Milovan Matovic

Unexpected effect of furosemide on radioiodine urinary excretion in patients with differentiated thyroid carcinomas treated with iodine 131.

BACKGROUND In patients receiving (131)I for therapeutic purposes, diuretics are frequently used in an attempt to accelerate elimination of unbound radioiodine, reduce its adverse effects, and shorten the hospital stay. The aims of our study were to investigate the influence of furosemide therapy on urinary excretion of (131)I in patients with differentiated thyroid cancer (DTC), referred to radioiodine ablation after thyroidectomy, and to investigate whether diuretics are useful in daily practice in patients with DTC. METHODS Forty-three patients with DTC who had normal renal function and low (131)I uptake in cervical region (3.55 +/- 3.45%) were included in this study. The furosemide (20 mg) and potassium chloride (250 mg) were given orally to 23 patients 3 hours after the (131)I administration, and then q8h for 3 days. Twenty patients did not receive either furosemide or potassium chloride. After (131)I administration, the patients collected their urine for 3 days, and radioactivity of urine sample from each micturition was expressed as percentage of the administered dose. Radioactivity of blood samples was measured after 72 hours, and the values were corrected for decay of (131)I and expressed in relation to the administered dose. Initial whole-body measurement (immediately after (131)I administration) and the whole-body measurement after 72 hours were recorded for all patients. The 72-hour whole-body measurement was corrected for decay of (131)I, and expressed as a percentage of the initial whole-body measurement. RESULTS Urinary excretion of (131)I was significantly lower in the patients who were taking furosemide and potassium chloride compared with the control group. The whole-body measurements after 72 hours (13.22 +/- 6.55% vs. 8.24 +/- 3.39% of the initial; p < 0.01, respectively) and the blood radioactivity (34.66 +/- 24.84 vs. 11.64 +/- 8.32 cpm/mL per 1 MBq of administered (131)I, p < 0.01) were found to be unexpectedly higher in the patients who were taking furosemide and potassium chloride compared with the control group. CONCLUSION Our results demonstrated that furosemide given as an adjuvant medication in patients with DTC causes a significant decrease in urinary excretion of radioiodine and its higher blood concentration. Therefore, furosemide should not be recommended as an adjuvant therapy to radioiodine ablation in patients with DTC previously iodine depleted by low-iodine diet.

Carboplatin and Etoposide in Patients with Advanced Gastric Cancer

Thirty-six patients with advanced gastric cancer were treated with combination chemotherapy following surgery. Chemotherapy consisted of carboplatin (CBDCA) 300 mg/m2, days 1-3, and etoposide (VP 16) 100 mg/m2, days 1-5. 10/36 (28%) patients had objective response. The median duration of response was 8 months. Currently 26/36 patients have shown progressive disease at a median of 4 months. Three patients remain progression-free 7, 14, and 15 months after study entry, respectively. 26/36 patients have died and 10/26 remain alive at a median time of 16 months. Estimated survival for all patients is 7 months. Two groups of toxicities were observed: hematological and gastrointestinal. They were generally assessed as mild with only two grade 3 (ECOG) toxicities and with no grade 4 toxicity observed during this study.

Cisplatin and 5-fluorouracil as induction chemotherapy followed by radiation therapy in metastatic squamous cell carcinoma of an unknown primary tumor localized to the neck. A phase II study

