Toxicity study of DE-EDCP as a potential drug for cancer therapy: Toxicity profile of DE-EDCP.

It was reported that novel O, O'-diethyl-(S, S)-ethylenediamine- N, N'-di-2-(3-cyclohexyl) propanoate dihydrochloride (DE-EDCP) displayed in vitro antiproliferative activity on several human and mouse cancer cell lines, which was comparable to that of the prototypical anticancer drug cisplatin. In order to reveal its toxicity profile, acute and repeated-dose toxicity studies were performed in Naval Medical Research Institute (NMRI) Han mice. The intravenous LD50 values of DE-EDCP were found to be 95.3 and 101.3 mg/kg body weight in female and male mice, respectively. In the subacute toxicity study, DE-EDCP was administered intravenously at the doses of 15, 25, and 40 mg/kg/day for a period of 28 days. There were no adverse effects on general condition, growth, feed and water consumption, and hematological parameters. There was a significant increase in urea and alanine aminotransferase in female mice and aspartate aminotransferase and alkaline phosphatase in both genders in 40 mg/kg/day dose-treated group. The histopathological changes confined to the liver and kidney, but in other organs were not found. Satellite group revealed that changes in the kidney and liver were less pronounced, suggesting their reversibility. Interactions with DNA could also be of importance for understanding DE-EDCP toxic side effects. Hyperchromic effect obtained with ultraviolet-visible, suggested electrostatic interactions between DE-EDCP and calf thymus DNA. The toxicity testing of DE-EDCP was conducted to predict human outcomes.

The impact of the chromium supplementation on insulin signalling pathway in different tissues and milk yield in dairy cows.

Thirty days before expected time of parturition, 20 Holstein cows were divided into -Cr and +Cr groups. From day 25 before parturition (BP) up to day 30 after parturition (AP), +Cr cows received 10 mg of Cr (chromium-enriched yeast) daily. Muscle and adipose tissue samples were taken at days -30, -10, +7 and +10 related to parturition, when body condition score (BCS) was also determined. Hepatic tissue samples were taken at days -10 and +7. Tissue samples were used for determination of the insulin signalling pathway protein expressions. Intravenous glucose tolerance test (IVGTT) was performed at days -28, -7, +10 and +30. Milk yield was recorded during first 14 weeks AP. Milk composition was obtained at days 7 and 28 AP. At day 10 BP, protein content of ß-subunit of insulin receptor (IRß) was significantly higher (p Ë‚ 0.05) in muscle, and phosphorylation of insulin receptor substrate 1 at serine 307 (pIRS-1 Ser307 ) was significantly lower (p Ë‚ 0.05) in hepatic tissue of +Cr group. After parturition, pIRS-1 Ser307 was significantly lower in muscle tissue at days 7 and 28 (p Ë‚ 0.05 and p Ë‚ 0.001, respectively), while phosphorylation of Akt at serine 473 (pAkt Ser473 ) was significantly higher (p Ë‚ 0.01) in hepatic tissue at day 7 AP in +Cr group. Chromium had opposite effect on insulin kinetics during IVGTTs obtained BP and AP. Insulin secretion was significantly reduced at day 7 BP and significantly enhanced at day 10 AP, when NEFA concentration was also significantly increased. Milk yield and ECM value were depressed in +Cr group. DMI and BCS were significantly enhanced in +Cr group at day 7 BP. In conclusion, chromium modulates insulin signalling pathway in dairy cows, but targeted signalling molecules are different in antepartal then post-partal period, probably due to duration of exposure to chromium and different energy status between those periods.

The effect of lipophilicity on the hepatobiliary properties of iminodiacetic acid derivatives in the conditions of hyperbilirubinemia.

