99mTc-labeled antimicrobial peptides for detection of bacterial and Candida albicans infections.

UNLABELLED: This study compared the possibilities and limitations of 99mTc-labeled synthetic peptides derived from two human antimicrobial peptides, namely, ubiquicidin (UBI) and lactoferrin (hLF), for the scintigraphic detection of bacterial and fungal infections in mice and rabbits. The rationale of our approach was that selected peptides accumulate in infected areas but not in sterile inflammatory lesions, because they bind preferentially to microorganisms. 99mTc-labeled human neutrophil peptides (defensins), ciprofloxacin, and human polyclonal IgG were included as control agents. METHODS: 99mTc-labeled peptides and control agents were injected intravenously into animals that had been injected intramuscularly 18 h earlier with multidrug-resistant Staphylococcus aureus, Klebsiella pneumoniae, or fluconazole-resistant Candida albicans. Sterile inflammatory sites were induced by the injection of heat-killed microorganisms or lipopolysaccharide (LPS) into the thigh muscle. Up to 4 h after injection, the accumulation of 99mTc-labeled compounds in the infected/inflamed thigh muscles was determined using scintigraphic techniques and radioactivity counts in dissected tissues. RESULTS: Scintigraphy revealed that 99mTc-labeled peptides UBI 29-41, UBI 18-35, UBI 31-38, hLF 1-11, and defensins, which showed preferential in vitro binding to microorganisms in a former study, accumulated at a significantly higher rate (P < 0.01) in bacterial and C. albicans infections in mice and rabbits than in inflamed tissues induced by heat-killed microorganisms or by LPS. No significant difference in the accumulation of 99mTc-labeled ciprofloxacin was observed between infected and sterile inflamed thigh muscles in mice. CONCLUSION: 99mTc-labeled antimicrobial peptides UBI 29-41, UBI 18-35, UBI 31-38, hLF 1-11, and defensins accumulate significantly in tissues infected with gram-positive and gram-negative bacteria and C. albicans. Significantly lower (P < 0.01) accumulation of these peptides occurs in sterile inflamed tissues. These data indicate that the peptides preferentially tag microorganisms at the site of infection, which is in agreement with their preferential binding to the microorganisms in vitro and in vivo. 99mTc-labeled ciprofloxacin does not distinguish between infections and sterile inflammatory lesions, which implies that its specificity for the detection of bacterial infections is not warranted.

Clinical features, treatment and outcome in a series of 93 patients with low-grade gastric MALT lymphoma.

The purpose of this paper is to report the clinical characteristics and treatment outcome following different therapeutic approaches in a large series of patients with primary low-grade MALT lymphoma of the stomach. A total of ninety-three patients (median age 63 years) were reviewed. The patients were treated by different modalities (local treatment alone, combined treatment, chemotherapy, antibiotics alone); seven patients refused any treatment. The antibiotic-treated group of patients was prospectively followed with regular endoscopic biopsies, and their responses were histologically evaluated. The 5-years projected overall survival is 82% (95% C.I.; 67%-91%) in the series as a whole. Second tumors were observed in 21.5% of the patients in this series (95% CI 14%v to 31%). There was no apparent difference in overall survival and event-free survival between patients who received different treatments. In the antibiotic-treated group histologic regression of MALT lymphoma was documented in 67% of patients (95% CI 51% to 80%). In conclusion the indolent nature of the disease justifies a conservative approach. The use of antibiotics as first-line therapy may avert or at least postpone the indication for surgical resection in the majority of patients.

Ovine toxoplasmosis: seroconversion during pregnancy and lamb birth rate in Uruguayan sheep flocks.

Specific anti-Toxoplasma gondii antibodies were analyzed by latex agglutination during the 5 months of pregnancy in the serum of sheep from two flocks in the Uruguayan north-west: one flock (79 sheep) kept under an intensive management system and the other (494 sheep) kept under an extensive management system. Titers obtained using the latex test correlated with those obtained by indirect immunofluorescence. Pregnancy was confirmed by laparoscopy in all sheep from the smaller flock and by determination of serum progesterone levels in the seroconverted sheep from the larger flock. The percentage of sheep originally exhibiting significant serum levels of anti-T. gondii antibodies (13.9% in the smaller flock and 28.5% in the larger one) as well as the observed levels of seroconversion (22.8% and 7.7%, respectively), indicated a high prevalence of this infection in the north-west of Uruguay. In addition, birth rates of seroconverted sheep in the larger flock were significantly different from those of non-seroconverted animals. These results, although preliminary, suggest that Toxoplasma infection would produce considerable economic losses in extensive ovine production in Uruguay.

