i.p. administration. Pharmacokinetic studies showed that these effects were consistent with the markedly higher plasma drug concentrations occurring during early times following i.v. dosing, although the plasma drug profiles were otherwise similar for both routes. Kidney drug concentrations were slightly elevated in i.v.- versus i.p.-treated animals at the low dose (50 mg kg(-1)), with a correspondingly larger area under the curve. However, at the highest dose (200 mg kg(-1)), peak kidney drug concentrations were 20-fold higher following i.v. administration than after i.p., with marked kidney retention, resulting in a 50-fold greater kidney drug exposure for the i.v. versus the i.p. route. These data show that ZD9331 is non-nephrotoxic at active anti-tumour doses (50 mg kg(-1) i.p.) in mice, and only at very high bolus i.v. doses is there impaired renal function as a result of very high peak plasma concentrations. These adverse effects can be readily overcome by i.p. administration, indicating the likely need for short infusions in clinical settings.     

Antiasthmatic activity of the second-generation phosphodiesterase 4 (PDE4) inhibitor SB 207499 (Ariflo) in the guinea pig

We evaluated the airway activity of the novel phosphodiesterase type 4 inhibitor SB 207499 [Ariflo; c-4-cyano-4-(3-cyclopentyloxy-4-methoxyp henyl-r-1-cyclohexane carboxylic acid)], in the guinea pig. Ovalbumin (OA)-induced contractions of guinea pig isolated tracheal strips were inhibited by SB 207499 with an EC50 of 1 microM but had little or no effect on exogenous agonist-induced contraction, which suggests that its effect on OA-induced contraction in vitro is primarily due to inhibition of mediator release from mast cells. In anesthetized guinea pigs, SB 207499 inhibited OA-induced bronchoconstriction with i.v. and p.o. ID50 values of 1.7 and 17 mg/kg, respectively. At 1, 3 and 6 hr after SB 207499 (30 mg/kg p.o.), OA-induced bronchospasm was inhibited by 92%, 70% and 58%, respectively, corresponding to elevated plasma concentrations of 1.62 +/- 0.19, 1.65 +/- 0.29 and 0. 93 +/- 0.24 microg/ml, respectively, of SB 207499. SB 207499 also inhibited house dust mite-induced bronchoconstriction (ID50 = 0.9 mg/kg i.v. and 8.9 mg/kg p.o.). In contrast to its lack of bronchorelaxant activity in vitro, SB 207499 inhibited bronchospasm induced by i.v. leukotriene D4 (LTD4) [ID50 = 3 mg/kg i.v.]. The bronchorelaxant effect of i.v.-administered SB 207499 was at least additive with that of salbutamol in reversing infused histamine-enhanced airway tone, but it did not alter base line or enhance salbutamol-induced cardiovascular effects. In conscious guinea pigs, SB 207499 (10 or 30 mg/kg p.o.), 1 hr before antigen or LTD4 challenge, markedly reduced bronchospasm and subsequent eosinophil influx as measured by bronchoalveolar lavage 24 hr after provocation. SB 207499 administered after OA or LTD4 challenge also reduced airway eosinophilia measured at 24 hr after OA challenge or 96 hr after LTD4 challenge. These results, coupled with the broad anti-inflammatory activity of SB 207499 previously described (Barnett et al., 1998), suggest that SB 207499 will be useful in the treatment of asthma and other inflammatory disorders.     

Dosimetry of transmission measurements in nuclear medicine: a study using anthropomorphic phantoms and thermoluminescent dosimeters

