Azuwuike Owunwanne

The use of radiopharmaceuticals as an effective toxicologic technique for studying nephrotoxicity of drugs: cyclosporine-A.

The concept of altered biologic behavior of administered radiopharmaceuticals is used routinely in clinical nuclear medicine to increase the sensitivity of diagnosis, monitor the efficacy of chemotherapeutic drugs and radiation treatment, and determine injury caused by a drug whose effect has exceeded its therapeutic value. In this study, cyclosporine-A (CsA) an immunosuppressant drug known to cause nephrotoxicity due to tubular impairment and Tc- 99m MAG-3, a renal imaging radiopharmaceutical secreted by the tubules have been used in animal models to establish a method for investigating the nephrotoxicity of drugs. New Zealand rabbits and Wistar rats were used. The rabbits and rats were treated with 30 mg/kg of CsA for 4 and 28 consecutive days respectively. Plasma creatinine and urea were measured and renogram studies were performed in the rabbits prior to and on 1, 4, 8, 11 and 15 days after treatment with CsA. For the renogram, the rabbits were given an intravenous bolus injection of 44.4 MBq (1.5 mCi) of Tc-99m MAG-3. The Tmax, T1/2, TTHM and uptake slope of the Tc-99m MAG-3 were calculated. Each rat was injected intravenously with 185 MBq (5 mCi) of Tc-99m MAG-3, killed 3 min later, the kidneys removed and 20 mm frozen sections made. Autoradio-grams were generated from the frozen sections. Creatinine and urea levels were also measured in the rats. There was no consistent difference in creatinine and urea levels between control and CsA treated rabbits and rats. However, for the rabbit, on day 1 or 4 after treatment, there was significant increase in the values of Tmax, T1/2, TTHM and uptake slope between the control and CsA treated animals, indicating intrarenal vasoconstriction and delayed transit of Tc-99m MAG-3 from the parenchyma to the collecting system. This delay is dramatically shown in the tissue autoradiograms of the rats. The results are consistent with reported nephrotoxicity of CsA using other techniques. The results of this study, therefore, indicate that the concept of altered biologic behavior of Tc-99m MAG-3 can be used effectively as a toxicologic method for studying nephrotoxicity of drugs as exempli-fied by CsA.

Preparation of radiopharmaceuticals

The preparation of radiopharmaceuticals involves three basic steps: production of the radionuclides, synthesis of the non-radioactive compound and reaction of the radionuclide with the non-radioactive compound.

Experimental studies on multiorgan toxicity of cyclosporine-A in rats using a radiopharmaceutical and comparison with histopathological findings

Iodine-125 HIPDM was evaluated as a screening agent for studying multiorgan toxicity due to Cyclosporine-A (CsA) and the results were compared to histopathological findings of the tissues. The rats were injected subcuta neously with 50 mg/kg (body weight) of CsA or with equal volume of the vehicle, Cremophor-EL, for 7 consecutive days. A dose of 10 μCi of I-125 HIPDM was injected intravenously at the end of the treatment period. The results indicated that there was a significant increase in the uptake of 1-125 HIPDM in the kidney, liver, heart and blood compared to control rats (P < 0.05). However, there was a significant decrease in the uptake of 1-125 HIPDM in the spleen compared to control animals (P < 0.001). The lung and brain of CsA treated rats showed no change in the uptake of I-125 HIPDM when compared to control rats. The change in the uptake of I-125 HIPDM in these organs was assumed to indicate tissue response to the toxic effects of CsA. The radiopharmaceutical results were compar able with the histopathological findings in which the organs showed varying degrees of tissue degeneration. It is concluded that the lipophilic radiopharmaceutical, 1-125 HIPDM, can be used as an effective screening agent to study multiorgan toxicity due to CsA.

Technetium-99m radiopharmaceuticals

Technetium is a group VIIB transition element which has seven electrons beyond the noble gas electronic configuration. The other members of the group are manganese (Mn) and rhenium (Re); together they form a triad (Mn, Tc, Re). All three elements easily lose the seven electrons to yield the +7 oxidation state of permetallate anions (MnO− 4, TcO− 4, ReO− 4) similar to the perhalate anions of group VIIA (ClO− 4, BrO− 4,lO− 4).

Drug-radiopharmaceutical interactions

Radiopharmaceuticals are designed to have specific biodistribution and/or elimination patterns when administered to normal subjects. In the presence of biochemical and/or pathophysiologic changes, the normal biodis-tribution and elimination pattern may be altered. It is this altered biologic behavior that helps a physician make a diagnosis. Altered biologic behavior may also be due to interferences caused by pharmacodynamic effects of drug(s). Hence, drug-radiopharmaceutical in teraction will be defined as altered biologic behavior due to tissue response of administered drug. When the altered biologic behavior is desired, the alteration is used for diagnostic intervention or drug therapy monitoring; when it is undesired, it may be due to toxicity or direct interaction. Although there are various classifications for drug-radiopharmaceutical interactions, [1–3] the most practical approach is the one summarized in Figure 6.1.

Ideal characteristics of radiopharmaceuticals

Radiopharmaceuticals are used for imaging, therapy and hematologic studies, and they have both common and different ideal characteristics for these studies. The common ones include availability, cost, ease of preparation and biologic behavior, while the different requirements are those associated with the radionuclide.

Structure and Activities of Nuclear Medicine in Kuwait.

The practice of nuclear medicine in Kuwait began in 1965 as a clinic for treating thyroid diseases. The practice developed gradually and until 1981 when the Faculty of Medicine established the Division of Nuclear Medicine in the Department of Radiology, which later became a separate department responsible for establishing and managing the practice in all hospitals of Kuwait. In 1987, a nuclear medicine residency program was begun and it is administered by Kuwait Institute for Medical Specializations originally as a 4-year but currently as a 5-year program. Currently there are 11 departments in the ministry of health hospitals staffed by 49 qualified attending physicians, mostly the diplomats of the Kuwait Institute for Medical Specializations nuclear medicine residency program, 4 academic physicians, 2 radiopharmacists, 2 physicists, and 130 technologists. These departments are equipped with 33 dual-head gamma cameras, 10 SPET/CT, 5 PET/CT, 2 cyclotrons, 1 breast-specific gamma imaging, 1 positron-emitting mammography, 10 thyroid uptake units, 8 technegas machines, 7 PET infusion systems, and 8 treadmills. Activities of nuclear medicine in Kuwait include education and training, clinical service, and research. Education includes nuclear medicine technology program in the Faculty of Allied Health Sciences, the 5-year residency program, medical school teaching distributed among different modules of the integrated curriculum with 14 didactic lecture, and other teaching sessions in nuclear medicine MSc program, which run concurrently with the first part of the residency program. The team of Nuclear Medicine in Kuwait has been active in research and has published more than 300 paper, 11 review articles, 12 book chapters, and 17 books in addition to 36 grants and 2 patents. A PhD program approved by Kuwait University Council would begin in 2016.

Radioactive noble gases

Xenon and krypton are noble gases of group O. They are chemically inert at body temperature with limited solubility in aqueous media. The physical half-lives, decay mode and gamma energies of 127/133Xe and 81mKr are listed in Table 13.1.

Positron emission tomographic (PET) radiopharmaceuticals

There are two main sources of PET radiopharmaceuticals: cyclotron produced and generator produced.

Disposal of radioactive waste material

The radionuclides used in nuclear medicine have short half-lives, therefore radioactive waste disposal does not pose a serious problem. There are two practical methods of disposing of these radioactive wastes: sewer dilution and decay in storage.