12 patients with metastatic squamous cell carcinoma of an unknown primary tumor localized to the neck were treated with induction chemotherapy and radiotherapy. Median age was 54 years (range, 39-68 years) and male to female ratio was 2:1. Five (42%) patients had N3 disease and 7 (58%) had N2 disease. Induction chemotherapy consisted of cisplatin 60 mg/m2, days 1 and 2 and 5-fluorouracil (5-FU), 500 mg/m2, days 3 and 4. Cycles were repeated every 4 weeks to a total of 3 cycles. After 4 weeks rest, patients underwent radiation therapy. It was given to all possible sites of the primary tumor (nasopharynx, pyriform sinus, and the base of the tongue). The radiation therapy dosage planned to the whole neck, nasopharynx, and supraclavicular area was 45 Gy in 24 daily fractions in 5 weeks, increasing to 60-70 Gy to the metastatic site. We observed 9 (75%) complete responses and 1 (8%) partial response. 7 (58%) patients are currently with no evidence of disease. Median survival time for all patients is 36 months (range, 14+ to 56 months), while median survival time for N3 patients was 32 months (range, 26-56 months). Toxicities were predominantly mild to moderate nausea and vomiting and mucositis. This combined modality appears to be effective and feasible in treatment of metastatic squamous cell carcinoma of an unknown primary tumor localized to the neck.

The opposite effects of nandrolone decanoate and exercise on anxiety levels in rats may involve alterations in hippocampal parvalbumin–positive interneurons

The aim of this study was to evaluate the behavioral effects of chronic (six weeks) nandrolone decanoate (ND, 20 mg/kg, s.c., weekly in single dose) administration (in order to mimic heavy human abuse), and exercise (swimming protocol of 60 minutes a day, five days in a row/two days break), applied alone and simultaneously with ND, in male rats (n = 40). Also, we evaluated the effects of those protocols on hippocampal parvalbumin (PV) content and the possible connection between the alterations in certain parts of hippocampal GABAergic system and behavioral patterns. Both ND and exercise protocols induced increase in testosterone, dihydrotestosterone and estradiol blood levels. Our results confirmed anxiogenic effects of ND observed in open field (OF) test (decrease in the locomotor activity, as well as in frequency and cumulative duration in the centre zone) and in elevated plus maze (EPM) test (decrease in frequency and cumulative duration in open arms, and total exploratory activity), that were accompanied with a mild decrease in the number of PV interneurons in hippocampus. Chronic exercise protocol induced significant increase in hippocampal PV neurons (dentate gyrus and CA1 region), followed by anxiolytic-like behavioral changes, observed in both OF and EPM (increase in all estimated parameters), and in evoked beam-walking test (increase in time to cross the beam), compared to ND treated animals. The applied dose of ND was sufficient to attenuate beneficial effects of exercise in rats by means of decreased exercise-induced anxiolytic effect, as well as to reverse exercise-induced augmentation in number of PV immunoreactive neurons in hippocampus. Our results implicate the possibility that alterations in hippocampal PV interneurons (i.e. GABAergic system) may be involved in modulation of anxiety level induced by ND abuse and/or extended exercise protocols.

Parameters of Calcium Metabolism Fluctuated during Initiation or Changing of Antipsychotic Drugs.

Objective Serum parameters of calcium homeostasis were measured based on previously published evidence linking osteoporotic fractures and/or bone/mineral loss with antipsychotics. Methods Prospective, four-week, time-series trial was conducted and study population consisted of patients of both genders, aged 35-85 years, admitted within the routine practice, with acute psychotic symptoms, to whom an antipsychotic drug was either introduced or substituted. Serial measurements of serum calcium, phosphorous, magnesium, 25(OH)D, parathyroid hormone, calcitonin, osteocalcin and C-telopeptide were made from patient venous blood samples. Results Calcium serum concentrations significantly decreased from baseline to the fourth week (2.42±0.12 vs. 2.33±0.16 mmol/L, p=0.022, n=25). The mean of all calcemia changes from the baseline was -2.6±5.7% (-24.1 to 7.7) with more decreases than increases (78 vs. 49, p=0.010) and more patents having negative sum of calcemia changes from baseline (n=28) than positive ones (n=10) (p=0.004). There were simultaneous falls of calcium and magnesium from baseline (63/15 vs. 23/26, p<0.001; OR=4.75, 95% CI 2.14-10.51), phosphorous (45/33 vs. 9/40, p<0.001; 6.06, 2.59-14.20) and 25(OH)D concentrations (57/21 vs. 13/35, p<0.001; 7.31, 3.25-16.42), respectively. Calcemia positively correlated with magnesemia, phosphatemia and 25(OH)D values. Parathyroid hormone and C-telopeptide showed only subtle oscillations of their absolute concentrations or changes from baseline; calcitonin and osteocalcin did not change. Adjustment of final calcemia trend (depletion/accumulation) for relevant risk factors, generally, did not change the results. Conclusion In patients with psychotic disorders and several risks for bone metabolism disturbances antipsychotic treatment was associated with the decrease of calcemia and changes in levels of the associated ions.

