Bismuth chelate as a contrast agent for X-ray computed tomography.

BACKGROUNDS: Due to the unexpected side effects of the iodinated contrast agents, novel contrast agents for X-ray computed tomography (CT) imaging are urgently needed. Nanoparticles made by heavy metal elements are often employed, such as gold and bismuth. These nanoparticles have the advantages of long in vivo circulation time and tumor targeted ability. However, due to the long residence time in vivo, these nanoparticles may bring unexpected toxicity and, the preparation methods of these nanoparticles are complicated and time-consuming. METHODS: In this investigation, a small molecular bismuth chelate using diethylenetriaminepentaacetic acid (DPTA) as the chelating agent was proposed to be an ideal CT contrast agent. RESULTS: The preparation method is easy and cost-effective. Moreover, the bismuth agent show better CT imaging for kidney than iohexol in the aspect of improved CT values. Up to 500 µM, the bismuth agent show negligible toxicity to L02 cells and negligible hemolysis. And, the bismuth agent did not induce detectable morphology changes to the main organs of the mice after intravenously repeated administration at a high dose of 250 mg/kg. The pharmacokinetics of the bismuth agent follows the first-order elimination kinetics and, it has a short half-life time of 0.602 h. The rapid clearance from the body promised its excellent biocompatibility. CONCLUSIONS: This bismuth agent may serve as a potential candidate for developing novel contrast agent for CT imaging in clinical applications.

Laser-Induced Transformable BiS@HSA/DTX Multiple Nanorods for Photoacoustic/Computed Tomography Dual-Modal Imaging Guided Photothermal/Chemo Combinatorial Anticancer Therapy.

Suboptimal intratumor accumulation and poorly controllable release of encapsulated drugs remain unresolved challenges hampering further advancement of nanomedicines in cancer therapy. Herein, we conceived near-infrared (NIR) laser-triggered transformable BiS@HSA/DTX multiple nanorods (mNRs), which were made of small bundles of bismuth sulfide nanorods (BiS NRs) coated with docetaxel (DTX)-inlaid human serum albumin (HSA). The BiS@HSA/DTX mNRs had a lateral size of approximately 100 nm and efficiently accumulated in the tumor microenvironment upon systemic administration in tumor-bearing nude mice. NIR laser irradiation of the tumor area caused rapid disassembly of the BiS@HSA/DTX mNRs into individual HSA-coated BiS nanorods (BiS@HSA iNRs) and triggered the release of DTX from the HSA corona, due to the local temperature increase generated by BiS NRs via the photothermal effect. The laser-induced transformation into BiS@HSA iNRs facilitated their penetration and increased the retention time in tumor. The spatiotemporal delivery behavior of the BiS@HSA/DTX mNRs could be monitored by photoacoustic/computed tomography dual-modal imaging in vivo. Furthermore, because of the excellent photothermal conversion properties of BiS NRs and laser-triggered DTX release from BiS@HSA/DTX mNRs, efficient tumor combinatorial therapy was achieved via concurrent hyperthermia and chemotherapy in mice treated with BiS@HSA/DTX mNRs upon NIR laser irradiation.

Chelation of bismuth by combining desferrioxamine and deferiprone in rats.

Consumption and production of bismuth compounds are increasing, however, a little information on the toxic effect and also the effective method in removal of bismuth compounds are available. The present research aimed to characterize the potential efficiency of two chelators after bismuth administration for 55A days following two dose levels of 20 and 40A mg/kg body weight daily to male rats. However, we found abnormalities after bismuth administration in clinical signs, such as body weight, kidneys and liver damages, a black line on gums and skin reactions. Furthermore, the hypothesis that the two chelators might be more efficient as combined therapy than as single therapy in removing bismuth from the body was considered. Along this line, two known chelators deferiprone (1, 2-dimethy1-3-hydroxypyride-4-one, L(1)) and desferrioxamine (DFO) were chosen and tested in the acute rat model. Chelators were given orally (L(1)) or intraperitoneally (DFO) as a single or combined therapy for the period of a week. Doses of L(1) and DFO were 110A mg/kg body weight in experiments. Bismuth and iron concentrations in various tissues were determined by graphite furnace and flame atomic absorption spectrometry, respectively. The combined chelation therapy results show that DFO and L(1) are able to remove bismuth ions from the body, whereas iron concentration returned to the normal level and symptoms are also decreased. DFO was more effective than L1 in reducing bismuth concentration in tissues. The efficiency of DFOA +A L(1) is more than DFO or L(1) in removing bismuth from organs. Our results are indicative that the design procedure might be useful for preliminary in-vivo testing of the efficiency of chelating agents. Results of combined chelators' treatment should be confirmed in a different experimental model before extrapolation to other systems. This testing procedure of course does not provide all the relevant answers for efficiency of chelating agents in bismuth toxicity.

