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Background: Due to the potentially crucial role of vitamin K2 in calcium metabolism, a deficit can disrupt many mechanisms, resulting in an array of different issues, such as broken bones, stiff arteries and poor fertility. Although there has been existing research, the potential of vitamin K2 as a treatment for conditions including cerebral palsy, parathyroid disease, heart disease and gastrointestinal disease is unknown. This review discusses the biochemistry of vitamin K and the metabolism of calcium, followed by an analysis of the current literature available on vitamin K2 and its prospects. Methods: Using public libraries including PubMed and Wiley, we searched for existing research on the metabolism and use of vitamin K2 that has been conducted in the preceding two decades. Results: Data indicated that vitamin K2 had a positive impact on osteoporosis, cardiovascular disease, parathyroid disorders, cerebral palsy and sperm motility. Conclusion: Due to the existence of confounding variables and limitations in the quality and volume of research conducted, further investigation must be done to see whether the beneficial effects seen are reproducible and must assess the viability of vitamin K2 as treatment in isolation for these conditions.

Nowadays, the failure of major organs, such as the kidneys, heart, lungs, liver, small bowel and pancreas caused by a significant number of diseases, put thousands of patients each year on the transplants list. But the breakthrough of blood vessels reconnection techniques and improvements in immunosuppressant, methods of organ conservation during transplantation, as well as in the post-operative care had a major contribution in considering organ transplant surgeries the best possible treatment for organ failure at the moment. The aim of this report is to present an overview on organ donation, focusing on the diseases for which the transplantation of an organ may represent the best possible treatment. As the NHS statistics reported, the number of patients who receive a chance for living a better life by organ donation is significantly increasing every year in the UK and the number of donors has been in a continuous rise too in the last years. Moreover, the statistics recorded by NHS showed that out of approximately 4600 transplants performed every year, more than 3000 are only kidney transplantations, making the kidneys the most donated organ. As mentioned before, organ transplantations are the best possible treatment for end-stage organ failure, which occur in severe cases of numerous types of diseases. Kidney transplantations are usually performed for patients with chronic kidney failure, whereas a heart transplant is considered the best possible treatment for heart failure, valvular heart disease, congenital heart disease, coronary artery disease and cardiomyopathy. Lung transplantations are most commonly used as treatment for end-stage related diseases such as cystic fibrosis, pulmonary edema, emphysema and pulmonary hypertension and pancreas transplantations are performed in cases of Type I insulin-dependent diabetes mellitus. Congenital liver defects and chronic liver infections are the main medical conditions that can be best treated by a liver transplant. Many years of laboratory research has now open the ways of successful small bowel transplantations which can save the lives of patients diagnosed with short bowel syndrome. However, as a result of the research that I have done that led to the finding of an impressive number of diseases that can be cured only by organ donation, my opinion is that organ donation should not be compulsory due to ethical problems or Human Rights (religious beliefs).

Myocardial perfusion imaging is an established Nuclear Medicine investigation. Current myocardial perfusion imaging agents sestamibi and tetrofosmin have number of drawbacks; low heart uptake coupled with uptake into the surrounding tissues leads to a poorer image quality. There is a need for continued research into designing and evaluating potentially superior myocardial imaging agents. Tri-carbonyl-technetium and rhenium complexes were prepared by combination with mono-dentate and bi-dentate ligands. Complexes were characterized by HPLC, MAS, nuclear magnetic resonance, infrared, single-crystal X-ray diffraction and partition coefficient determinations. (99m) Tc(CO)3 complexes were administered intravenously to Sprague Dawley rats, and tissue distribution studies were carried out at 15 min and 1 h p.i. Radiochemical purity was assessed as >90%. 1-10-phenanthroline, 2,2'-bipyridine and imidazole complexes gave the highest heart uptake. The percentage injected dose per gram (n = 3) at 1 h for 1-10-phenanthroline/imidazole was blood 0.21 ± 0.01, heart 1.12 ± 0.11, kidney 3.61 ± 1.13, liver 0.62 ± 0.06, lung 0.28 ± 0.12, spleen 0.24 ± 0.05, small intestine contents 1.87 ± 0.92; and for 2,2'-bipyridine /imidazole was blood 0.23 ± 0.02, heart 1.07 ± 0.18, kidney 3.31 ± 1.28, liver 0.56 ± 0.09, lung 0.14 ± 0.02, spleen 0.2 ± 0.1, small intestine content 1.05 ± 0.48. Further investigation to evaluate more complexes based on 1,10-phenanthroline, 2,2'-bipyridine and imidazole derivatives could potentially lead to agents with an increased heart uptake and faster clearance from the liver and gastrointestinal tract.