The role of neuropeptide-Y in nandrolone decanoate-induced attenuation of antidepressant effect of exercise

Since the increased prevalence of anabolic androgenic steroids abuse in last few decades is usually accompanied by various exercise protocols, the scope of our study was to evaluate the effects of chronic nandrolone decanoate administration in supraphysiological dose and a prolonged swimming protocol (alone and simultaneously with nandrolone decanoate) on depressive state in male rats. Simultaneously, we investigated the possible alterations in neuropeptide Y (NPY) content in blood and the hippocampus, in order to determine the role of NPY in the modulation of depressive-like behavior.Exercise induced antidepressant effects in tail suspension test (decrease of the total duration of immobility), as well as significant increase in the number of hippocampal NPY-interneurons in CA1 region. Chronic nandrolone decanoate treatment attenuated the beneficial antidepressant effects of exercise as measured by the tail suspension test parameters. Simultaneously, nandrolone decanoate treatment resulted in diminution of NPY content both in blood (decreased serum levels) and in hippocampus (the significant decrease in NPY expression in all three investigated hippocampal regions—CA1, CA2/3 and DG). Our findings indicate that alterations in serum and hippocampal NPY contents may underlie the changes in depressive state in rats. The exercise was beneficial as it exerted antidepressant effect, while chronic nandrolone decanoate treatment resulted in depressive-like behavior. Furthermore, the behavioral indicators of depression showed strong correlations with the serum levels and the hippocampal content of NPY.

A five-compartment biokinetic model for 90Y-DOTATOC therapy

PURPOSE Neuroendocrine tumors (NETs) are now routinely treated by radiopeptide targeted therapy using somatostatin receptor-binding peptides such as 90 Y- and 177 Lu-DOTATOC. The objective of this work was to develop a biokinetics model of 90 Y labelled DOTATOC, which is applied in the therapy of NETs to estimate doses in kidney and tumor. METHODS A multi-compartment model described by two sets of differential equations, one set for the actual 30-min infusion and the other set for the post-infusion period was developed and activities were measured by liquid scintillation counting in blood (compartment 1) and the urine (compartment 3). The inter-compartment transfer coefficients, λij , were varied to yield the best fit of the calculated to the measured time-activity data and the 90 Y-DOTATOC time-activity data in the five-compartments comprising the human body were thus determined. The resulting time-activity curves were integrated over the interval from 0 to 72 h post administration to obtain the number of radioactive decays in each compartment and, in case of the kidneys and tumor, then multiplied by the self-dose 90 Y beta particle absorbed fraction, determined by Monte Carlo (MC) simulation, the kidney and tumor absorbed doses. RESULTS Transfer coefficients λij , were determined for five-compartments for all patients. Time- activity curves of 90 Y-DOTATOC in 14 patients were determined, and two typical ones are shown graphically. Absorbed doses in the tumor and kidneys, obtained by the developed method, were determined. The mean absorbed dose in a kidney per unit of administered activity is 1.43 mGy/MBq (range 0.73-2.42 mGy/MBq). The tumor dose was determined as 30.94 mGy/MBq (range 20.05-42.31 mGy/MBq). CONCLUSION Analytical solution of a biokinetic model for 90 Y-DOTATOC therapy enabled determination of the transfer coefficients and derivation of time-activity curves and kidney and tumor absorbed doses for 14 treated patients. The model can be applied to other radionuclides where elimination is predominantly through urine, which is often the case in radiopharmaceuticals.

