Effect of acute/subchronic samarium exposure on the concentration, motility, and morphology of sperm in male mice.

Male ICR mice were orally administered samarium nitrate [Sm(NO3)3] to investigate its effects on sperm concentration and sperm quality. After acute exposure to ≥2880.00 mg/kg Sm(NO3)3 via intragastric gavage, sperm motility and acrosome integrity were decreased, and the sperm malformation percentage was increased (P < 0.05). After subchronic exposure to ≥500.00 mg/L Sm(NO3)3 administered via drinking water for 90 days, relative gonad weight, sperm concentration, and sperm quality significantly decreased (P < 0.05). Sperm malformation also increased after subchronic exposure to Sm, which was found to be the most sensitive index. Sperm head malformation accounted for the largest proportion of all types of sperm malformations evaluated. Of the six different subtypes of head malformation, irregular shape accounted for the largest proportion.

Comparison of the effect of knee synovectomy in haemophilic patients with 153Sm- and 90Y-labelled hydroxyapatite 1 year after.

To compare the use of 740 Mbq (20 mCi) of (153) Sm and 185 Mbq (5mCi) of (90) Y, both labelling hydroxyapatite (HA), for knee synovectomy in haemophilic patients, 1 year after the intervention. Thirty three men (36 knees) were studied, divided into two groups: 1 - treatment using 740 Mbq of (153) Sm-HA: 20 knees of 18 patients, with mean age of 21.4 ± 13.3 years (ranging from 7 to 56 years) and mean Pettersson score of 5.3; 2 - treatment using 185 Mbq of (90) Y-HA: 16 knees of 15 patients, with mean age of 26.3 ± 10.3 (ranging from 7 to 51 years) and mean Pettersson score of 6.3. The following criteria were adopted for the evaluation before and 1 year after synovectomy: reduction in haemarthrosis episodes and pain using a visual analogue scale, as well as improved joint mobility. The occurrence of adverse events in the treatment was also considered. The chi-square, Wilcoxon and Mann-Whitney tests were used with P ≤ 0.05 set as significant. The occurrence of haemarthrosis declined by 65.7% with the use of (153) Sm-HA and 82.6% for (90) Y-HA, with no statistical difference between the groups (P = 0.632); pain reduction was 42.5% in group 1 and 30.7% in group 2, once again with no statistical difference (P = 0.637). Improvement in joint mobility was not significant for both groups. Two cases of mild reactive synovitis were observed in group 1 and one in group 2, which cleared up without medical intervention. Although the beta energy from (90) Y is the gold standard for knee synovectomy, higher activities of (153) Sm may be used in places which have only production of this material.

The use of 185 MBq and 740 MBq of 153-samarium hydroxyapatite for knee synovectomy in haemophilia.

The penetration of beta energy of 153-samarium ((153) Sm) (0.8 MeV) is not only appropriate for synovectomy of median articulations but is possible to improve the radiobiological effect using increased activities. The aim of this study was to assess the effectiveness of 185 MBq and 740 MBq of 153-samarium hydroxyapatite ((153) Sm-HA) in knees of haemophilic patients. Thirty-one patients--36 knees, 30 males, were divided into two groups without coinjection of corticosteroid: A - 14 patients (17 knees) treated with intra-articular dose of 185 MBq of (153) Sm-HA, average age 23 years; B--17 patients (19 knees) with 740 MBq of (153) Sm-HA, average age 21.3 years. The evaluation before and after 1 year of synovectomy used the following criteria: reduction in the number of haemarthroses and use of the coagulation factor and improvement in articular motility. Adverse-effects occurrence was considered too. Early and late scintigraphic studies were performed after synoviorthesis and no joint immobilization was recommended. The reduction in haemarthrosis and use of coagulation factor were: group 1--31.3% and 25%; group 2--81.5% and 79% with P < 0.001 respectively; no significant improvement in knees motility was noted for both groups. Four cases of mild reactional synovitis were observed in each group. The scintigraphic control showed homogenous distribution of the radiopharmaceuticals with no articular escape; the material was considered safe by its permanence in the articulation. We have significant improvement in the synovectomy of haemophilic knees with 740 MBq of (153) Sm-HA; the less penetration of its beta radiation was compensated by the increased biological effect with the higher used activity.