Endothelial cell adherence to uncoated gelatin-impregnated Dacron (Gelseal) is poor but can be significantly improved by precoating with a suitable basement membrane such as fibronectin. To assess the suitability of fibronectin-coated Gelseal for endothelial cell seeding, fibronectin binding to Gelseal and its dissociation kinetics were investigated. Fibronectin binding was quantified by radiolabeling human fibronectin with iodine 125, concentrations of 10, 25, 50, 150, and 250 micrograms/ml being used to coat Gelseal at 30, 60, and 90 min of incubation. The amount of fibronectin bound was directly proportional to the concentration used and increased with time of incubation (p < 0.05). However, the percentage attachment decreased with increasing concentration (p < 0.001). The number of molecules bound per centimeter squared of graft was calculated. In the first 30 min, 75% of bound fibronectin was lost after exposure to a flow rate of 200 ml/min in a pulsatile artificial circulation; thereafter, the fibronectin-Gelseal bond was stable for up to 2 h.

Gastro-retentive dosage forms have the potential to improve local therapy and decrease the variation in bioavailability that is observed with a number of commercially available immediate and modified release preparations. In this study, a dosage form has been developed, utilising freeze-dried calcium alginate beads, designed to float on the surface of the stomach contents thus prolonging the retention time. The aim of the study was to also assess the in vivo behaviour of the radio-labelled calcium alginate beads when they were administered under fasting conditions with either water or an aqueous solution of citric acid, a potential gut transit delaying substance. The study was performed in healthy male volunteers who swallowed the radio-labelled calcium alginate beads after a 10h overnight fast. Gamma scintigraphy was selected as the method to monitor the movement of the calcium alginate beads. The volunteers consumed no further food or drink until gastric emptying of the calcium alginate beads was complete. The results indicated that prolonged gastric retention was achieved when the dosage form was administered with the citric acid solution when compared to retention in the absence of citric acid. Citric acid, therefore, has the potential to delay the gastric emptying of the calcium alginate beads when administered to fasted volunteers.

A floating dosage form based on calcium alginate beads has been developed. Riboflavin, was selected as the model drug and successfully incorporated into calcium alginate beads. The aims of the current study were to: (a) assess the influence of prolonged gastro-retention on the bioavailability of riboflavin from freeze dried calcium alginate beads administered under varying conditions of food intake and (b) to investigate the potential of citric acid to delay the gastric emptying of the calcium alginate beads. Gamma scintigraphy was selected as the method to monitor the movement of the calcium alginate beads in vivo. Riboflavin concentrations in the urine were analysed by HPLC. Prolonged gastro-retention can be achieved, in the fasted state, when citric acid solution is used as an administering vehicle. However, prolonged gastro-retention is not achieved to the same extent when the gastric emptying times are compared to those obtained in the fed state. The bioavailability of riboflavin improved when calcium alginate beads were administered in the fasted state with citric acid solution, compared to the bioavailability obtained when the calcium alginate beads were administered in the absence of citric acid.

The radiolabelling of blood cellular elements with PET radionuclides offers a higher sensitivity and resolution than conventional imaging, but short-lived PET radionuclides have limited clinical use in cell labelling. Medium half-life PET radionuclides, such as 55 Co (t 1 /2 = 18.2 h), 52 Fe (t 1 /2 = 8.3 h) and 66 Ga (t 1 /2 = 9.4 h), enable quantitative uptake and cell kinetic studies with radiolabelled blood cellular elements. Co(II) oxine, Co(III) tropolonate, Fe(III) oxine, Ga(III) oxine and Ga(III) MPO were prepared using gamma-emitting radionuclides and a number of cell labelling parameters were investigated. The uptake of 57 Co(II) oxine into erythrocytes was only 37%, and 65% of the activity eluted from the cells in cell-free plasma within 30 min. In contrast, high leukocyte and erythrocyte labelling efficiencies (> 90%) were obtained with 57 Co(III) tropolonate containing cobalt carrier and the elution in cell-free plasma over 4 h was < 8%. High labelling efficiencies were also observed with 59 Fe(III) oxine and 67 Ga-MPO and the elution from leukocytes over 4 h was < 25%. We conclude that Co(III) tropolonate, Fe(III) oxine and Ga-MPO may be useful for radiolabelling leukocytes for PET investigations.

Gastroretentive dosage forms have potential for use as controlled-release drug delivery systems. The use of floating dosage forms (FDFs) is one method to achieve prolonged gastric residence times (GRTs), providing opportunity for both local and systemic drug action. Multiple-unit systems avoid the 'all-or-nothing' gastric emptying nature of single-unit systems. A freeze-dried calcium alginate multiple-unit FDF has been developed which demonstrated favourable in vitro floating characteristics. The aim of this study was to investigate the in vivo behaviour of this system compared to a multiple-unit non-floating dosage form manufactured from identical material. The study was performed in seven healthy volunteers, who swallowed the radiolabelled formulations after a standard breakfast. Transit was monitored by gamma-scintigraphy and subjects were maintained in the fed state. Prolonged GRTs of over 5.5 h were achieved in all subjects for the floating formulations, which remained high up in the stomach for the whole of the test period. In contrast, the non-floating beads displayed short GRTs, with a mean onset emptying time of 1 h. The results of this study suggest that, in the fed state, this FDF has potential for sustained drug delivery for either local or systemic purposes.

