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.

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.

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.

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.

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.

Clinical dosimetry in the treatment of bone tumors: old and new agents.

Treatment of multisite, sclerotic bone metastases is successfully performed by radionuclide therapy. Pain palliation is the most common aim for the treatment. Two radiopharmaceuticals are currently approved by the European Medicines Agency ((153)Sm-EDTMP and (89)Sr-Cl2) whilst other radiopharmaceuticals are at different stages of development, or are approved in some European countries ((186)Re-HEDP, (117)Snm-DTPA and (223)Ra-Cl2). The tissues at risk for the treatment are bone marrow and normal bone. A review of the methods applied for dosimetry for these tissues and for tumours is performed, including the calculation of S values (the absorbed dose per decay) and optimal procedures on how to obtain biodistribution data for each radiopharmaceutical. The dosimetry data can be used to individualise and further improve the treatment for each patient. Dosimetry for radionuclide therapy of bone metastases is feasible and can be performed in a routine clinical practice.

Gamma spectrometry and chemical characterization of ceramic seeds with samarium-153 and holmium-166 for brachytherapy proposal.

Ceramic seeds were synthesized by the sol-gel technique with Si:Sm:Ca and Si:Ho:Ca. One set of seeds was irradiated in the TRIGA type nuclear reactor IPR-R1 and submitted to instrumental neutron activation analysis (INAA), K(0) method, to determine mass percentage concentration of natural samarium and holmium in the seed as well as to determine all existing radionuclides and their activities. Attention was paid to discrimination of Si-31, Ca-40, Ca-45, Ca-47, Ca-49, Sm-145, Sm-155, Sm-153 and Ho-166. A second sample was submitted to atomic emission spectrometry (ICP-AES) also to determine samarium and holmium concentrations in weight. A third sample was submitted to X-ray fluorescence spectrometry to qualitatively determine chemical composition. The measured activity was due to Sm-153 and Ho-166 with a well-characterized gamma spectrum. The X-ray fluorescence spectrum demonstrated that there is no discrepancy in seed composition. The maximum ranges in the water of beta particles from Sm-153 and Ho-166 decay were evaluated, as well as the dose rate and total dose delivered within the volume delimited by the range of the beta particles. The results are relevant for investigation of the viability of producing Sm-153 and Ho-166 radioactive seeds for use in brachytherapy.

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.

Effectiveness of radiation synovectomy with samarium-153 particulate hydroxyapatite in rheumatoid arthritis patients with knee synovitis: a controlled randomized double-blind trial.

OBJECTIVES: The aim of the present study was to investigate the effectiveness of Samarium(153)-particulate hydroxyapatite radiation synovectomy in rheumatoid arthritis patients with chronic knee synovitis. METHODS: Fifty-eight rheumatoid arthritis patients (60 knees) with chronic knee synovitis participated in a controlled double-blinded trial. Patients were randomized to receive either an intra-articular injection with 40 mg triamcinolone hexacetonide alone (TH group) or 40 mg triamcinolone hexacetonide combined with 15 mCi Samarium(153)-particulate hydroxyapatite (Sm/TH group). Blinded examination at baseline (T0) and at 1 (T1), 4 (T4), 12 (T12), 32 (T32), and 48 (T48) weeks post-intervention were performed on all patients and included a visual analog scale for joint pain and swelling as well as data on morning stiffness, flexion, extension, knee circumference, Likert scale of improvement, percentage of improvement, SF-36 generic quality of life questionnaire, Stanford Health Assessment Questionnaire (HAQ), Lequesne index, use of non-steroidal anti-inflammatory drugs or oral corticosteroids, events and adverse effects, calls to the physician, and hospital visits. RESULTS: The sample was homogeneous at baseline, and there were no withdrawals. Improvement was observed in both groups in relation to T0, but no statistically significant differences between groups were observed regarding all variables at the time points studied. The Sm/TH group exhibited more adverse effects at T1 (p<0.05), but these were mild and transitory. No severe adverse effects were reported during follow-up. CONCLUSION: Intra-articular injection of Samarium(153)-particulate hydroxyapatite (15 mCi) with 40 mg of triamcinolone hexacetonide is not superior to triamcinolone hexacetonide alone for the treatment of knee synovitis in patients with rheumatoid arthritis at 1 y of follow-up.

[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.

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.