The partition coefficients (log P) of theoretically possible alkyliodinated iminodiacetic acid (IDA) derivatives and commercial IDA derivatives were calculated using two computer programs: ChemSketch Log P and ChemOffice Ultra. Newly synthesized ligands (DIETHYLIODIDA and DIISOPROPYLIODIDA) with the highest calculated log P were labeled with technetium-99m. The biodistribution and the influence of bilirubin on their biokinetics were investigated in rats and compared to corresponding results for commercial (99m)Tc-BROMIDA. Log P of (99m)Tc-complexes of synthesized ligands were determined experimentally as well as the protein binding. In comparison to (99m)Tc-BROMIDA, (99m)Tc-DIETHYLIODIDA has: (a) better biliary excretion (2.76±0.15%ID/g versus 1.83±0.10%ID/g); (b) faster hepatic clearance (2.90±0.21%ID/g versus 7.47±0.70%ID/g) and decreased biliary excretion (for 14% versus 22%) in conditions of hyperbilirubinemia after 15min. It is proved that (99m)Tc-DIISOPROPYLIODIDA has a prolonged hepatic transit time and decreased biliary excretion.

Targeted alpha therapy in vivo: direct evidence for single cancer cell kill using 149Tb-rituximab.

This study demonstrates high-efficiency sterilisation of single cancer cells in a SCID mouse model of leukaemia using rituximab, a monoclonal antibody that targets CD20, labelled with terbium-149, an alpha-emitting radionuclide. Radio-immunotherapy with 5.5 MBq labelled antibody conjugate (1.11 GBq/mg) 2 days after an intravenous graft of 5.10(6) Daudi cells resulted in tumour-free survival for >120 days in 89% of treated animals. In contrast, all control mice (no treatment or treated with 5 or 300 micro g unlabelled rituximab) developed lymphoma disease. At the end of the study period, 28.4%+/-4% of the long-lived daughter activity remained in the body, of which 91.1% was located in bone tissue and 6.3% in the liver. A relatively high daughter radioactivity concentration was found in the spleen (12%+/-2%/g), suggesting that the killed cancer cells are mainly eliminated through the spleen. This promising preliminary in vivo study suggests that targeted alpha therapy with (149)Tb is worthy of consideration as a new-generation radio-immunotherapeutic approach.

[Multiple intracranial aneurysms and asymmetrical circle of Willis]. / Multiple intrakranijalne aneurizme i asimetricni Willisov prsten.

In a consecutive series of 268 patients harboring saccular aneurysms confirmed by digital subtraction angiography (DSA) all major blood vessels of the brain, 36 patients (13.4%) with multiple aneurysms were identified. Majority of them (around 58%) were between 40 to 60 years of age, around 22% were below 40 years of age, but no was younger than 30 years of age. The asymmetric Willis circle was identified in 26 patients (74.2%) A hypoplastic A1 segment of the anterior cerebral artery was revealed in 10 patients; a combination of the hypoplastic A1 segment and the fetal type of the posterior communicating artery with a hypoplastic P1 segment of the posterior cerebral artery were found in 9 cases, while 7 patients had only the fetal posterior communicating artery. A suggestion was put that the asymmetric circle of Willis, prenatal or acquired in postnatal life is inclined of developing aneurysm (multiple aneurysms) only if there exist a hemodynamic stress in postnatal life producing degenerative lesions of the circle of Willis at the site of the augmented hemodynamic vascular wave.

[Diagnostic value of electroencephalography and evoked potentials in monitoring brain maturation in children with febrile convulsions]. / Dijagnosticki znacaj elektroencefalografije i evociranih potencijala u pracenju cerebralne maturacije kod dece sa febrilnim konvulzijama.

A group of 31 children aged 4-14 was presented with clinical manifestations of febrile convulsions, which after clinical examination, were followed--up in outpatient clinics during 1-12 year period. Together with continuous electroencephalographic monitoring, visual and somatosensory potentials were measured with the aim to stress a diagnostic significance of these neurophysiological methods for cerebral maturation assessment in children with febrile convulsions. Results reveal that electroencephalography (EEG) and somatosensory potentials (SEP) have higher diagnostic sensitivity compared to the visual ones (VEP). In 25 children (80.64%) SEP changes were registered in the form of prolonged central conductivity time (CCT) and EEG revealed changes in the form of slower cerebral activity and posterior theta activities fr. 4-7 Hz (P-O bilaterally) in 10 children (32.26%). Registered SEP changes, particularly prolonged CVP, as well as changes in the form of slower basic cerebral activity or posterior theta rhythm could be explained by slower maturation of some CNS regions. EEG and SEP findings show positive correlation with clinical findings and different diagnostic sensitivity, therefore their use in clinical follow-up of children with febrile convulsions is important.