We have used the Big Blue lacI transgenic mouse reporter system to investigate mutation induction in the testes, spleen and liver after exposure to an internally incorporated radionuclide, 114mIn, whole body irradiation with 60Co gamma-rays and systemically administered cyclophosphamide. Spontaneous mutation frequencies were 6-17x10(-6). No statistically significant mutation induction was observed in testes or spleen at 35 days after exposure to any test agent, although mutation frequencies tended to be increased (by approximately 1.5-fold) after exposure to 1 Gy gamma-rays. However, liver mutation frequencies were doubled after treatment with 100 mg/kg cyclophosphamide and were elevated by approximately 2.5-fold after systemic administration of 114mIn and 4.5-fold after 1 Gy 60Co gamma-rays. When data from all organs were pooled, mutation frequency was doubled after exposure to 1 Gy gamma-rays, but no other significant increases were observed. These findings support the hypothesis that the lacI transgenic mouse may be relatively inefficient at detecting mutations induced by exposure to ionizing radiation or other agents which produce a spectrum of deletion sizes, including those which are larger than the lacI transgene.

The orally active platinum anti-tumour complex JM216 [bis-acetatoamminedichlorocyclohexylamineplatinum(IV)] is at present in stage II clinical trials. A procedure for synthesising the complex labelled with 191Pt or 188Pt at the platinum centre has been developed. The purity (shown by HPLC) is 98% and the specific activity (0.3–0.4 Ci/kg) is enough for in vivo and in vitro studies.

The radiochemical separation of 101m Rh produced from a pressed Rh powder target via its precursor 101 Pd is described. The procedure employs a novel method for the dissolution of Rh metal powder using Au(III) as an oxidising agent. The solvent extraction of 101 Pd from the target solution has been carried out by α-benzoin oxime. This method of extraction has been found to be considerably better than using ion-exchange column chromatography with Dowex 1 × 8 resin or the use of dimethyl glyoxime (DMG) as extractant, which were tried for comparison. The total time taken for the extraction of 101 Pd from irradiated Rh target was approximately 2 h and the overall yield of 101 Rh was 53%.

Systems that exhibit gastric retention are of value in several areas of therapy. A novel floating system based on ion exchange resins has been investigated and evaluated in vivo. The method relies on ion exchange resins loaded with bicarbonate, which, on contact with media containing hydrochloric acid, release carbon dioxide causing the resin to float. Extension of the floating time is achieved by coating the bicarbonate loaded resin particles with a semipermeable membrane. Two resins were investigated and both exhibited in vitro floating times of over 24 h using a standardised procedure. Studies in human volunteers were carried out using gamma scintigraphy. The coated resins were compared to an uncoated control in subjects receiving a light breakfast. The coated resin based on Dowex 2 × 10 showed significantly prolonged residence times ( P

Ion exchange resin beads can be loaded with bicarbonate and coated with a semipermeable membrane. These beads exhibit prolonged gastric residence due to release of carbon dioxide which is trapped inside the coating of the beads. In addition to the bicarbonate, a model drug, theophylline, has also been loaded onto the resin. This system gives a controlled release of drug, mediated by the coating, and has potential applications as a controlled release gastric retentive system.

Using isolated rat seminiferous tubules as an in vitro model, we have found that 238Pu can cross the blood-tubule barrier and accumulate within tubules in a time dependent manner. Furthermore, similar to 59Fe, tubule 238Pu uptake was inhibited by the addition of excess transferrin, suggesting that plutonium may utilize the physiological iron-transferrin pathway to cross the blood-tubule barrier. However unlike 59Fe, 238Pu was only transiently associated with the tubules, suggesting differences in the intracellular processing of these radionuclides. The assumptions made in the estimation of doses to the human testis from incorporated plutonium are considered.

We have investigated the ability of dietary vitamin C (ascorbic acid) to mitigate radiation induced damage to the testis arising from exposure to x-rays or the Auger emitting radionuclide 114mIn (half-life 50 days). Male mice were maintained on a normal or an ascorbate enriched diet (1% by weight) for 5 days then irradiated with 3 Gy 300kVp x-rays or injected intraperitoneally with 114mIn (1.85-14.8 MBq kg-1). Diets were continued for the duration of the experiment. At 35 days post-irradiation animals were killed and testicular damage was assessed using testis weight and spermhead counts as biological endpoints. Acute irradiation with 3 Gy x-rays resulted in severe damage to the seminiferous epithelium manifested as a 50% reduction in testis weight and more then 80% reduction in spermhead count, no differences were observed between control and ascorbate treated animals. Similarly chronic irradiation by tissue-incorporated 114mIn caused a dose-dependent reduction in testis weight and spermhead count and no abrogation of this effect was observed with ascorbate. While the enriched diet did result in elevated testicular ascorbate levels this effect was short-lived and appeared to be subject to diurnal variation. These results suggest that vitamin C does not have a role as a radioprotectant in the testis against medical or environmental radiation exposures.