Colonic delivery of metronidazole-loaded capsules for local treatment of bacterial infections: A clinical pharmacoscintigraphy study.

Drug delivery to the colon offers great promise for local treatment of colonic diseases as it allows bypassing systemic absorption in the small intestine, thereby increasing luminal drug concentrations in the colon. The primary objective of this in vivo pharmaco-scintigraphy study was to assess the colon drug targeting accuracy of a metronidazole benzoate colonic drug delivery system intended for local treatment of Clostridioides difficile infections. Additionally, it was assessed if the concept of mucoadhesion would increase colonic residence time and promote higher drug bioavailability. Two different capsule formulations were designed and tested in healthy human subjects. Capsules contained either non-mucoadhesive (NM) or mucoadhesive (M) microgranules, both loaded with 100 mg metronidazole benzoate (antibiotic prodrug) and 5 mg samarium oxide (scintigraphy tracer). Filled capsules were coated with a colonic-targeting technology consisting of two functional layers, which allow for accelerated drug release mediated by the intestinal pH in combination with colonic bacteria. Coated capsules were neutron-activated to yield the radioisotope 153Sm prior to administration to 18 healthy subjects. Gamma-scintigraphy imaging was combined with the measurement of drug plasma levels. Formulation NM showed high colon-targeting accuracy. Initial capsule disintegration within the targeted ileocolonic region was observed in 8 out of 9 subjects (89%) with colonic arrival times in the range of 3.5-12 h and reduced systemic exposure. In contrast, the mucoadhesive formulation M showed some inconsistency regarding the site of initial capsule disintegration (targeting accuracy 56%). Variability of drug release was attributed to self-adhesion and agglomeration of the mucoadhesive microparticles within the capsule. Accurate ileocolonic delivery of metronidazole-loaded microgranules was achieved following oral administration of colonic-targeted capsules. Delayed drug release from NM microparticles in the colon leads to a reduced systemic exposure compared to immediate-release data from literature and presumably elevated drug concentrations in the colonic lumen. This approach offers promising options for the local treatment of colonic diseases.

A Phase II study of (153)Sm-EDTMP and high-dose melphalan as a peripheral blood stem cell conditioning regimen in patients with multiple myeloma.

Multiple myeloma (MM) remains an incurable illness affecting nearly 20,000 individuals in the United States per year. High-dose melphalan (HDM) with autologous hematopoietic stem cell support (ASCT) is one of the mainstays of therapy for younger patients, but little advancement has been made with regards to conditioning regimens. We opted to combine (153)Samarium ethylenediaminetetramethylenephosphonate ((153)Sm-EDTMP), a radiopharmaceutical approved for the palliation of pain caused by metastatic bone lesions, with HDM and ASCT in a Phase II study. Individualized doses of (153)Sm were based on dosimetry and were calculated to deliver 40 Gy to the bone marrow. The therapeutic dose of (153)Sm-EDTMP was followed by HDM and ASCT. Forty-six patients with newly diagnosed or relapsed disease were treated. Study patients were compared to 102 patients contemporaneously treated with HDM and ASCT. Fifty-nine percent of study patients achieved a very good partial response (VGPR) or better. With a median follow-up of 7.1 years, the median overall survival and progression free survival (PFS) from study registration was 6.2 years (95% CI 4.6-7.5 years) and 1.5 years (1.1-2.2 years), respectively, which compared favorably to contemporaneously treated non-study patients. Addition of high-dose (153)Sm-EDTMP to melphalan conditioning appears to be safe, well tolerated, and worthy of further study in the context of novel agents and in the Phase III setting.

A phase I study of samarium lexidronam/bortezomib combination therapy for the treatment of relapsed or refractory multiple myeloma.

