Anne-Marie Smith

Selective drug delivery to the colon using pectin:Chitosan:hydroxypropyl methylcellulose film coated tablets.

A study has been carried out to assess the potential of pectin:chitosan:hydroxypropyl methylcellulose (HPMC) (P:C:H) films for colonic drug delivery. Radiolabelled (99mTc) tablets were coated with a 3:1:1, P:C:H film and administered to human volunteers. The gastro-intestinal transit of the tablets was assessed by gamma scintigraphy. The results showed that in all cases (n=4), the tablets were able to pass through the stomach and small intestine intact. Break up of the tablets commenced once they were in the colon, due to degradation of the coat by colonic bacteria. The study has highlighted the potential of this coating system for colonic drug delivery.

Excitation functions for deuteron induced reactions in natural nickel: Production of no-carrier-added 64Cu from enriched 64Ni targets for positron emission tomography

Abstract The excitation functions for the production of 64Cu and other radionuclides by the deuteron irradiation of natural Ni targets have been measured up to 19 MeV incident energy. The excitation function for the 64Ni(d, 2n)64Cu reaction shows a maximum effective cross section of 7.2±0.9 mbarn at 16.2 MeV for the natural Ni target. Data have been used for the production of large quantities of 64Cu by the deuteron irradiation of enriched (96.4%) 64Ni targets. The radiochemical extraction procedures developed can produce either carrier-free 64Cu or utilize a small amount (50 μg) of carrier. The thick target yield of 64Cu is 107 ± 16 GBq/C (10.5 ± 1.6 mCi/μ Ah) and the contamination with 61Cu is only 0.29% at EOB. Data on the production yields of 61Cu, 64Cu, 57Ni, 55Co, 56Co 57Co and 58Co during the deuteron irradiation of natural Ni and enriched 64Ni targets are presented.

Evaluation of 99mTc(CO)5I as a potential lung perfusion agent

INTRODUCTION The use of (99m)Tc-macroggregated albumin for lung perfusion imaging is well established in nuclear medicine. However, there have been safety concerns over the use of blood-derived products because of potential contamination by infective agents, for example, Variant Creutzfeldt Jakob Disease. Preliminary work has indicated that Tc(CO)(5)I is primarily taken up in the lungs following intravenous administration. The aim of this study was to evaluate the biodistribution and pharmacokinetics of (99m)Tc(CO)(5)I and its potential as a lung perfusion agent. METHODS (99m)Tc(CO)(5)I was synthesized by carbonylation of (99m)TcO(4-) at 160 atm of CO at 170 degrees C in the presence of HI for 40 min. Radiochemical purity was determined by HPLC using (99)Tc(CO)(5)I as a reference. (99m)Tc(CO)(5)I was administered by ear-vein injection to three chinchilla rabbits, and dynamic images were acquired using a gamma camera (Siemens E-cam) over 20 min. Imaging studies were also performed with (99m)Tc-labeled macroaggregated albumin ((99m)Tc-MAA) and (99m)TcO(4-) for comparison. (99m)Tc(CO)(5)I was administered intravenously to Sprague-Dawley rats, and tissue distribution studies were obtained at 15 min and 1 h postinjection. Comparative studies were performed using (99m)Tc-MAA. RESULTS Radiochemical purity, assessed by HPLC, was 98%. The retention time was similar to that of (99)Tc(CO)(5)I. The dynamic images showed that 70% of (99m)Tc(CO)(5)I appeared promptly in the lungs and remained constant for at least 20 min. In contrast, (99m)TcO(4-) rapidly washed out of the lungs after administration. As expected (99m)Tc-MAA showed 90% lung accumulation. The percentage of injected dose per gram of organ +/-S.D. at 1 h for (99m)Tc(CO)(5)I was as follows: blood, 0.22+/-0.02; lung, 12.8+/-2.87; liver, 0.8+/-0.15; heart, 0.15+/-0.01; kidney, 0.47+/-0.08. The percentage of injected dose per organ +/-S.D. at 1 h was as follows: lung, 22.47+/-2.31; liver, 10.53+/-1.8; heart, 0.18+/-0.01; kidney, 1.2+/-0.17. Tissue distribution studies with (99m)Tc-MAA showed 100% lung uptake. CONCLUSION (99m)Tc(CO)(5)I was synthesized with a high radiochemical purity and showed a high accumulation in the lungs. Further work on the mechanism and optimization of lung uptake of (99m)Tc-pentacarbonyl complexes is warranted.