Indium-111 oxine labeling is widely used as a marker of endothelial cell attachment to vascular prostheses. The long term effect of labeling human adult endothelial cells (HAECs) with this isotope has not been determined. In this study the viability of labeled HAECs, leakage of isotope from labeled cells and adherence of circulating isotope to fibronectin coated prostheses were investigated over 24 h. The effect of incubation time on labeling efficiency was also assessed. There were significant differences in cell viability between the labeled and unlabeled groups beyond 4 h (p < 0.005, 2-tailed, unpaired t-test). In the control group cell numbers increased by 42% while in the labeled group this had decreased by 20% at 24 h. Spontaneous leakage increased with time but was maximal in the first 2 h. Adherence of circulating isotope to fibronectin coated expanded polytetrafluoroethylene (ePTFE) grafts was minimal but was significantly greater to gelatin impregnated Dacron (GEL-SEAL) beyond 1 hour (p < 0.05). Incubation times greater than 5 minutes during labeling do not significantly improve labeling efficiency, and may contribute to toxicity by prolonging exposure to oxine. Indium-111 oxine labeling of HAECs is a suitable technique for acute studies of endothelial cell kinetics up to 4 h, but its use in chronic studies may lead to significant underestimations of cell retention.

Adult (70 d) and neonatal (7 d) male rats were dosed (i.p.) with 37 MBq/kg (1 mCi/kg; approximately 1 fig elemental indium/kg) 114m In, a transferrin-binding radionuclide. In adults, approximately 0.25% of the injected activity localised within the testis by 48 h postinjection and remained constant for up to 63 d. In neonates, 0.06% of the activity was in the testis by 48 h, and this declined such that by 63 d only 0.03% remained. At 63 d, treated rats had reduced sperm head counts and abnormal testicular histology that was more marked in animals dosed as adults than as neonates. In vitro, uptake of 114m In into seminiferous tubules isolated from 7-, 20-, or 70-d-old rats was compared with that of 125 I. Both radionuclides were readily accumulated by the tubules. Whilst 114m In uptake into 20- and 70-d tubules was inhibited by excess transferrin, uptake into 7-d tubules was unchanged. 125 I uptake was not affected by excess transferrin. These data support the contention that some radionuclides may cross the blood-testis barrier by utilisation of the physiologic iron-transferrin pathway, which may lead to greater testicular damage in adult compared to neonatal animals.

An investigation has been undertaken to assess, in vitro, the potential of several pectin formulations as colonie drug delivery systems. Experiments were conducted on the release of model compounds from matrix tablets under conditions pertaining to those in vivo. The monitoring of release gives a sensitive indication of the behaviour of the pectin under the different conditions. The type of pectin, the presence of calcium and the solubility of the calcium salt all influence release. Additionally, pectins with a low degree of methoxylation were more susceptible to enzymic breakdown. Calcium enhanced the enzymic activity. Rheological studies indicated that gel strength was a factor in determining release. These findings suggest that either a high methoxy pectin formulation or a low methoxy pectin with a carefully controlled amount of calcium should maximise colonie specificity by providing optimal protection of a drug during its transit to the colon and a high susceptibility to enzymic attack.

A novel colonic drug delivery system based on the polysaccharide pectin has been investigated. In vitro experiments demonstrated that high methoxy pectin (pectin USP), when applied as a compression coat, proved capable of protecting a core tablet during conditions mimicking mouth-to-colon transit and was susceptible to enzymatic attack. In vivo gamma scintigraphic studies confirmed the in vitro findings. In all the volunteers, the pectin-coated tablets disintegrated in the colon indicating that site-specificity had been achieved and illustrating the potential of a colonic drug delivery system utilising pectin.

The effect of a pH-dependent polymer coating, Eudragit S, on its ability to protect a model drug and control its release from rapidly disintegrating tablets has been examined in vitro. Conditions were chosen to mimic those likely to occur during transit from the mouth to the colon. Dissolution was affected by coating thickness and pH. At a given pH, the nature of the buffer system dramatically affected dissolution and disintegration. Profiling experiments involving pH changes and mimicking the extremes of conditions prevailing in vivo indicated that release of drug may commence in the duodenum or not at all.

The increasing use of Positron Emission Tomography (PET) has highlighted the need to standardize and improve the quality of decay scheme data for some positron emitters. This paper presents the results of such work for 124 I.

An improved synthetic procedure for the preparation of high specific activity 195mPt labelled cisplatin, carboplatin and iproplatin is reported. The procedure involves synthetic strategies which optimise the yields at each stage of the synthesis, giving products of high purity and in high yield (ie. cisplatin and carboplatin, 43%, and iproplatin, 22%). A new procedure for the synthesis of carboplatin using silver 1,1-cyclobutanedicarboxylate is also reported.