Bilateral breast involvement in a 71-year-old white man with lambda light chain disease. Regression after a new chemotherapy combination. A case report.

A rare case of lambda light chain disease with bilateral breast involvement is described. A complete regression after a new chemotherapy combination (peptichemio + teniposide + dexamethasone) was obtained. A previous treatment with prednisone + melphalan was ineffective.

Linear relationships in systems with non linear kinetics.

The elimination rate of drug from a capacity-limited one-compartment model can be expressed by equation (1): [formula: see text] Traditionally equation (1) was linearized according to equation (2): [formula: see text] Here, an alternative linear relationships between concentration and the area under the curve of C/(Km + c]) is proposed: [formula: see text] By iteration of Km into equation (3) until the statistic of analysis of variance for the regression is maximized, both Km and Vmax can be obtained. Several cases were considered: a) Intravenous bolus (single dose): Km (mg/L), Vmax (mg/L h), Vd (L) and V (mg/h) can be estimated. b) Extravascular administration (single dose): by the method of residuals it is possible to make additional estimations of FD/Vd (mg/L) and Ka (1/h). c) Bioequivalence studies: with parameters obtained at single dose, the simulated levels at steady-state are considered for the bioequivalence assessments. d) Km, Vmax estimation with two (C,t) points (single dose): double iteration (Km values and interpolated fictitious third points) are needed. e) Multiple dose: [formula: see text] If t2-t1 = T (interval of administration) it is possible to calculate operatives Km, Vmax, FD/Vd and to estimate Css (steady-state concentration). C1 and C2 correspond to different intervals. All the areas were calculated by the trapezoidal rule.

Average parameters in bioavailability studies: an application to slow-release amitriptyline formulation.

In order to assess the extent and the rate of absorption in bioavailability studies, area under the curve (AUC), experimental maximum concentration (Cmax) and experimental time to reach Cmax (Tmax), are used. But when slow-release formulations are considered, the drug concentration-time curves usually show multiple peaks, and it is difficult to compute a Cmax and Tmax value. In case a Cmax value is computed, important variability in this parameter results in high values in the residual variance of the ANOVA test. So in order to decrease the high variability, average parameters: average concentration (Cav), average maximum concentration (Cmax,av) and Cmax,av x 100/Cav (%Cmax,av), are proposed. These new parameters were applied in a bioavailability study of slow-release amitriptyline formulation.

Influence of the emulsion sign in phenytoin bioavailability.

To study the influence of the emulsion sign in phenytoin bioavailability, two emulsions (w/o and o/w) were prepared. Bioavailability studies were carried out with both emulsions in Wistar male rats. The study was of a randomized two-way cross over design. A radiotracer technique was chosen as analytical procedure, due to the small blood sample collected. 14C-phenytoin was synthesized with a high yield and suitable radiochemical purity. It is concluded, from a biopharmaceutic point of view, that the emulsion sign does not seem to affect the amount of phenytoin absorbed, as it is shown through the comparison of the areas under curve up to 24 h. An emulsion with oil as an external phase is responsible of a longer absorption, taking into account the apparent elimination constant rates.

Lipidic matrix of albendazole: an alternative for systemic infections.

Albendazole is a poorly water soluble drug, with low oral bioavailability, used in pharmacological treatment of a systemic disease as hydatid parasitosis. Lipidic matrices of Gelucires (44/14 and 35/02) were developed. After "in vitro" studies, one formulation was chosen for a single dose study in 8 healthy volunteers, with a cross-over and randomised design, taking a commercially available tablet as reference. Drug absorption was followed by albendazole sulphoxide dosage in urine by high pressure liquid chromatography. Neither albendazole nor albendazole sulphoxide were recovered in urine after tablet administration while 0.18% (+/- 0.06) of dose was recovered after lipidic matrix administration in the first 24 hours. Besides ageing control were performed up to 18 months post-elaboration. Lipidic matrix with Gelucire 44/14 was revealed as a promising attempt for oral pharmaceutical form in albendazole systemic treatment.

Lipidic matrix of albendazole sulphoxide: is it an alternative for systemic infections?