Blood clearance of radioactively labelled cis-diammine 1,1-cyclobutane dicarboxylate platinum(II) (CBDCA) in cancer patients

SummaryThe blood and urinary clearances of cis-diammine 1,1-cyclobutane dicarboxylate platinum(II) (CBDCA, JM8) were determined in four patients with malignancy. A 40 μCi iv injection of 191Pt/193Pt (3:1)-labelled CBDCA was followed by serial blood and urine sampling to 72h.The blood clearance was triphasic, mean values for the fast, intermediate, and slow phases being 10.8 min, 2.5 h, and 125 h, respectively. The fraction of activity excreted in the urine within the first 6 h had a mean value of 66.7%, contrasting with 26.4% for cisplatin. There was only a small fraction of CBDCA excreted by the slow phase (1.5%) as against an average of 20% for CHIP and 27% for cisplatin.The early and rapid renal clearance of CBDCA may account for reduced nephrotoxicity.

Blood clearance of three radioactively labelled platinum complexes: cis-dichlorodiammine platinum II, cis, trans-dichlorodihydroxy-bis-(isopropylamine) platinum IV, and cis-dichloro-bis-cyclopropylamine platinum II, in patients with malignant disease

SummaryThe blood clearances of three platinum compounds, cis-dichlorodiammine platinum II (DDP), cis, trans-dichlorodihydroxy-bis-(isopropylamine) platinum IV (CHIP), and cis-dichloro-bis-cyclopropylamine platinum II (CP), were determined in nine patients with malignant disease. The complexes were prepared using radioactive platinum (191Pt and 193Pt). A 10-μCi dose of each complex, containing the equivalent of 1–2 mg elemental platinum, was injected IV into groups of three patients. Serial blood and urine samples were collected over 72 h.No obvious difference was found between the three complexes for blood clearance, median t1/2α being 16.8 (range 11.2–23.5) min and median t1/2β 89 (range 63.7–127) h. The urinary excretion was greatest for CHIP, 60% of injected dose as against 42.6% for CP and 38.8% for DDP.Differences in renal excretion of DDP analogues could indicate potentially less nephrotoxic agents. The use of radioactive Pt will allow in vivo dynamic imaging of the distribution of platinum compounds in areas of interest.

In vivo distribution studies of radioactively labelled platinum complexes; cis-dichlorodiammine platinum(II), cis-trans-dichlorodihydroxy-bis-(isopropylamine) platinum(IV), cis-dichloro-bis-cyclopropylamine platinum(II), and cis-diammine 1,1-cyclobutanedicarboxylate platinum(II) in patients with malignant disease, using a gamma camera

SummaryThe in vivo distribution in man of the four platinum derivatives cis-dichlorodiammine platinum(II) (DDP), cis-trans-dichlorodihydroxy-bis-(isopropylamine) platinum (IV) (CHIP), cis-dichloro-bis-cyclopropylamine platinum (II) (CP), and cis-diammine 1,1-cyclobutanedicarboxylate platinum(II) (CBDCA) has been observed. The availability of these compounds labelled with the radioactive isotope of platinum, platinum-191, has made serial in vivo imaging of their distribution possible.Injection of 17–35 MBq (5–28 mg) of the labelled compound IV was followed by imaging, using a gamma camera, with particular reference to the kidneys, liver, and tumour site.Hepatic and renal clearances were observed in all nine patients, but no unequivocal evidence of tumour uptake was found. The left kidney uptake was estimated at times up to 7 days after injection. Mathematical analysis of some of the uptake curves failed to show any significant difference between the clearance times observed. However, the two patients who received CBDCA did show a higher initial renal uptake, falling within the 1st day to levels comparable with those of the other compounds, and the three patients who received DDP showed consistently liver uptake.

In vivo behavior of hydrogel beads based on amidated pectins.