Effectiveness of radiation synovectomy with samarium-153 particulate hydroxyapatite in rheumatoid arthritis patients with knee synovitis: a controlled randomized double-blind trial

OBJECTIVES: The aim of the present study was to investigate the effectiveness of Samarium153-particulate hydroxyapatite radiation synovectomy in rheumatoid arthritis patients with chronic knee synovitis. METHODS: Fifty-eight rheumatoid arthritis patients (60 knees) with chronic knee synovitis participated in a controlled double-blinded trial. Patients were randomized to receive either an intra-articular injection with 40 mg triamcinolone hexacetonide alone (TH group) or 40 mg triamcinolone hexacetonide combined with 15 mCi Samarium153-particulate hydroxyapatite (Sm/TH group). Blinded examination at baseline (T0) and at 1 (T1), 4 (T4), 12 (T12), 32 (T32), and 48 (T48) weeks post-intervention were performed on all patients and included a visual analog scale for joint pain and swelling as well as data on morning stiffness, flexion, extension, knee circumference, Likert scale of improvement, percentage of improvement, SF-36 generic quality of life questionnaire, Stanford Health Assessment Questionnaire (HAQ), Lequesne index, use of non-steroidal anti-inflammatory drugs or oral corticosteroids, events and adverse effects, calls to the physician, and hospital visits. RESULTS: The sample was homogeneous at baseline, and there were no withdrawals. Improvement was observed in both groups in relation to T0, but no statistically significant differences between groups were observed regarding all variables at the time points studied. The Sm/TH group exhibited more adverse effects at T1 (p<0.05), but these were mild and transitory. No severe adverse effects were reported during follow-up. CONCLUSION: Intra-articular injection of Samarium153-particulate hydroxyapatite (15 mCi) with 40 mg of triamcinolone hexacetonide is not superior to triamcinolone hexacetonide alone for the treatment of knee synovitis in patients with rheumatoid arthritis at 1 y of follow-up.

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.

Combined use of zoledronic acid and 153Sm-EDTMP in hormone-refractory prostate cancer patients with bone metastases.

PURPOSE: (153)Sm-ethylenediaminetetramethylenephosphonic acid (EDTMP; Quadramet) is indicated for the treatment of painful bone metastases, whereas zoledronic acid (Zometa) is indicated for the prevention of skeletal complications. Because of the different therapeutic effects, combining the treatments may be beneficial. Both, however, accumulate in areas with increased osteoblastic activity. Possible drug interactions were investigated. METHODS: Patients with hormone-refractory prostate cancer were treated with 18.5 MBq/kg (153)Sm-EDTMP in weeks 1 and 3 and with 37 MBq/kg in week 15. Treatment with 4 mg zoledronic acid began in week 3 and continued every 4 weeks through week 23. In weeks 3 and 15, zoledronic acid was administered 2 days before (153)Sm-EDTMP treatment. Urine was collected 48 h after injection of (153)Sm-EDTMP, and whole-body images were obtained 6, 24 and 48 h post-injection. The effect of zoledronic acid on total bone uptake of (153)Sm-EDTMP was measured indirectly by the cumulative activity excreted in the urine in weeks 1, 3 and 15. Biodistribution, safety, tolerability and effect on prostate-specific antigen level were also studied. RESULTS: The urinary excretion in week 3 divided by the urinary excretion in week 1 (baseline) times 100% was mean 98.4 +/- 11.6% (median 96.2%). From week 1 to 15, after four zoledronic acid treatments, the mean ratio was 101.9 +/- 10.7% (median 101.8%). Bioequivalence could be concluded by using a two-sample t test for both per-protocol (n = 13) and full-analysis sets (n = 18). Toxicity was comparable to of monotherapy with (153)Sm-EDTMP. CONCLUSION: Zoledronic acid treatment does not influence (153)Sm-EDTMP skeletal uptake. Combined treatment is feasible and safe.

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.

A novel method to radiolabel gastric retentive formulations for gamma scintigraphy assessment.