Radioimmunodetection of tumours with monoclonal antibodies is becoming an established procedure. Positron emission tomography (PET) shows better resolution than normal gamma camera single photon emission tomography and can provide more precise quantitative data. Thus, in the present study, these powerful methods have been combined to perform radioimmuno PET (RI-PET). Monoclonal antibodies directed against carcinoembryonic antigen (CEA) an IgG, its F(ab')2 and a mouse-human chimeric IgG derived from it were labelled with 124I, a positron-emitting radionuclide with a convenient physical half-life of four days. Mice, xenografted with a CEA-producing human colon carcinoma, were injected with the 124I-MAb and the tumours were visualized using PET. The concentrations of 124I in tumour and normal tissue were determined by both PET and direct radioactivity counting of the dissected animals, with very good agreement. To allow PET quantification, a procedure was established to account for the presence of radioactivity during the absorption correction measurement (transmission scan). Comparison of PET and tissue counting indicates that this novel combination of radioimmunolocalization and PET (RI-PET) will provide, in addition to more precise diagnosis, more accurate radiation dosimetry for radioimmunotherapy.

Thin-walled expanded polytetrafluoroethylene (ePTFE), woven Dacron® and gelatin-impregnated Dacron (Gelseal®) vascular grafts were compared, the grafts being coated with three different matrices: collagen IV, fibronectin and preclot matrix. In addition, untreated ePTFE and Gelseal were examined. The graft segments, coated with these matrices, were incubated with radiolabelled adult human endothelial cells for 30, 60 and 90 min. Endothelial cell adherence was calculated from the ratio of radioactive counts in the grafts to counts in grafts plus supernatants. Endothelial cell attachment to untreated grafts was poor, but a suitable matrix significantly improved adherence. All three matrices tested gave good results, although preclot was best; 30–60 min incubation was sufficient for optimum cell attachment. Cell adherence to both Dacron and ePTFE was significantly better than to Gelseal. The type of prosthetic polymer and the substrate protein coating used to promote endothelial cell adherence are two important factors which may determine the ultimate success of endothelial seeding in the operating room.

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.

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°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.

The complex cis-[Pt(NH3)282Br2] has been prepared as a possible model for cisplatin, cis-[Pt(NH3)2Cl2]. The stability of cis-[Pt(NH3)282Br2] was investigated in 0.9% saline solution and sterile water. In both cases the 82Br label was rapidly displaced in the first hour (t1/2 = 73 min and 96 min respectively). Thus, cis-[Pt(NH3)282Br2]cannot be used for determining the fate of the labile ligands of cisplatin.

The oral availability of a drug may be limited by the residence time of the dose in the upper GI tract. Among the methods proposed to delay the transit of oral pharmaceutical formulations is the use of bioadhesion. The GI transit of four potential bioadhesive polymers, presented in a number of different formulations, was investigated in the rat. Formulations were dosed orally, and GI transit was assessed by killing animals at various intervals and sectioning the GI tract. Significant differences in oro-caecal transit were obtained with certain formulations, with 4% and 5% solutions of Carbopol 934 showing delays of 25% in transit to the ileo-caecal junction.

It is known that the oral availability of certain drugs can be limited by the residence time of the dose in the upper GI tract. Among the methods proposed to delay the transit of oral pharmaceutical formulations is the use of bioadhesion. In this work, the gastric emptying and small intestinal transit of some potentially adhesive formulations were studied in man by gamma scintigraphy. Two different capsule formulations were investigated, in combination with two potentially bioadhesive polymers and a non-adhesive control. Small differences in oro-caecal transit were seen with certain combinations, but no dramatic effects on GI transit were observed.

Animal studies have shown that endothelial seeding of vascular prosthetic grafts reduces thrombogenicity and improves their patency. However, for endothelial seeding to be of clinical benefit in humans, it must withstand shear stress of blood flow. Endothelial cells labelled with Indium-111-oxine were seeded in supra-confluent densities on preclot or fibronectin coated ePTFE graft segments over a period of 90 min. These grafts with rapidly formed endothelial cell monolayers were then exposed to varying shear stresses up to a flow rate of 300 ml/min, using tissue culture medium in an artificial flow circuit. Grafts coated with preclot matrix showed 2 h cell retentions of 82.4 +/- 6.8% at 25 ml/min, 79.9 +/- 8.2% at 100 ml/min, 75.4 +/- 9.5% at 200 ml/min and 58.3 +/- 15.5% at 300 ml/min whilst those for the fibronectin matrix were 57.8 +/- 9.9%, 55.2 +/- 13.3%, 55.4 +/- 12.9% and 56.5 +/- 15.2% respectively. Overall the preclot matrix was found to be better than fibronectin (P less than 0.001). Light and scanning electron microscopy revealed well-formed endothelial cell monolayers retained on preclot matrix up to a flow rate of 200 ml/min whereas uncovered patches were seen at 300 ml/min and at all flow rates on fibronectin matrix.