[Effect of acid suppression therapy for eradicating Helicobacter pylori infection on bismuth absorption from colloidal bismuth pectin].

OBJECTIVE: To investigate whether acid suppression therapy influences the absorption of bismuth from colloidal bismuth pectin (CBP). METHODS: 48 male SD rats were randomly divided into five groups to be administer with different medicines once a day for 14 days: group A1 (administered with CBP only and killed on the cessation day of administration), group B1 (administered with CBP only and killed 8 weeks after the cessation of administration), group A2 [administered with CBP + amoxicillin (AMO) + metronidazole (MTR) + losec and killed on the cessation day of administration], group B2 (administered with CBP + AMO + MTR + losec and killed 8 weeks after the cessation of administration), and control group (administered with distilled water). The kidney issue sections were counterstained after AMG development. The bismuth deposited in tissues was observed by microscopy. The gray level of kidney tissue sections were measured and compared through image processing program. The deposition of bismuth and the degrees of cell organ's impairment were observed by electron microscopy. By using electron probe microanalysis bismuth was identified from the chemical elements in the specimens. RESULTS: Under the light microscopy, black-brown granules were discovered in the cell bodies of the proximal convoluted renal tubule. The amounts of bismuth accumulated in kidney of the 2 quadruple therapy groups were much more than those of the 2 single compound therapy groups (all P < 0.05). The amount of bismuth accumulated in kidney on the cessation day of administration was more than that eight weeks later (both P < 0.01). Under electron microscopy, black-brown granules were observed exclusively in the lysosomes of the proximal convoluted renal tubule cell. Electron microscopy found cell impairment in the quadruple therapy groups. Impairment of these cells could be recovered 8 weeks after the cessation of administration. CONCLUSION: Acid suppression therapy causes an increase of absorption and accumulation of bismuth from CBP in the kidney. Bismuth can be accumulated in the cell bodies of proximal convoluted renal tubule after its absorption. The absorbed bismuth can be discharged out of the body via kidney. Large amounts of bismuth accumulation in kidney can impair the functions of proximal convoluted renal tubule cells.

[The difference of the bismuth absorption from a single colloidal bismuth pectin therapy and quadruple therapy for eradicating Helicobacter pylori infection].

OBJECTIVE: To investigate whether the quadruple therapy influences the absorption of bismuth from Colloidal Bismuth Pectin (CBP). METHODS: 24 male Wistar rats weighing from 400 g to 500 g were randomly divided into two groups: CBP group (group A(1)) and CBP+AMO+MTR+ LAN group (group A(2)). The serum bismuth concentration was observed at 0,1,2,3,4,5,6 hour after these medicines were fed. Other 24 male Wistar rats weighing from 200 g to 250 g were randomly divided into two groups: CBP group (group B( 1)), CBP+AMO+MTR+LAN group (group B(2)). These medicines had been taken every day for 14 days. The accumulation of bismuth in the heart, brain, kidney and liver of rats were detected eight weeks later. RESULTS: The serum peak value of bismuth is not significantly different between group A(1) and group A(2) (P > 0.05), but the peak time of bismuth of the group A(2) is one hour earlier than that of group A(1). The amounts of the accumulation of bismuth in the kidney are 154 +/- 15 ng/g and 212 +/- 20 ng/g in the group B(1) and B(2) respectively at the eighth week after the medicines were fed in rats with a significant difference (P < 0.05). CONCLUSION: The quadruple therapy causes an increase of the absorption and the accumulation of bismuth from CBP in the kidney in rats.

Pretargeting radioimmunotherapy of a murine model of adult T-cell leukemia with the alpha-emitting radionuclide, bismuth 213.