[Magnetic stimulation of the motor cortex in healthy persons]. / Magnetna stimulacija motornog korteksa kod zdravih ispitanika.

In 49 healthy volunteers the motor cortex was stimulated transcranially by the intensive short magnetic field and the responses of the m. abductor digiti minimi (m. ADM) in 20 volunteers were recorded and of the m. tibialis anterior (m. TA) in 29 volunteers in relaxation and in mild contraction. In all volunteers by the electric stimulation of the ulnar nerve in the region of the wrist and the peroneal nerve in the region of the fibular capitulum there have been measured the F wave latency, distal latency of M responses and the conduction time of the peripheral motor neuron has been calculated. The difference between the latency of m. ADM and n. TA responses and the conduction time of the peripheral motor nerve represented the central motor conduction time from the motor cortex to the motor neurons of the anterior horns of the spinal cord (C8 and L4 segments). The normative values of the absolute latencies of the muscle responses and the central motor conduction time in the relaxed and contracted muscle are calculated as well as the normatives of the normal differences in latencies and the central motor conduction time between the left and right side of the same subject.

[Multimodal evoked potentials and the blink reflex in patients with primary brainstem lesions]. / Multimodalni evocirani potencijali i blink-refleks u pacijenata sa primarnom lezijom mozdanog stabla.

In 17 patients with primary brainstem injury, out of 60 patients with severe head trauma, diagnostic and prognostic values of multimodal evoked potentials and blink reflex were evaluated in relation to clinical syndromes of the brainstem, the duration of coma and the outcome. Clinical classification of the brainstem syndromes according to Gerstenbrand and Rumpl was used for the evaluation of the clinical findings, the Innsbruck Coma Scale (ICS) for the evaluation of the coma level, and the Glasgow Outcome Scale (GOS) for the outcome. Analyses and measurements of the multimodal evoked potentials and blink reflex were used many times in the period of assessment (six months after the injury). The analysis of our results with multimodal evoked potentials and blink reflex revealed different correlation and sensitivity in relation to the clinical syndromes of the brainstem, the duration of coma and the outcome of the injury. The blink reflex and somatosensory evoked potentials had the best correlation and the greatest sensitivity, the auditory evoked potentials had somewhat, while the visual evoked potentials had none. Multimodal evoked potentials and blink reflex increase the specificity of the diagnosis of brainstem injury compared to clinical observation only, and improve prognostic reliability.

[The terminal ileum and chronic diarrhea: endoscopy, histology and parasitology]. / Terminalni ileum i hronicni proli: endoskopija, histologija i parazitologija.

In 53 patients with chronic diarrhea ileoscopy was done following colonoscopy. Beside the microscopic examination, terminal ileum biopsies and mucosal smears were also performed. Endoscopy of the terminal ileum was abnormal in eight patients (15.1%); biopsy itself was diagnostic in 22 patients (41.5%): primary bile acid malabsorption with mucosal atrophy and reduced retention of 75ScHCAT (10), mucosal atrophy after cholecystectomy (4), Crohn's disease (6), backwash ileitis in ulcerative colitis (1), and postirradiation ileitis (1). Biopsies were normal but mucosal smear indicated the cause of diarrhea in a further 10 patients: giardiasis was found in 7, and candidiasis in 3 patients. All in all, endoscopy, biopsy and mucosal smear of terminal ileum showed a sensitivity of 58.5%. In 38 patients in whom laboratory, roentgenologic and endoscopic investigation failed to establish the etiology of diarrhea, the sensitivity of ileoscopy itself was 0%, of ileoscopy with biopsy 36.8% and ileoscopy with biopsy and mucosal smear 47.4%. We conclude that endoscopy, biopsy and mucosal smear of the terminal ileum are indicated in the investigation of patients with chronic diarrhea.