As albendazole sulphoxide (ABZS) shows better dissolution properties than albendazole (ABZ), a lipidic matrix with this drug was formulated in order to evaluate if its absorption and so systemic infection chemotherapy could be improved. A cross-over, randomised study in 8 healthy volunteers was carried out, after single administration of 1 g of albendazole or albendazole sulphoxide in lipidic matrix of Gelucire 44/14 (ABZLM and ABZSLM). Absorption was followed performing albendazole sulphoxide dosage in urine samples by high pressure liquid chromatography analysis, during 48 hours. Significant differences were found (p = 0.02) between the urinary recoveries (% E48), being 1.74% and 0.19% the percentage of dose recovered when ABZSLM or of ABZLM were respectively administered. In a previous study of our group similar values were obtained of urinary recovery percentages after albendazole sulphoxide powder administered to another group of healthy volunteers. Lipidic matrix does not improve the physicochemical properties of albendazole sulphoxide powder.

(99m)Tc glucarate as a potential radiopharmaceutical agent for assessment of tumor viability: from bench to the bed side.

Several radiotracers have been used for assessing cell death, whether by necrosis or apoptosis. (99m)Tc glucarate, which has initially been reported to be concentrating/accumulating in myocardial infarction or zones of cerebral injury, has also shown some tumor-seeking properties in a few preliminary studies. Under International Atomic Energy Agency (IAEA)'s coordinated research program, we report here the standardization, quality control, and clinical evaluation (detection, evaluation of response, and comparison with (18)F Fluorodeoxyglucose) of this tracer in well-characterized lung cancer and head neck malignancies in a single-arm prospective observational study. Forty-seven patients (29 inoperable lung carcinoma and 18 head and neck malignancies) were prospectively enrolled and underwent (99m)Tc glucarate imaging [whole body planar and single-photon emission computed tomography of the region of interest] 4-5 hours after injection of 20 mCi of the radiopharmaceutical. Excellent (99m)Tc glucarate concentration was noted in the target lesion in lung cancer and head and neck malignancies. The sensitivity was found to be better in lung cancer. Avid concentration of tracer was seen in the metastatic sites. During response evaluation, the glucarate concentration correlated well with the clinical and other radiological findings. (99m)Tc glucarate showed avid concentration of tracer in the tumor, suggesting it to be a potential tumor imaging agent which can be used for detection and assessment of therapeutic response in malignancy.

[Laboratory contribution to the diagnosis of micromolecular myeloma. Description of 5 cases]. / Contributo del laboratorio alla diagnosi di mieloma micromolecolare. Descrizione di 5 casi.

Five cases of micromolecular myeloma, discovered with systematic electrophoretic study of proteinurias, are described. Technical details useful for diagnosis are discussed.

Assessment of the diagnostic value of 99mTc-radiolabelled specific antibodies in experimental hydatidosis.

We assessed the potential of 99mTc labelled specific polyclonal antibodies (99mTc-PoAb) for the diagnosis of hydatid disease by immunoscintigraphy. Experimentally infected mice and rabbits were used for this purpose. A specific rabbit antibody recognizing total somatic antigen from hydatid membranes (HCMA) was obtained. PoAb biological activity before labelling was checked according to Barbieri et al. 99mTc-PoAb labelling was performed according to Thakur et al.; the radiochemical purity was higher than 90%. The following studies of 99mTc-PoAb were made: post-labelling biological activity; in vitro stability; blood and renal kinetics in normal mice up to 24 hours after intravenous (i.v.) and intraperitoneal (i.p.) administration; biodistribution in normal and infected mice after i.p. or i.v. injection, and in rabbits after i.v. administration. Biodistribution studies in normal mice, after both administration routes, showed considerable hepatic uptake of activity. An important uptake in cysts after i.p. administration in mice, indicating successful targeting, was also confirmed by autoradiography images. Intravenously administered 99mTc PoAb was not significantly targeted to peritoneal cysts in either animal species, due to inherent limitations to these animal models. Results obtained with i.p. administration suggest that specific hydatid imaging may be possible. Both the mice and rabbit models revealed hepatic uptake which, combined with the short isotope half-life, prevent the drawing of any final conclusions regarding the usefulness of 99mTc-labelling in hydatid disease.

Intraocular pressure and progression of visual field damage.

Contradicting results concerning IOP control and visual field deterioration are presented. Some of these inconsistencies may be due to the statistical method of analysis. Sixty POAG patients with a perimetric follow-up over 3 years were selected. Mean and maximum IOPs were considered during the same period. The patients were divided into two groups according to the IOP control (well controlled or poorly controlled). Visual field progression was defined as a reduction in sensitivity over the fifth percentile in more than four points. Mean IOPs were not significantly different in the group of patients with a visual field deterioration compared to the stable ones, but the percentage of patients with a visual field deterioration was significantly higher in patients with higher IOPs. This holds especially true if IOP below 16 mmHg (G) is considered the 'target pressure'. IOP reduction seems to play an essential role in visual field progression. In glaucomatous patients, a strict (<16 mmHg (G)) might be necessary.