We used a pretargeting technique to treat a nonobese diabetic/severe combined immunodeficient murine model of human adult T-cell leukemia with an anti-Tac antibody-streptavidin (HAT-SA) conjugate, which recognizes CD25, followed by bismuth 213 ((213)Bi)-1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA)- biotin. In the 3-step pretargeting radioimmunotherapy protocol, HAT-SA (140 or 400 microg) was administered intravenously (i.v.) to bind to the interleukin 2 receptor alpha (IL-2R alpha; CD25)-expressing tumor cells. After 24 hours, 100 microg of a synthetic clearing agent was administered i.v. to remove unbound circulating HAT-SA conjugate from the circulation. Four hours later, (213)Bi-DOTA-biotin was administered i.v. for therapy. Tumor growth was significantly inhibited in 3 trials by using 250 microCi (9.25 MBq) of (213)Bi-DOTA-biotin with a pretargeting technique as monitored by serum levels of soluble IL-2R alpha and/or human beta-2-microglobulin (P <.05, t test) and by survival of tumor-bearing mice in the treatment groups (P <.02, log rank test) as compared with the control groups. No prolongation of survival was observed with a nonspecific antibody-SA conjugate or in the absence of the radionuclide. Additionally, no prolongation of survival resulted from administration of (213)Bi directly linked to intact HAT. Furthermore, there was no prolongation of survival when the beta-emitting radionuclide yttrium 90 instead of the alpha-emitting radionuclide (213)Bi was used. The pretargeting approach with (213)Bi inhibited tumor growth more effectively than did immunotherapy with unmodified HAT. The best results were obtained with combination therapy that involved (213)Bi-DOTA-biotin with a pretargeting technique supplemented by 4 weekly doses of HAT. The findings of this study support the use of this combination approach in a clinical trial in patients with IL-2R alpha-expressing leukemias.

Uptake of bismuth in motor neurons of mice after single oral doses of bismuth compounds.

Bismuth, a component of many gastrointestinal medications, is a heavy metal little studied as regards nervous system uptake. We were interested to see if low doses of intragastric bismuth entered the nervous system, and if dietary selenium influenced the amount of bismuth detected. Mice were given 40 to 1200 mg/kg of bismuth subnitrate (BSN), bismuth subsalicylate (BSS), colloidal bismuth subcitrate (CBS), or ranitidine bismuth citrate (RBC) intragastrically. Mice on low- or high-selenium diets were given 4 to 32 mg/kg of bismuth from RBC. One week later, sections of nervous tissue were stained with autometallography to detect bismuth grains (Bi(AMG)). Bismuth was found in neurons with axons outside of the nervous system, in particular motor neurons, and in cells outside the blood-brain barrier. The lowest bismuth dose which resulted in Bi(AMG) in motor neurons was 696 mg/kg from BSN, 57 mg/kg from BSS, 29 mg/kg from CBS, and 26 mg/kg from RBC. No bismuth was seen in motor neurons of mice on the low-selenium diet. Intragastric doses of bismuth therefore enter mouse motor neurons, and the amount detectable varies with dietary selenium.

Histochemical tracing of bismuth in testis from rats exposed intraperitoneally to bismuth subnitrate.

The histochemical silver amplification technique autometallography (AMG), was used to trace bismuth in the testis of Wistar rats injected intraperitoneally with bismuth subnitrate. In the seminiferous tubules, bismuth was located in lysosomes of Sertoli cells closely associated with heads of spermatids in the late stages of the spermatogenesis, i.e. shortly before the release of Step 19 spermatids in Stage XIII. No bismuth-specific AMG silver grains were detected in the spermatogenic cell line. However, tails of free sperm cells located in the tubular lumen showed autometallographic grains in close contact to the nine outer microtubule doublets in the axonema. Leydig cells concentrated huge amounts of AMG-bismuth in their lysosomes. Furthermore, parallel exposure to selenium significantly increased the amount of histochemically traceable bismuth in the rat testis.

Evaluation of dithiol chelating agents as potential adjuvants for anti-IL-2 receptor lead or bismuth alpha radioimmunotherapy.