Radio-labeled hydrogel beads, based on amidated pectin, have been produced by adding droplets of an amidated pectin solution to calcium chloride. Incorporation of model drugs into the beads and measurement of the dissolution rate showed that the properties of the beads were unaffected by the incorporation of the radiolabel. The labeled beads were used to carry out an in vivo study of their behavior in the gastrointestinal tract using human volunteers. The volunteers were given the beads after an overnight fast and images were obtained at frequent intervals during transit through the upper gastrointestinal tract and the colon. The beads exhibited rapid gastric emptying and proceeded to pass through the small intestine individually before regrouping at the ileo-caecal junction. Once in the colon, the beads again proceeded as individuals and evidence of the degradation of the beads was observed.

A comparative study of the distribution in the male rat of platinum-labelled cis-dichlorodiammine platinum (II), cis-trans-dichlorodihydroxy-bis-(isopropylamine) platinum (I), and cis-dichloro-bis-cyclopropylamine platinum (II).

SummaryThree platinum derivatives, cis-dichlorodiammine platinum (II), (DDP), cis-trans-dichlorodihydroxy-bis-(isopropylamine)platinum (IV) (CHIP) and cis-dichloro-bis-cyclopropylamine platinum (II) (CP), have been prepared with a gamma-emitting platinum label. The distribution of these complexes was studied in male rats.The results are presented as fractions of the administered radiolabel per gram of tissue and per total organ. Accumulation in the liver was highest initially following CP and lowest after DDP, but by 14 days the levels in kidney and liver were highest with CP. The concentration in the skin was relatively high after all the compounds, but was the most conspicuous after DDP at the early times. In general, patterns of distribution between the other organs were similar with DDP and CP.CHIP, however, exhibited a different pattern of distribution. Over the first 24 h the level of platinum in most tissues declined more rapidly than after either of the other two compounds but the residual label persisted for a longer period. In the kidney there appeared to be a secondary uptake of labelled material, presumably from other tissues. The level present at 14 days after CHIP was also significantly higher in a number of other organs than after the other two drugs. The increase in label in the spleen at the later times may be due to the removal of circulating damaged cells and consistent with the higher levels of residual platinum in the blood. There was also a higher level of residual platinum in the blood especially after IV administration of the labelled agent.The results show that CHIP was cleared at a faster rate from blood and kidney than the other two complexes, results which closely resembled clinical findings with these three agents, to be published elsewhere.The greater retention time of label after CHIP also suggests that longer-term toxicity may follow its repeated administration.

Comparative intraperitoneal pharmacokinetics of three platinum analogues.

SummaryThe pharmakokinetic profiles of intraperitoneally infused platinum analogues were determined in 13 women exhibiting minimal residual disease following surgery and systemic chemotherapy for epithelial ovarian cancer of fallopian tube carcinoma by following the disposition of tracer doses of195mPt radiolabel. Six patients received iproplatin, four were given cisplatin and three received carboplatin. The present data demonstrate no difference in the disposition of total platinum between these three analogues, but differences in the kinetics of free platinum may exist.

Autologous lymphocytes as vectors to target therapeutic radiation, using indium‐114m, in patients with lymphoid cell malignancy

Summary. Autologous lymphocytes provide a potential vector for the delivery of a cytotoxic agent in patients with lymphoid cell malignancy. This report describes a phase I–II study using autologous lymphocytes to target the radionuclide indium‐114m (114mIn) in patients with refractory chronic lymphocytic leukaemia or small lymphocytic non‐Hodgkins lymphoma. Nineteen patients, the majority of whom had been heavily pretreated with conventional chemotherapy and radiotherapy, received between 69 and 211 MBq 114mIn‐labelled autologous lymphocytes. Approximately 80% of the administered activity was localized in the liver and spleen, with around 5% accumulating in the bone marrow. Ten patients (53%) responded (one complete response and nine partial responses). The median duration of response was 7 months. The median survival for the responders was 14 months and for the non‐responders was 3 months. The first notable response in every patient was a fall in peripheral lymphocyte count. The indium treatment was not associated with any subjective toxicity, although all patients suffered from myelosuppression, with thrombocytopenia being the dose‐limiting factor. This study has demonstrated a significant anti‐tumour effect in a group of patients with late‐stage highly resistant disease.