[ 195m Pt]carboplatin has been administered intravenously, intraperitoneally and orally to Wistar rats and the tissue distribution, metabolism, and pharmacokinetics of the drug investigated. The urinary and faecal excretion and toxicity following oral [ 195m Pt]carboplatin administration has also been studied. Virtually identical results have been observed following i.v. and i.p. administration, indicating a rapid absorption of the unaltered compound from the abdominal cavity into the systemic circulation. Thus i.p. administered drug should produce a similar therapeutic response as i.v. administration, but may produce an additional local effect within the peritoneal cavity. Orally administered compound shows a pattern of distribution which is similar to that following parenteral injection for all tissues (except for the increased relative concentration in the stomach tissue), the concentration being lower by a factor of 4–5. However, the overall fraction of the dose retained within the body at 24 h is similar to that following i.v. administration. The toxicity is considerably lower for the orally administered drug compared with i.v. injection. These results clearly show that oral doses could be adjusted to produce a comparable therapeutic effect as i.v. or i.p. doses, and should also result in a higher efficacy against gastric carcinomas than achievable with parenteral administration.

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.

The gastrointestinal transit and in vivo drug release behaviour of a film-coated tablet formulation was investigated in five healthy human subjects using the technique of gamma scintigraphy. The film coating system consisted of a mixture of pectin, chitosan and HPMC in a ratio of 6:1:0.37 applied to 750 mg cores at a coat weight gain of 9%. The estimated mean values of the gastric emptying time (62+/-17 min), small intestinal transit time (219+/-53 min), ileocaecal junction lag time (79+/-30 min) and the colon arrival time (345+/-33 min), were similar to published values for the transit of similar sized tablets in humans. The amount of radioactive tracer released from the labelled tablets was minimal when the tablets were in the stomach and the small intestine. There was increased release of radioactivity when the tablets were in the colon due to increased degradation of the film coatings by pectinolytic enzymes resident in the colon. The pectin/chitosan/HPMC film coating system thus acts as a colonic delivery system.

A macroscopic quantity of quasi-spherical fullerene-like shells (see Figure) that encapsulate iron nanoparticles containing radioisotope Tc-99m are prepared for the first time. The nanocomposite is acid-non-leachable, retaining radioactivity at an extremely high level. This method will enable rigorous studies of what are currently theoretical descriptions of nanometer-scale medicinal delivery vehicles for diagnostic and therapeutic purposes.

The production and radiochemical separation of 89 Zr from deuteron irradiation of natural yttrium targets is described. The production is optimized in order to minimize the level of the long lived 88 Zr. The yield of 89 Zr at 16 MeV incident deuteron energy is 18 ± 1.5 GBq/C (1.8 ± 0.15 mCi/ μ Ah) for a target thickness of 240 mg/cm 2 and the contamination of 88 Zr is only 0.008% at EOB. The radiochemical separation of 89 Zr from the irradiated Y targets is by anion exchange chromatography with an overall yield of 80%. The intended use of 89 Zr is to label monoclonal antibodies (MoAbs) for tumour imaging using PET.

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.

An in vitro assessment was undertaken of the parameters influencing the bioadhesive strength of lyotropic liquid crystalline gels formed by the monoglyceride blend Myverol 18-99 and water. The gels were found to bind more strongly to a dry Perspex surface than to moist mucosal tissue and were shown to be weaker bioadhesives than Carbopol 934P and sodium alginate. The works of adhesion and forces of detachment were independent of contact time, were reduced by the presence of surface water and increased with an increase in the compression force, suggesting that interpenetration was not the mechanism of bioadhesion. The bioadhesion of Myverol 18-99/water gels appeared to be due to secondary chemical bonds, such as van der Waals forces, but was limited by their cohesive strength. An in vivo gel retention assessment by gamma scintigraphy showed that the gels were retained within the vaginal cavity for a period of at least 6 h.

Improved patency of endothelial cell seeded grafts relies on good initial adherence and cell retention when the circulation is restored. In this study human adult endothelial cells (HAECs) were used to evaluate the suitability of commercially available prostheses for seeding. Acutely seeded indium-111 oxine labeled HAECs were used to measure cell adherence to plain and fibronectin (FN)-coated expanded polytetrafluoroethylene (ePTFE), gelatin-impregnated Dacron (Gelseal), and collagen-impregnated Dacron (Hemashield) grafts. Cell loss from FN-coated prostheses, when exposed to a simulated human arterial blood flow of 200 ml/min in an artificial pulsatile circulation, was quantified from the loss of gamma activity from the graft over 24 hours, pressure in the circulation being reduced to 15 mm Hg to reduce fluid loss. Initial HAEC adherence (mean [SD]) to plain grafts was 3(1)%, 47(9)%, and 53(9)% for ePTFE, Gelseal, and Hemashield, respectively. This improved significantly with FN coating (78[6]%, 60[8]%, and 76[4]%). Cell retention after 24 hours of flow to FN-coated grafts was 16(10)%, 25(5)%, and 65(4)% and was confirmed qualitatively by scanning electron microscopy and environmental scanning electron microscopy. FN significantly improved initial cell adherence with Dacron grafts showing the better adherence. Cell retention after 24 hours of flow was better with FN-coated Dacron than with ePTFE but was best with Hemashield grafts.