PURPOSE: This open-label, phase I dose-escalation study assessed the safety, tolerability, and initial efficacy of Samariam 153 (153Sm)-lexidronam/bortezomib combination therapy for patients with relapsed/refractory multiple myeloma. EXPERIMENTAL DESIGN: Patients were enrolled in six cohorts and given bortezomib (1.0 or 1.3 mg/m2) on days 1, 4, 8, and 11 and 153Sm-lexidronam (0.25, 0.5, or 1.0 mCi/kg) on day 3 of a 56-day cycle (maximum of four cycles). The primary endpoints were safety and tolerability of the 153Sm-lexidronam/bortezomib regimen. RESULTS: Twenty-four patients were enrolled. Median values for age, time since diagnosis, and number of prior treatments were 63 years, 29 months, and three regimens, respectively. The most common toxicities were hematologic; during the first cycle, median neutrophil and platelet nadirs were 1,000/mm3 and 98,500/mm3, respectively, and observed generally 3 to 4 weeks post-treatment. The incidences of grade 4 neutropenia and thrombocytopenia were 12.5% and 8.3%, respectively, during treatment cycle 1. Dose-limiting toxicity, reached in cohort 6 as a result of hematologic toxicity, defined the maximum tolerated dose as 0.5 mCi/kg 153Sm-lexidronam in combination with 1.3 mg/m2 bortezomib. The maximum tolerated dose for 153Sm-lexidronam in combination with the 1.0 mg/m2 bortezomib was not reached. No nonhematologic dose-limiting toxicities were observed; both the incidence and the severity of peripheral neuropathy were low. Responses occurred in 5 (21%) patients, including 3 (12.5%) complete and 2 (8.3%) minimal responses. CONCLUSIONS: Bortezomib combined with 153Sm-lexidronam appears to be a well-tolerated regimen, which showed clinical activity in this phase I trial for patients with relapsed or refractory multiple myeloma.

Clinical evaluation after 1 year of 153-samarium hydroxyapatite synovectomy in patients with haemophilic arthropathy.

The aim is to evaluate the efficiency of the treatment with 153-samarium hydroxyapatite (153-Sm-HA) in haemophilic arthropathy. Thirty-one patients (30 males) with ages ranging from 8 to 34 years (average age = 20.6 years) were treated with fixed intra-articular dose of 185 MBq (5 mCi) and divided into two groups: infantile-juvenile (13 patients with up to 18 years of age, an average age of 12.7 years and arthropathy evolution of 7.8 years), and adult (18 patients older than 18 years, an average age of 24 years and arthropathy evolution of 18.7 years). The clinical evaluation before and after 1 year of synovectomy used the following criteria: subjective (pain through visual scale, articulation inspection), objective (articular movement through flexion level, sensitivity to palpation and leakage through joint circumference), reduction on the use of the coagulation factor, number of haemarthrosis, and the occurrence of adverse effects. The results were classified as: 1, good (remission from 70% to 100% of manifestations); 2, moderate (remission from 40% to 69%); and 3, poor (remission from 0% to 39%). Seventy-eight joints were tested: 15 knees, 36 elbows, 24 ankles, 1 shoulder and 2 hips. Early scintigraphic (1-2 h) and late scintigraphic (24-72 h) studies were performed after synoviorthesis. The cost of the procedure per joint was also estimated. No significant difference in the synoviorthesis result between groups was observed. The results were good for 75% of elbows, 87.5% of ankles and 40% of knees; the reduction in haemarthrosis and use of the coagulation factor was respectively 78% and 80% for elbows, 82% and 85% for ankles and 30% and 35% for knees. Four cases of reactional synovitis were observed in the 31 patients. The scintigraphic control showed homogeneous distribution of the material with no articular escape. The use of 153 Sm-HA in the treatment of the haemophilic arthropathy is effective for intermediate-size joints (elbows and ankles), but less effective for knees. Moreover, this treatment presents an excellent safety profile and accessible cost.

[Bone targeting of antitumor conjugate phenamine acid aryolysine-hexanedioic acid bridge grafting-bisphosphonates].

OBJECTIVE: To develop a new bone targeting antitumor therapy system which uses diphosphonate and bone-seeking nuclide to enhance the coordinated effects of chemotherapy and radiotherapy on bones, and to validate the targeting of the new therapy system in vitro and in vivo. METHODS: Phenamine acid caryolysine was connected to bisphosphonates, and then combined with radioactive nuclide 153Sm to establish a new bone targeting chemotherapeutic and radioactive drug for bone cancers. The targeting of this new therapy system was validated by hydroxyapatite crystal absorbing test and body distribution in vivo methods. RESULTS: The optical spectrum of the phenamine acid caryolysine-bisphosphonates conjugate detected by the nuclear magnetic resonance was consistent with the standard structure of synthesized drugs. The conjugate had good absorbability to hydroxyapatite crystals. The body distribution of the conjugate showed higher radiocounting in bones than in other tissues. CONCLUSION: The conjugate has a structure that is consistent with the active compound targeting bone tumors.