The dithiol chelating agents 2,3-dimercapto-1-propanesulfonic acid (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) were evaluated for use as potential adjuvants to reduce or prevent radiotoxicity in anti-interleukin-2 receptor (IL-2R) Lead-212 or Bismuth-212 alpha-radioimmunotherapy. DMPS was less toxic than DMSA to tumor cell lines in culture. No adverse effects on the ability of an anti-IL-2R monoclonal antibody (MAb) to bind to its specific antigen were detected using DMPS or DMSA at concentrations up to 600 ug/mL in 10% or 100% mouse serum. After a 5-day oral administration of chelating agent, neither acute nor chronic toxicities on blood hematology, blood chemistry or organ weights were observed for treated mice. DMPS and DMSA were effective in accelerating whole body clearance of the gamma-emitting tracer Bismuth-206. Both chelates significantly reduced femur uptake of tracer when compared to nontreated control mice. However, only DMPS prevented early (2 h postinjection) renal accumulation. These studies support the use of DMPS as a potential adjuvant chelation therapy in Lead-212 or Bismuth-212 radioimmunotherapy protocols.

[Clinico-pharmacologic considerations in Helicobacter pylori eradication therapy]. / Klinisch-pharmakologische Uberlegungen zur Helicobacter pylori-Eradikationstherapie.

Problems and pitfalls of treatment regimens for eradication of Helicobacter pylori (Hp) are discussed from a clinical, pharmacological and microbiological point of view. Problems concerning the physician who treats the patient consists mainly in inappropriate indication and suboptimal knowledge of drugs, doses and duration of therapy against Hp. For successful triple therapy with complicated dosage protocols cooperation with and compliance by the patient is stressed. Physicochemical, pharmacological and pharmacokinetic properties of bismuth salts and antibiotics as well as physiological aspects of pH and motility in the stomach must be considered in order to achieve optimal antibactericidal concentrations in the special micro milieu of Hp in the mucus/on the mucosa of the stomach. In addition, present pretreatment resistance of Hp against antibiotics and possible acquired resistance during antibiotic treatment are important aspects. Successful eradication of Hp mainly depends on the physician's clinical and pharmacological knowledge of bismuth salts and antibiotics, on considerations of microbiological aspects of Hp, on good doctor-patient-relationship and compliance by the patient.

[Effect of meals on resorption of bismuth from an oral bismuth gallate/bismuth nitrate preparation]. / Einfluss von Mahlzeiten auf die Resorption von Wismut aus einem oralen Wismutgallat/Wismutnitrat-Präparat.

In a cross-over study in ten healthy volunteers the effect of food on the absorption of bismuth following a single oral dose of 1200 mg (= 12 Bismofalk tablets) was evaluated by measuring its serum levels (0 to 24 h) and urinary excretion (for seven days). If this high dose was ingested one hour prior to the breakfast maximal serum concentrations (16.5 +/- 13.7 micrograms/l; mean +/- SD) were rapidly achieved (tmax = 0.7 +/- 0.5 h). These levels and the low urinary recovery of 0.32 +/- 0.25 mg (corresponding to 0.027% of the dose) indicated a minimal absorption. If the tablets were taken one hour after the breakfast absorption was slightly delayed (tmax = 1.9 +/- 2.4 h), however, the extent appeared to be unchanged. In spite of the high dosage as well as the large interindividual variability in the urinary recovery and the serum concentrations potential "toxic" serum levels of 100 micrograms/l were never reached. Thus, it can be concluded that the bismuth preparation used is suitable for topical action.

Surface to nuclear distances in human bronchial epithelium: relationships to penetration by Rn daughters.

Lung cancer in U miners is thought to be related to the inhalation of particulate Rn daughters. Since the depth of penetration by alpha particles is short, the thickness of the epithelium lining the bronchial tree may be a critical factor in the development of cancers at specific sites in the lung. The objectives of the study were to measure the thickness of the epithelium at all levels of the human bronchial tree, to determine the distances of epithelial nuclei from the mucociliary surface, and to compare these parameters in smokers and nonsmokers. Twenty-nine surgically removed specimens were examined; 26 were from smokers. No significant differences were found between smokers and nonsmokers, allowing us to treat the 29 cases as a homogeneous group. With progressive divisions of the bronchi, the epithelium decreases in thickness, and distances of nuclei from the surface are also less in the peripheral bronchi. Allowing for artefacts of tissue preparation, the mean distance from the mucociliary surface to the underlying nuclei varies between 17 and 38 microns.