The ammine/amine platinum(IV) dicarboxylates have been developed as orally active platinum antitumor agents, and one of these, [PtCl2(NH3)(C6H11NH2) (OCOCH3)2] (JM216), is undergoing clinical trials at present. A synthesis method was developed to radiolabel JM216 with carbon 14 at the carboxylate carbon. The labeling efficiency was 92%, and the purity as shown by high-performance liquid chromathography (HPLC) was 96% after recrystallisation. The radiolabeled JM216 was given orally to BALB/c mice and detailed tissue-distribution data were obtained (blood plasma, kidney, liver, spleen, brain, lung, muscle and skin) for time points of 2 h and 2, 6 and 10 days. Comparison of these data with previously reported data for distribution of platinum obtained by atomic absorption spectroscopy has shown distinct differences, especially for the liver and the kidney. This clearly indicates a difference in behaviour between the labeled ligand and the platinum centre, suggesting detachment of the ligand in vivo.

After intravenous doses of the plasma-bound radionuclides 59 Fe, 114 In m and 109 Cd, only a minute percentage localizes in the rat testis and remains largely unchanged with time. Intratesticular injection of appropriately reduced volumes led to much higher proportionate percentage retention of 14, 65 and 11 for 59 Fe, 114 In m and 109 Cd, respectively. By this route, significant feedback of the elements escaping initial binding was prevented. Distinct but different testicular turnovers were now discernible. As a receptor of fluid and spermatozoa from the testicular tubules, the epididymis provides an indication of entry into and interaction of the metals with spermatogenic cells. For 59 Fe no measurable changes were detected, whereas a progressive increase in epididymal 114 In m occurred, which had not reached a plateau by 70 days. 109 Cd, now demonstrated within the testicular tubules by autoradiography, remained at constant organ level for upwards of 16 days but had declined by 25% by 57 days. At this point, the epididymis showed a five-fold increase in the radionuclide, declining to one-half this value by 126 days. Since 109 Cd is carrier free, the data reflect a body turnover of dietary cadmium. These results, overall, are compatible with the entry of a proportion of each radionuclide into the seminiferous tubules and reaction with spermatogenic cells. Possible interpretations of the observed differences are presented

Objective To develop an animal model of chronic progressive hydronephrosis; to establish patterns of diuretic renography during development of the condition; and to relate renographic abnormality to morphological change in the renal parencyma. Materials and methods The cellophane sclerosis technique was used to produce a hydronephrosis in the left kidney of six rabbits. Post-operatively MAG3 diuretic renography was performed at weekly intervals. When a steady renographic trend was noted the rabbits were killed and the kikneys examined histologically. Results Four rabbits had persistent type II renogrphic curves on the left for 12 weeks. The measured split renal function fell steadily to

The incidence of childhood leukaemia in the offspring of workers at the Sellafield nuclear reprocessing plant has been associated with preconception al paternal radiation exposure (Gardner et al., 1990). One possible causative factor for this effect may be that in addition to external radiation, workers may also be subject to internal radionuclide contamination. Local testicular exposure to radionuclides offers a route for increased potential for transmission of genetic damage via sperm, irradiated during their developmental stages, which could be a contributory factor to childhood leukaemogenesis.

Plasma protein binding of 195mPt-labelled cisplatin, carboplatin and iproplatin has been studied in vivo in rat and in vitro in mouse, using both electrophoresis and trichloroacetic acid precipitation. After intravenous injection plasma clearance rates were biphasic for all 3 compounds, (t1/2 alpha, 13-17 min) but cisplatin was retained thereafter longer than the others. By 5 min, gel electrophoresis showed protein labelling with all 3 drugs but none involved low mol.wt. proteins (< 16 kDa). At 2 h a notable proportion of the protein bound platinum was associated with the latter components. There was a general resemblance between the distribution patterns of cisplatin and carboplatin whereas iproplatin showed a persistent retention of the label with time to higher mol. wt. proteins. From in vitro incubation with mouse plasma, rates of interaction respectively were cisplatin t1/2 alpha, 35 min, beta 8 h, carboplatin t1/2, 44 h and iproplatin t1/2, 104 h. By electrophoresis the protein bound fraction pattern (1 h) was again similar for cisplatin and carboplatin with virtually no binding to low mol. wt. proteins. After 24 h these were now involved to a high degree (40%). Iproplatin showed relatively marked binding to proteins of higher mol. wt. but no transfer with time to the low mol. wt. protein zone. A possible explanation is the need for in vivo metabolism for this compound as manifest in the rat. It is suggested that the significance of interaction with low mol. wt. proteins merits further investigation in relation to the antitumour and toxicological actions of these drugs.