Effect of Au-197 nanoparticles along with Sm-153 radiopharmaceutical in prostate cancer from simulation method.

AIMS: Based on recent studies, it was indicated that gold (Au-197) nanoparticles could be safely prescribed and used to enhance the absorbed dose during radiation therapy. SUBJECTS AND METHODS: We evaluated the samarium-153 (Sm-153) radiopharmaceutical and Au-197 and Sm-153 radiopharmaceutical absorbed dose rate by means of the Monte Carlo technique in prostate cancer. RESULTS: The results show that absorbed dose rate in entire prostate volume due to 20 mCi of Sm-153 radiopharmaceutical is 27.339 µGy/s, 48.837 µGy/s, and 76.176 µGy/s for γ-interaction, ߯ particle interaction, and γ+߯ interaction, respectively. The results in the exterior of the prostate for ߯ interaction, ߯ particle interaction, and γ+߯ interaction were 20.971 µGy/s, 1.110 µGy/s, and 22.081 µGy/s, respectively. CONCLUSIONS: The calculation results for Au-197 and Sm-153 radiopharmaceutical show that the absorbed dose rate in entire prostate volume 3% was increased and undesirable dose value in exterior of prostate 7% was decreased.

Neutron activation based gamma scintigraphic evaluation of enteric-coated capsules for local treatment in colon.

The fate of two colon-specific formulations developed in our previous study was investigated using a gamma scintigraphic imaging method. The formulations contained paracetamol and samarium oxide (Sm2O3) and either microcrystalline cellulose (MCC) or hypromellose (HPMC K4M) as diluent and were coated with Eudragit S polymer. The gamma scintigraphic evaluation proved that the products remained intact in the stomach and the upper gastrointestinal tract. The gastric residence time was less that 1h. Three to four hours after administration the formulations had reached the ileo-caecal junction, i.e. the small intestine transit time was approximately 3h. The capsules disintegrated in the ileo-caecal junction or in the ascending colon. The capsules containing MCC released the marker momentarily, the capsules containing HPMC K4M gradually spreading it to the whole colon. The gamma images also verified that the HPMC gel disintegrates completely in 12-14 h. While comparing the results to those previously obtained from the bioavailability studies it could be concluded that it is possible to develop colon specific drug products that begin releasing the drug in the ileo-caecal junction or at the beginning of the ascending colon and spread the drug dose to a larger surface area by using enteric coats and hydrophilic polymers.

Development of samarium [32P] phosphate colloid for radiosynoviorthesis applications: preparation, biological and preliminary clinical studies experience.

A new therapeutic radio colloid for radiosynoviorthesis (RS) applications is reported. The method of preparation involves the reaction of SmCl3 carrier with carrier added [32P]H3PO4 in the presence of gelatin. The pure colloid was recovered by dialysis purification leading to radiochemical yield of around 90%. The radiochemical purity of the pure colloid formulated in isotonic saline was over 98%, for the usage period of 14 days, as assessed by paper chromatography. Ninety percent of colloid particles were in the size of 1-10 microm as evident from the laser diffraction particle size analysis, ideally suitable for the intended end use. Animal studies revealed complete retention of the radio colloid in the rabbit knee joint. The results of clinical trials in humans are satisfactory and encouraging, satisfactory retention of the colloid in the knee joint and negligible leakage into the systemic circulation.

Marrow irradiation with high-dose 153Samarium-EDTMP followed by chemotherapy and hematopoietic stem cell infusion for acute myelogenous leukemia.