PURPOSE: To develop a robust radiolabeling technique to enable evaluation of difficult to radiolabel gastric retentive formulations using gamma scintigraphy. The use of a successful radiolabel will allow accurate assessment of the gastric residence time of the formulations. MATERIALS AND METHODS: The retention of two radionuclides, indium ((111)In) and samarium ((153)Sm), with and without further processing to improve radiolabel performance were evaluated in simulated gastric pH in vitro. The most successful formulation from the in vitro screening was further evaluated in preclinical and clinical studies. RESULTS: In vitro evaluation revealed significant radionuclide leakage at pH 1.5 for most radiolabeling attempts. Radionuclide leakage at pH 4.5 was less pronounced. The most successful radiolabel was formulated by adsorbing indium chloride onto activated charcoal, followed by entrapment in a cellulose acetate polymer melt. This provided the best radiolabel retention under both pH conditions in vitro. The radiolabel also proved to be successful during preclinical and clinical evaluations, allowing evaluation of gastric retention performance as well as complete gastrointestinal transit. CONCLUSION: A simple, yet robust radiolabel was developed for gastric retentive formulations to be evaluated pre-clinically or in a clinical setting by entrapping the radionuclide in an insoluble polymer through a simple polymer melt process.

Systemic Radionuclide Therapy of Painful Prostate Cancer Bone Metastases With Samarium-153-edtmp

Most patients with prostate cancer (PC) will develop painful bone metastases, which alters their quality of life. Objective: This study aimed to evaluate the efficacy and toxic hematological profile of samarium for the treatment of PC metastases’ bone pain. Methods: Twenty-nine PC patients (median age: 69 years, range: 46-84; Gleason score equal to or higher than 7 in 66.7% and under 7 in 33.3% of patients presenting multiple painful bone metastases were treated with intravenous injection of 153Sm-EDTMP. Response to treatment was defined as either a reduction of at least 25% in patient’s pain score, using a 0 to 10 scale (score 0: no pain, score 10: maximum pain), or in daily analgesic dosage. Complete blood counts were performed before 153Sm–EDTMP administration and 4 and 8 weeks after treatment with the purpose of evaluating hematological side effects of the agent. Results: Twenty-five patients (86.2%) responded to treatment (median time: 1.5 month, range: 1.0 to 2.0 months). A reduction equal to or higher than 25% in post-treatment values compared to baseline values was seen in hemoglobin (Hb) of 3 (12.0%) patients, in leukocytes (Lo) of 16 (64.0%) patients, and in platelets (Pl) of 19 (76.0%) patients. Hb under 10g/dl, Lo under 2.0x103/ul, and Pl under than 50.0x103/ul were seen in 7 (28.0%), 3 (12.0%) and 2 (8.0%) out of 25 patients analyzed after 153Sm–EDTMP, respectively. No infectious or bleeding episodes were seen in any patient during the study. Conclusion: 153Sm-EDTMP is effective for acute control of PC patients’ bone pain. However, additional studies with bone marrow assessment before and after 153Sm–EDTMP are necessary to clarify the origin of cytopenias found in our cases.

[Primary investigation of dose-effect relationship of 153Sm-EDTMP in treating multiple bone metastases].

BACKGROUND & OBJECTIVE: Dose calculation of radionuclide internal irradiation is a hot topic and difficulty of nuclear medical researches. This study was to calculate the focus absorption dose of 153Sm-EDTMP with the Monte Carlo EGS4 method for treatment of bone metastases from nasopharyngeal carcinoma or breast cancer, and investigate the relationship between the focus absorption dose and painkilling effect of 153Sm-EDTMP. METHODS: Four patients with multiple bone metastases from nasopharyngeal or breast carcinoma and suffered from grade IV bone pain were treated with radionuclide internal irradiation of 153Sm-EDTMP. The absorption dose and dose distribution of bone metastases and other targeted organs were calculated with MC EGS4 program based on the time-order SPECT/CT scanning and the measurement of the radioactivity in the urine accumulation. The release of bone pain and the improvement of life quality were observed. RESULTS: Bone pain of the patients was significantly alleviated to grade II for 3-4 weeks after internal 153Sm-EDTMP irradiation. The 3-dimensional absorption dose distribution image of bone metastases and targeted organs showed that the dose distribution in bone metastases was not asymmetrical. After injection of 0.65x37 MBq/kg 153Sm-EDTMP, the highest absorption dose in bone lesions was about 4.9-5.9 Gy, and the dose in the lesion margin was about 2.0 Gy. Use the highest dose as reference dose point, the relative absorption dose values of bone marrow, bone cortex, and soft tissue near lesions were 0.48-1.1 Gy, 0.51-0.85 Gy, and 0.01-0.14 Gy, respectively. CONCLUSIONS: The absorption dose of bone metastases is significantly lower than treatment dose of 30 Gy after single irradiation of 153Sm-EDTMP. The painkilling effect is limited and in accordance with clinical observation.