Quantification in positron emission tomography (PET) and single photon emission tomographic (SPET) relies on attenuation correction which is generally obtained with an additional transmission measurement. Therefore, the evaluation of the radiation doses received by patients needs to include the contribution of transmission procedures in SPET (SPET-TM) and PET (PET-TM). In this work we have measured these doses for both PET-TM and SPET-TM. PET-TM was performed on an ECAT EXACT HR+ (CTI/Siemens) equipped with three rod sources of germanium-68 (380 MBq total) and extended septa. SPET-TM was performed on a DST (SMV) equipped with two collimated line sources of gadolinium-153 (4 GBq total). Two anthropomorphic phantoms representing a human head and a human torso, were used to estimate the doses absorbed in typical cardiac and brain transmission studies. Measurements were made with thermoluminescent dosimeters (TLDs, consisting of lithium fluoride) having characteristics suitable for dosimetry investigations in nuclear medicine. Sets of TLDs were placed inside small plastic bags and then attached to different organs of the phantoms (at least two TLDs were assigned to a given organ). Before and after irradiation the TLDs were placed in a 2.5-cm-thick lead container to prevent exposure from occasional sources. Ambient radiation was monitored and taken into account in calculations. Transmission scans were performed for more than 12 h in each case to decrease statistical noise fluctuations. The doses absorbed by each organ were calculated by averaging the values obtained for each corresponding TLD. These values were used to evaluate the effective dose (ED) following guidelines described in ICRP report number 60. The estimated ED values for cardiac acquisitions were 7.7 x 10(-4) +/- 0.4 x 10(-4) mSv/MBq.h and 1.9 x 10(-6) +/- 0.4 x 10(-6) mSv/MBq.h for PET-TM and SPET-TM, respectively. For brain scans, the values of ED were calculated as 2.7 x 10(-4) +/- 0.2 x 10(-4) mSv/MBq.h for PET-TM and 5.2 x 10(-7) +/- 2.3 x 10(-7) mSv/MBq.h for SPET-TM. In our institution, PET-TM is usually performed for 15 min prior to emission. SPET-TM is performed simultaneously with emission and usually lasts 30 and 15 min for brain and cardiac acquisitions respectively. Under these conditions ED values, estimated for typical source activities at delivery time (22,000 MBq in SPET and 555 MBq for PET), were 1.1 x 10(-1) +/- 0.1 x 10(-1) mSv and 1.1 x 10(-2) +/- 0.2 x 10(-2) mSv for cardiac PET-TM and SPET-TM respectively. For brain acquisitions, the ED values obtained under the same conditions were 3.7 x 10(-2) +/- 0.3 x 10(-2) mSv and 5.8 x 10(-3) +/- 2.6 x 10(-3) mSv for PET-TM and SPET-TM respectively. These measurements show that the dose received by a patient during a transmission scan adds little to the typical dose received in a routine nuclear medicine procedure. Radiation dose, therefore, does not represent a limit to the generalised use of transmission measurements in clinical SPET or PET.     

Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 2nd communication: drops with ethanol

The pharmacokinetics and the absolute bioavailability of tramadol hydrochloride (CAS 36282-47-0) after oral administration of Tramal drops (with ethanol) were determined in a balanced cross-over study in 8 (4 male and 4 female) volunteers in comparison with the intravenous injection. Each fasting volunteer received two single doses of 100 mg tramadol-HCl, one by oral (1 ml of drops) and one by intravenous route (2 ml of a solution for injection). The formulations were administered in the morning; the washout period was one week. Serum and urine concentrations of tramadol-HCl were determined by gas chromatography-mass spectrometry and gas chromatography, respectively, and the pharmacokinetic evaluation was carried out model-dependently. Only the extent of bioavailability and the renal clearance were calculated model-independently. The extent of the absolute bioavailability (F) of tramadol after oral administration of the drops, based on AUC data, was 66.3% (point estimate; n = 8) with a 95% confidence interval of 58.1-75.6% (ANOVAlog). The areas under the serum concentration curves of tramadol-HCl calculated by curve fitting (AUC), which agreed very well with the model-independently determined areas (AUC), were 2390 +/- 712 h.ng/ml (p.o.) and 3490 +/- 510 h.ng/ml (i.v.) (mean +/- SD; n = 8). After oral administration the means of the serum concentration peaks were 308 +/- 89 ng/ml (cmax) and 1.20 +/- 0.39 h (tmax), the half-life of absorption was 0.34 +/- 0.18 h (t1/2,ka) and the lag time 0.23 +/- 0.01 h (t0). The biological half-life in the terminal phase (t1/2,beta) was 5.5 +/- 0.9 h and agreed well with the value of 5.2 +/- 0.8 h determined after i.v. injection. There were large differences between the volunteers in the distribution rate. For the slower distribution half-life (t1/2,alpha) mean values of 1.2 +/- 0.7 h (p.o.; n = 6) and 1.9 +/- 0.7 h (i.v.; n = 6) were obtained. The values determined after i.v. injection for the total distribution volume and the total and renal clearance were 216 +/- 21 l (Vd,beta), 487 +/- 71 ml/min (Cltot) and 77 +/- 20 ml/min (Clren), respectively. These results show that after administration of the drops (with ethanol) the active ingredient tramadol is rapidly absorbed and that the extent of the absolute bioavailability is about the same as after oral administration of tramadol capsules.     