99mTc-ADP: a potential agent for in vivo tumor detection.

The possibility of using 99mTc-labelled nucleotides as tumour seeking agents has been proposed by different research groups. We have recently reported the preparation of a 99mTc-ADP complex with a high radiochemical purity (> 95%), good in vitro and in vivo stability and promising biodistribution results when injected in mice bearing spontaneous mammary adenocarcinomas. Here we report the results of further investigations in animals with spontaneous neoplastic processes, including whole-body autoradiography in mice (20 minutes and 60 minutes post injection) and gamma-camera imaging studies in Wistar rats. Dynamic studies (up to 45 minutes) and static images (up to 18 hours) were acquired to determine the pharmacokinetics of 99mTc-ADP and the tumour/muscle and tumour/blood ratios. Blood-pool studies were also performed as a control. Tumours were visualized by autoradiography as was to be expected from the biodistribution studies. Dynamic studies showed a rapid blood clearance and a behaviour that fitted to a tricompartimental model. Radioactivity was rapidly taken up by the kidneys and excreted in the urine. No evidence of in vivo instability of the complex was observed. Tumour uptake reached the maximum values after 20 minutes post-injection. Tumour/blood and tumour/muscle ratios improved over time, enhancing tumour visualization. The best images were obtained after 3 hours post injection. In summary, our studies suggest that 99mTc-ADP is a promising radiopharmaceutical for tumour diagnosis.

Labelling, control and radiopharmacological evaluation of 99mTc-adenosine 5'-diphosphate (99mTc-ADP) as tumour seeking agent.

A study of 99mTc-adenosine-5'-diphosphate (99mTc-ADP) as a radiopharmaceutical for tumour diagnosis is presented. Two different labelling methods, using SnCl2 in alkaline solution and Zn as reducing agents, were developed. Reduction with Sn(II) alkaline solution was the selected method because a lower concentration of ADP (0.5 mg/mL) could be used and a higher radiochemical yield was achieved. A labelled molecule with a radiochemical purity higher than 95%, in vitro stability of at least 6 hours and an over all negative charge was obtained Biodistribution studies carried out in normal mice and rats revealed rapid urinary excretion and no specific accumulation of activity in any other particular organ. This behaviour was similar to that reported for 99mTc-adenosine-5'-triphosphate (99mTc-ATP). Rapid blood clearance, that could be fitted to a bicompartimental model, was also verified. No evidence of in vivo instability was observed. Studies in mice and rats bearing spontaneous mammary adenocarcinomas were performed and the results were compared to those from the 99mTc-ATP studies. Although the tumour models used were not the same, the incorporation of both labelled compounds was very similar. Radioactivity uptake in the tumour and the tumour-to-blood ratio were not notably high. However, a significant increment was observed in the tumour-to-muscle ratio (1.0 +/- 0.2 at 30 minutes to 2.7 +/- 0.4 at 240 minutes). Whole-body autoradiography enabled tumour visualization. Further investigations, including scintigraphic imaging, must be carried to complete the clinical evaluation of 99mTc-ADP as a tumour seeking agent.

Linfoma primario del sistema nervioso central en un paciente con sida / Primary central nervous system lymphoma in patient with AIDS

Se presenta una caso clínico de linfoma primario del sistema nervioso central (LPSNC) en una paciente con infección por virus de la inmunodeficiencia humana (VIH) en estadio sida. En este caso particular se destaca la confirmación por histopatología mediante intervención neuroquirúrgica de una lesión ocupante de espacio (LOE), lo que permitió instalar tratamiento oncoespecífico y terapia antirretroviral, lográndose buena evolución clínica. El obejtivo de la presente comunicación es realizar una revisión y actualización bibliográfica del LPSNC en pacintes con VIH destacando principalmente el aporte de los métodos diagnósticos y terapéuticos.

Quality control of 188W/188re generators

Quality control of 188W/188Re generators from two different manufacturers and two levels of activity each, was carried out.Elution yields, chemical as well as radionuclidic and radiochemical purities, elution profiles along six months, were evaluated.Broad elution profile, high efficiency, with tandem alumina column added, ionic exchange column needed for increase of radionuclidic concentration were characteristics of type I generators.Easy handling with slightly lower yields and high concentrations of activity were observed in type II generators. Similar radionuclidic impurities namely 192Ir, 191Os, 188W, 110mAg, 54Mn, 134Cs and 60Co as well as similar radiochemical yields obtained in the labelling of 188 Re-HEDP were observed with eluates of both generator types.Absorbed doses to radiopharmacy staff were less important in type II generators.