In four patients, aged 15 - 20 years, with high-risk acute myeloid leukemia (AML), high-dose samarium 153-labelled ethylenediaminetetramethylenephosphonate (153Sm-EDTMP) was used for targeted marrow irradiation before preparative chemotherapy conditioning regimens and allogeneic (three patients) or autologous (one patient) hematopoietic stem cell transplantation. The dose of 153Sm-EDTMP was 703 MBq/kg (n = 1) or 1110 MBq/kg (n = 3). No side-effects occurred during the 30-min infusion of 153Sm-EDTMP. Samarium - melphalan regimens were given to three patients; one had 153Sm-EDTMP - busulfan + cyclophosphamide. Total body radioactivity was below the 133 MBq safe limit before infusion of stem cells (day 14 after 153Sm-EDTMP). No hemorrhagic cystitis, nephrotoxicity or serious infections occurred. Leukocyte engraftment (white blood cell count >0.5 x 10(9)/l) occurred between 12 and 23 days after stem cell infusion (mean of 17 days). Complete cytogenetic and morphologic remission of AML was evident on follow-up marrow aspirate and biopsy specimens from all patients. In two of the four study patients, the disease remains in complete remission and the patients have an excellent quality of life (Eastern Cooperative Oncology Group performance status 0; no medications) and no organ toxicity more than 2 years and more than 4 years, respectively, after their blood and bone marrow transplantations. Thus, in adolescents and adults, 153Sm-EDTMP may provide a relatively simple and effective means for using irradiation to eliminate AML within the marrow.

Binding Specificity of Radiolabeled Cyclic Peptide 153Sm-DTPA-c(CGRRAGGSC) to MHCC97-H Human Liver Cancer Cells and its Antitumor Effects in vivo.

OBJECTIVE: This objective of this study is to investigate the effects of the radiolabeled cyclic peptide 153Sm-DTPA-c(CGRRAGGSC) on MHCC97-H human liver cancer cells in vitro and in vivo. METHODS: The protein expression levels were examined by Western blot analysis. Biological activity of 153Sm-DTPA-c(CGRRAGGSC) was assessed with the radioligand binding assay and competitive inhibition experiment. Subcellular localization of the cyclic peptide was observed by fluorescence microscopy. Animals were implanted with MHCC97-H cells and administered with 153Sm-DTPA-c(CGRRAGGSC). Hematoxylin and eosin staining, electron microscopy, and immunohistochemistry were performed to evaluate the effects of 153Sm-DTPA-c(CGRRAGGSC) on implanted tumors. RESULT: The expression levels of interleukin 11 receptor were significantly elevated, by 2-to 5-fold, in tumor cell lines, especially for MHCC97-H cells. Characterization of 153Sm-DTPA-c(CGRRAGGSC) showed that the biological activity of the cyclic peptide was not altered after labeling, and the radiolabeled cyclic peptide exhibited sufficient binding affinity to interleukin 11 receptor . The cyclic peptide of c(CGRRAGGSC) was mainly distributed in the cytoplasm and on the cell membrane of MHCC97-H cells. The in vivo experiments showed that the tumor growth was significantly inhibited by the treatment of 153Sm-DTPA-c(CGRRAGGSC). The inhibitory effect of 153Sm-DTPA-c(CGRRAGGSC) on tumor growth was further confirmed by Hematoxylin and eosin staining, electron microscopy, and immunohistochemistry. Moreover, the expression levels of interleukin 11 receptor in implanted tumors were significantly decreased in the treatment groups. CONCLUSION: 153Sm-DTPA-c (CGRRAGGSC) could specifically bind to interleukin 11 receptor on MHCC97-H liver tumor cells, inhibiting the cell proliferation and inducing cellular apoptosis. These findings provide experimental evidence for the development of individual treatment of liver cancers, as well as recurrence and metastasis.

Accumulation and distribution of samarium-153 in rat brain after intraperitoneal injection.

It is well known that rare earth elements (REEs) have come into extensive use in a number of fields. As a result, REEs are becoming closely related to human's daily life. However, until now, the distributions of REEs in the brain are not yet very clear. In this study, Sprague-Dawley male rats were intraperitoneally injected with 0.25 mL of (153)SmCl(3) solution (containing 10 microg Sm). The brains were perfused with saline to minimize the blood influence. The radioactivities of (153)Sm in the five brain regions (hypothalamus, cerebellum, hippocampus, corpus striatum, and cerebral cortex) were counted. The results suggested that Sm did enter into the brain. Although only about 0.0003% of the given dose was accumulated in the brain, Sm seemed to be remain in the brain for a long time. The highest amounts and lowest concentrations of (153)Sm were found in the cerebral cortex, and the highest concentrations of (153)Sm were found in the hypothalamus.