Iodine-131-metaiodobenzylguanidine dosimetry in cancer therapy: risk versus benefit

In the treatment of neural crest tumors, such as pheochromocytoma, with[131I]MIBG, bone marrow toxicity limits the amount of administered activity and, thus, a therapeutically useful tumor dose. METHODS: We calculated tumor doses in a series of diagnostic studies with [123I]MIBG using accurate quantification of SPECT and planar scintigraphy. By extrapolating diagnostic results to therapeutic activities of [131I]MIBG, we could compare the results with whole-body doses from a series of therapies. RESULTS: The tumor dose was DT = 2.2 mGy MBq(-1) (median value of 27 measurements, range 0.04 < or = DT < or = 20 mGy MBq(-1) and the whole-body dose in a series of 16 patients undergoing 50 therapies was DWB = 0.12 +/- 0.04 mGy MBq(-1) (mean +/- s.d.). The therapeutic ratio varied between 130 to below 10 in some patients. CONCLUSION: The results were compared with published data. We found clearly skewed distribution of tumor doses, with a majority of tumors receiving only a few mGy per MBq administered activity. In some patients, however, doses did reach 20 mGy MBq(-1).     

Fluorine-18-fluoromisonidazole radiation dosimetry in imaging studies

Fluoromisonidazole (FMISO), labeled with the positron emitter 18F, is a useful hypoxia imaging agent for PET studies, with potential applications in patients with tumors, cardiovascular disease and stroke. METHODS: Radiation doses were calculated in patients undergoing imaging studies to help define the radiation risk of FMISO-PET imaging. Time-dependent concentrations of radioactivity were determined in blood samples and PET images of patients following intravenous injection of [18F]FMISO. Radiation absorbed doses were calculated using the procedures of the Medical Internal Radiation Dose (MIRD) committee, taking into account the variation in dose based on the distribution of activities observed in the individual patients. As part of this study we also calculated an S value for brain to eye. Effective dose equivalent was calculated using ICRP 60 weights. RESULTS: Effective dose equivalent was 0.013 mSv/MBq in men and 0.014 mSv/MBq in women. Individual organ doses for women were not different from men. Assuming bladder voiding at 2- or 4-hr intervals, the critical organ that received the highest dose was the urinary bladder wall (0.021 mGy/MBq with 2-hr voiding intervals or 0.029 mGy/MBq with 4-hr voiding intervals). CONCLUSION: The organ doses for [18F]FMISO are comparable to those associated with other commonly performed nuclear medicine tests and indicate that potential radiation risks associated with this study are within generally accepted limits.     

Function of the C-terminal domain of the alpha subunit of Escherichia coli RNA polymerase in basal expression and integration host factor-mediated activation of the early promoter of bacteriophage Mu

Crescentic glomerulonephritis (GN) demonstrates immunopathological features of a T helper (Th)1-directed delayed-type hypersensitivity (DTH) response. The capacity of Th2 cytokines to attenuate crescentic glomerular injury in this disease was examined by administering interleukin (IL)-4 and IL-10, singly and in combination. GN was induced by i.v. administration of sheep anti-mouse glomerular basement membrane (GBM) globulin to mice sensitized to sheep globulin 10 days earlier. Treatment (2.5 microg, i.p.) with IL-4, IL-10, or both IL-4 and IL-10 (IL-4 + 10), was started 1 h before sensitization and continued daily until the end of the study (10 days after administration of anti-GBM globulin). Control mice treated with PBS developed GN with glomerular accumulation of T cells and macrophages, crescents in 42.5 +/- 4.5 % of glomeruli (normal 0 %), proteinuria (8.3 +/- 0.9 mg/24 h, normal 0.74 +/- 0.08 mg/24 h, p <0.001) and renal impairment (creatinine clearance [cr/cl]: 93 +/- 12 microl/min, normal 193 +/- 10 microl/min, p < 0.001). Treatment with either IL-4, IL-10, or IL-4 + 10 prevented crescent formation (crescentic glomeruli: 0.8 +/- 0.5, 1.2 +/- 0.9, and 1.4 +/- 1.0 %, respectively, all p < 0.01 compared to control) and attenuated proteinuria (3.6 +/- 1.0, 2.2 +/- 0.5, and 2.9 +/- 0.5 mg/24 h, respectively, all p < 0.01 compared to control). IL-4 + 10 prevented development of renal impairment (cr/cl: 183 +/- 22 microl/min); IL-10 given alone limited the decline in renal function (cr/cl: 150 +/- 20 microl/min), but IL-4 alone did not provide any significant protection (cr/cl: 121 +/- 17 microl/min). All treatments markedly diminished glomerular T cell and macrophage accumulation, reduced interferon-gamma production by splenic T cells, prevented cutaneous DTH to the disease-initiating antigen and reduced antigen-specific immunoglobulin of the IgG2a and IgG3 isotypes. These data demonstrate that crescentic GN and renal impairment can be prevented by administration of Th2 cytokines and that this effect is associated with attenuation of the Th1 response to the disease-initiating antigen.