Hybrid Vision-Fusion system for whole-body scintigraphy

Radioiodine therapy in the treatment of differentiated thyroid carcinoma (DTC) is used in clinical practice for the ablation of thyroid residues and/or destruction of tumour tissue. Whole-body scintigraphy for visualization of the spatial 131I distribution performed by a gamma camera (GC) is a standard procedure in DTC patients after application of radioiodine therapy. A common problem is the precise topographic localization of regions where radioiodine is accumulated even in SPECT imaging. SPECT/CT can provide precise topographic localization of regions where radioiodine is accumulated, but it is often unavailable, especially in developing countries because of the high price of the equipment. In this paper, we present a Vision-Fusion system as an affordable solution for 1) acquiring an optical whole-body image during routine whole-body scintigraphy and 2) fusing gamma and optical images (also available for the auto-contour mode of GC). The estimated prediction error for image registration is 1.84 mm. The validity of fusing was tested by performing simultaneous optical and scintigraphy image acquisition of the bar phantom. The fusion result shows that the fusing process has a slight influence and is lower than the spatial resolution of GC (mean value ± standard deviation: 1.24 ± 0.22 mm). The Vision-Fusion system was used for radioiodine post-therapeutic treatment, and 17 patients were followed (11 women and 6 men, with an average age of 48.18 ± 13.27 years). Visual inspection showed no misregistration. Based on our first clinical experience, we noticed that the Vision-Fusion system could be very useful for improving the diagnostic possibility of whole-body scintigraphy after radioiodine therapy. Additionally, the proposed Vision-Fusion software can be used as an upgrade for any GC to improve localizations of thyroid/tumour tissue.

COMPARTMENT BIOKINETIC MODEL FOR 90Y-DOTATOC

Biokinetic of 90Y-DOTATOC in human body during treatment of neuroendocrine and medullary thyroid tumors is described in this work. For this purpose, the human body may be represented by 4 compartments: blood, kidneys, urinary bladder and tumor. System of differential equations was developed, whose solution is presented in this paper. The aim is the determination of transfer coefficients between individual compartments for a better estimation of the dose in the tumor and other organs of the human body. A computer program is written in standard Fortran90 programming language.

Population pharmacokinetics of 25-hydroxyvitamin D in healthy young adults.

OBJECTIVES The aim of our study was to develop a population pharmacokinetic (PPK) model for 25-hydroxyvitamin D clearance in a healthy young adult population in Serbia. METHODS Study sample consisted of 70 healthy young students of the Faculty of Medical Science, University of Kragujevac, Serbia, with a mean age and body mass index of 22.39 ± 1.82 years and 21.31 ± 2.69 kgm-2, respectively. Non-linear mixed-effect modeling (NONMEM) software was used for data analysis. A validation set of 16 participants was used to estimate the predictive performance of the pharmacokinetic model. RESULTS In the base model (without covariates), we had parameter estimates of 0.01 L/h for apparent clearance, 0.25 L for apparent volume of distribution, while value of minimum objective function (MOF) was 383.468. The full regression model was established by estimating the effects of 12 covariates. Mean intake of vitamin D from foods (DD) and value of phosphate in serum (PHO) were covariates included in the final model, while others were excluded in this process. The estimated value in the final MOF model was 274.555. The final regression model formula was: clearance (CL) (L/h) = 0.0711 + 0.738 x DD + 0.618 x PHO. CONCLUSIONS The PPK model obtained determined clearance of 25-hydroxyvitamin D in a healthy young adult population in Serbia. Mean intake of vitamin D from foods and serum phosphate level are the most important covariates that influence value of 25-hydroxyvitamin D clearance in healthy young adults.