High-dose treatment with (186)Re-HEDP or (153)Sm-EDTMP combined with amifostine in a rabbit model.

UNLABELLED: The aim of this experimental study was to investigate the myeloprotective potential of amifostine in rabbits receiving high-dose treatment with either (153)Sm-ethylenediaminetetramethylene phosphonate (EDTMP) or (186)Re-hydroxyethylidene diphosphonate (HEDP) and to check for drug interactions impairing the skeletal uptake of these radiopharmaceuticals by amifostine. METHODS: To a total of 24 rabbits, we administered 1,000 MBq of either (153)Sm-EDTMP (n = 12) or (186)Re-HEDP (n = 12). Six animals of each group received 500 mg amifostine intravenously 10-15 min before injection of the radiopharmaceutical, whereas the other 6 animals served as controls. Up to 8 wk after treatment, blood samples were collected every 3-5 d to measure platelet and leukocyte counts. Furthermore, whole-body images were acquired at 3 min, 3 h, and 24 h after injection of the radiopharmaceutical to quantify the skeletal uptake. RESULTS: For (186)Re-HEDP, the mean decrease in platelets was significantly less in the amifostine group (35.5% +/- 2.4%) than in the control group (61.3% +/- 5.4%, P < 0.001). Similar results were found for (153)Sm-EDTMP (36.5% +/- 8.3% vs. 52.3% +/- 14.0%, P < 0.05). No significant differences in leukocyte counts were found for (186)Re-HEDP (75.3% +/- 12.3% in the amifostine group and 72.5% +/- 4.1% in the control group, P > 0.05), whereas rabbits treated with (153)Sm-EDTMP plus amifostine showed a significantly greater decrease in leukocytes (69.2% +/- 10.8%) than did the control group (56.6% +/- 4.0%, P < 0.05). Bone uptake in percentage of initial total whole-body activity was significantly decreased in animals treated with amifostine compared with the control groups for both (186)Re-HEDP (15.8% +/- 3.1% vs. 30.9% +/- 1.9%, P < 0.001) and (153)Sm-EDTMP (31.7% +/- 8.9% vs. 44.0% +/- 6.5%, P < 0.05). CONCLUSION: For amifostine, we found a highly significant cytoprotective effect on platelets but no leukoprotective effect. The latter probably relies on the intrinsic myelotoxicity of high-dose amifostine, which seemed to potentiate the leukodepression of the radiopharmaceuticals. The lower bone uptake in amifostine-treated animals may be caused by the chemical structure of amifostine, which is a potentially complex-forming compound that may be able to displace bisphosphonates from the rhenium- and samarium-bisphosphonate complexes, resulting in altered biodistribution patterns.

Clinical and clinicopathologic effects of samarium-153-EDTMP administered intravenously to normal beagle dogs.

A study was undertaken to determine the degree of acute bone marrow and vital organs injury sustained when dogs were administered doses of 153Sm-EDTMP calculated to irradiate an acute bone lesion arising from cancer metastasis to a dose considered palliative or even therapeutic (20-160 Gy). The study revealed significant (p less than 0.05) temporary depression of the bone marrow in all doses in the therapeutic (greater than 40 Gy) range. Palliative (20 Gy) doses caused significant leukocyte depression but insignificant (p greater than 0.05) depression of platelet and packed cell volumes when compared to control animals. A mild transient rise in the levels of serum alkaline phosphatase occurred immediately following radioisotope administration. All hematologic parameters had returned to normal by six weeks after the last injection of radioisotope. The study indicates potential for this compound as a safe, therapeutic radiopharmaceutical for treatment of cancer bone metastasis.

Dose response relationship and multiple dose efficacy and toxicity of samarium-153-EDTMP in metastatic cancer to bone.