Clinical utilisation of positron emission tomography could be enhanced by the availability of short-lived radionuclides derived from generator systems. The zinc-62/copper-62 combination is one such system which could be used as a source for a number of copper-62 radiopharmaceuticals. We have developed and optimised a high activity (5.6 GBq, 150 mCi) zinc-62/copper-62 generator to provide 62Cu in a form that is suitable for direct labelling of pyruvaldehyde-bis-(N4-methylthiosemicarbazone)-copper(II), Cu(PTSM). The distribution coefficients of Zn(II) and Cu(II) between anion-exchange resin and various hydrochloric acid/organic solvent mixtures were measured. Based on these measurements a generator eluent of 0.3 M HCl/40% ethanol provided 62Cu in greater than 90% yield in a 3-ml volume. A very low 62Zn breakthrough of less than 3 x 10(-7)% was achieved. Copper-PTSM was successfully labelled with the no-carrier-added 62Cu eluent directly from the generator with 94% radiochemical yield.

Lining the luminal surface of small diameter vascular prostheses with living endothelial cells reduces thrombogenicity, decreases infection and improves patency. In vitro adherence and kinetics studies of adult human endothelial cell seeded Polytetrafluoroethylene (ePTFE) and Gelatin impregnated Dacron (Gelseal) were performed. Endothelial cell adherence on ePTFE and Gelseal coated with collagen IV, fibronectin and preclot matrices was compared. Untreated ePTFE and Gelseal were also used. Ten graft segments in each group coated with these matrices were incubated with radio-labelled adult human endothelial cells for 30, 60 and 90 min. Labelled endothelial cells seeded in supra-confluent densities on fibronectin coated ePTFE and Gelseal grafts were used for kinetics studies. Resultant endothelial cell monolayers were then exposed to varying shear stress at flow rates of 200 and 300 ml/min in an artificial flow circuit. Endothelial cell attachment to untreated grafts was poor and a suitable matrix significantly improved adherence with fibronectin and preclot but less so with collagen. A 30 min incubation was sufficient for optimum cell attachment. Cell adherence to ePTFE was significantly better than Gelseal. Scanning electron micrographs (SEM) of ePTFE showed preferential attachment to the nodes whilst on Gelseal, cells conformed to Dacron fibres at different levels and directions. Rapidly formed endothelial cell monolayers on ePTFE and Gelseal grafts resisted shear stress of flow with significant cell retention at 2 h. There was patchy coverage of both grafts with evidence of bridging of gaps between individual fibres in Gelseal.

Forty-six comparative studies were performed on 41 patients with hyperthyroidism. Clinically these comprised two groups: those with Graves' disease, and those with multinodular goitre. All patients underwent an ultrasound examination and positron emission tomography (PET) using 124I, then gamma camera pinhole imaging following their 131I therapy administration. Although the 131I pinhole imaging was not performed for diagnostic purposes, there was good correlation (78% agreement) between it and 124I PET in determining relative lobe size. Hence either imaging modality could be used as an indicator of the relative radiation dose delivered to each thyroid lobe at a macroscopic level. In terms of gland morphology the PET images corresponded well to the high resolution ultrasound images (78% agreement), unlike the pinhole images which correlated poorly (only 28% agreement). The results showed that PET imaging gives better anatomical and physiological detail than 131I pinhole imaging. In 77% of cases where the pinhole image showed a uniform distribution of radioisotope, the improved spatial resolution of the PET images revealed non-homogeneous distribution indicating a non-uniform distribution of radiation dose. Since all dosimetry calculations are based on the assumption of uniform distribution of radioiodine, this non-uniformity could possibly have important consequences in the outcome of radioiodine therapy in thyrotoxicosis.

Although fibronectin's role as a matrix to improve endothelial seeding has been demonstrated by other workers, the optimum concentration for use has never been described. Attachment of fibronectin to expanded polytetrafluoroethylene (ePTFE) was measured, using 125I-radiolabeled protein, at different concentrations and for different time periods. The absolute amount of fibronectin bound to the graft increased with the concentrations used in coating (p less than 0.001) and also with time (p less than 0.01); e.g., at 50 micrograms/ml, 90 min of incubation produced a molecular attachment of 4.0 x 10(11)/cm2 of graft. However, its percentage attachment decreased with a rise in concentration (p less than 0.001). After an initial loss of 22% in 30 min, the fibronectin-graft bond was found to be stable when exposed to a shear stress produced by flow at 200 ml/min. No significant difference in the cell adherence could be found in grafts coated with fibronectin concentrations of 50, 150, and 250 micrograms/ml, although it was significantly less at 10 and 25 micrograms/ml (p less than 0.05).