INTRODUCTION: The optimal dose of samarium-153-EDTMP (153Sm-EDTMP) for effective palliation of painful metastases to bone is under investigation. It is not known whether increased doses of 153Sm EDTMP will lead to better and longer pain and tumour control and survival. Multiple dose efficacy and toxicity is of importance as most Patients will require prolonged support for pain. METHODS: Twenty-eight (28) patients were treated with 0.75 mCi/kg, 35 patients with 1.5 mCi/kg and 19 patients with 3 mCi/kg in three sequential Phase I-II trials. Multiple doses were given to patients on the 0.75 mCi/kg and 1.5 mCi/kg dose levels. RESULTS: At all dose levels adequate pain control was achieved in 78-95% of patients. The duration of pain control was 40-56 days with the best results in the 1.5 mCi/kg group (56 days). There is no evidence that increasing dose leads to better and longer pain control, tumour response and survival, but toxicity is increased. Multiple doses can be given with acceptable toxicity and pain control, however, only 38% of patients will qualify for multiple treatments. CONCLUSION: 153Sm-EDTMP provides adequate and safe palliation but multiple doses can only be given in 38% of patients. There is not a clear dose-response relationship. The length of pain control is satisfactory but not ideal and hospitalisation for 4 days every 6-8 weeks is a disadvantage. Further research is required to combine 153Sm-EDTMP with cytostatics and to administer it on an out patient basis.

Gamma scintigraphic evaluation of the fate of microcrystalline chitosan granules in human stomach.

In several reports of in vitro studies it has been suggested that the mucoadhesive chitosans could be of value in preparing gastro-retentive formulations. The aim of this study was to obtain direct in vivo evidence of whether microcrystalline chitosan (MCCh) formulations acted as gastro-retentive systems in humans. Neutron-activation-based gamma scintigraphy was used to study gastric residence times of MCCh granules in healthy male volunteers. Possible effects of neutron irradiation on the properties of the MCCh granules were studied in advance, in vitro. In vivo gamma scintigraphic evaluations were carried out with the subjects in a fasted state, using granules containing 95% (F1) or 40% (F2) of MCCh of molecular weight 150 kDa. Reference formulation (F3) was lactose granules. The reference granules passed rapidly from the stomach (mean t50% 0.5+/-0.3 h (n=5)). MCCh in granules prolonged gastric residence times of the formulations in only a few cases (in one volunteer in the F1 group (n=4) and in two volunteers in the F2 group (n=5)). Maximum individual t50% values were 2.1 h (F1) and 2.3 h (F2). It was concluded that the in vivo mucoadhesion of MCCh formulations is erratic, and that the formulations studied are not reliable gastro-retentive drug delivery systems.

Scintigraphic evaluation of a new capsule-type colon specific drug delivery system in healthy volunteers.

Colonic drug delivery is intended for local or systemic therapies. The lack of predictive in vitro or animal model leads to considerable time delays in colonic product development. The objective of this scintigraphic study was to provide "proof of concept" for a novel capsule-type colonic delivery system (Colon-Targeted Delivery Capsule) in healthy volunteers. The human data validates the design concept behind the release mechanism, in that capsule disintegration, and hence drug release, did not start until 5 h after gastric emptying, irrespective of whether the product was administered to fasted or fed subjects. However, the potential for prolonged gastric residence for large enteric coated products intended for intestinal targeting was also observed; overall, the study provides a focus for subsequent product development and highlights the role of scintigraphy in dynamically visualizing the drug delivery process.

Influence of neutron activation factors on matrix tablets for site specific delivery to the colon.

The impact of the neutron activation procedure, i.e. incorporation of samarium oxide (Sm(2)O(3)) and neutron irradiation, on the compression properties (including the crushing strength) and in vitro dissolution of potential colonic delivery systems based on matrix tablets of amidated pectin (Am.P) or two types of hydroxypropyl methylcellulose (HPMC) was investigated. The neutron activation factors did not influence the compression properties of the tablets. Replacement of magnesium stearate with samarium stearate in directly compressed Am.P tablets to achieve both radiolabelling and lubrication resulted in a greater extent of concentration-dependent reduction of the crushing strength. Dissolution tests demonstrated that irradiation increased the release of the model drug ropivacaine from the tablets. The extent of this increase was unexpectedly low considering the previously observed degradation of the polymer expressed as an irradiation-induced viscosity reduction in solutions prepared from the polymers. Delayed-release coating with Eudragit L 100 protected the HPMC tablets against the release-increasing effect of irradiation until the late phases of release. Sm(2)O(3) retarded the release to a varying extent depending on particle characteristics. Incorporation of Sm(2)O(3) in the coating layer did not influence the release. However, one-third of the radioactivity leached from the coating within 60 min in 0.1 M HCl.