Synthesis, characterization and myocardial uptake of cationic bis(arene)technetium(I) complexes.

A series of bis(arene)technetium(I) complexes has been synthesized from 99mTcO4- in order to study their organ distribution. Syntheses using either ultrasound/Al/AlCl3 or Zn/HCl gave products relatively free from transalkylation. The identity of the complexes was verified by comparison to the 99Tc complexes. Equivalence of the 99Tc and 99mTc complexes was demonstrated by HPLC techniques. Biodistribution studies in rats reveal substantial myocardial uptake for many members of the series, especially those containing benzene rings substituted with about four to six carbon atoms. The myocardial uptake is related to the lipophilicity of the complexes as measured by octanol/buffer partition ratios (OBPR). Optimal ranges of lipophilicity for maximal myocardial uptake occur for OBPR from 2 to 9. Rat and human plasma binding of the complexes increases with lipophilicity after a threshold value is exceeded.

Comparison of technetium-99m MAG3 kit with HPLC-purified technetium-99m MAG3 and OIH in rats.

Technetium-99m (99mTc) mercaptoacetylglycylglycylyglycine (MAG3) in high (greater than or equal to 95%) radiochemical purity is prepared from lyophilized kits containing benzoylMAG3, sodium tartrate, lactose, and stannous chloride by adding sodium [99mTC]pertechnetate and heating the contents briefly. Constant-infusion renal whole-blood clearance obtained with [99mTc] MAG3 kits was compared with that obtained with high performance liquid chromatography (HPLC) pure [99mTc]MAG3 and with co-infused iodine-131 (131I) iodohippurate (OIH) in anesthetized rats. Average renal whole-blood clearance of [99mTc]MAG3 from kits was 3.9 +/- 0.4 ml/min/100 g body weight (mean +/- s.e.m. n = 5) and that for HPLC-pure [99mTc]MAG3 was 4.6 +/- 0.3 (n = 3). Renal whole-blood clearance ratios for [99mTc]MAG3 to co-infused iodine-131 (131I) OIH were greater than unity for both kit formulation (1.7 +/- 0.1) and HPLC-pure [99mTc]MAG3 (1.9 +/- 0.2). Differences in these two measures were not significant. Plasma binding (determined from blood drawn at the end of the infusion) of [99mTc]MAG3 prepared from both kits (75 +/- 2%, n = 4) and HPLC-separation (76 +/- 4%) were greater than that of [131I]OIH in corresponding plasma samples (31 +/- 1% and 32 +/- 2%) respectively). Renograms performed in anesthetized rats revealed no statistically significant differences between kit-prepared [99mTc]MAG3 and [131I]OIH in terms of time-to-peak renal activity (5.0 +/- 1.7 min, n = 6; and 2.2 +/- 0.2 min, n = 3, mean +/- s.e.m. for [99mTc]MAG3 and [131I]OIH, respectively), in terms of time to fall to half-maximal activity (15.3 +/- 2.4 min and 9.6 +/- 2.1 min, respectively), or in terms of fraction of peak radioactivity in right kidney (0.53 +/- 0.01 for both substances). To assess possible interference from hepatobiliary uptake and excretion in renal failure, radioactivity in liver regions of interest was followed by gamma camera scintigraphy for 30 min after intravenous injection of [131I]OIH and kit and HPLC-purified [99mTc]MAG3 in anesthetized rats rendered anephric by ligating renal peduncles. Liver activity was 25% of total for both preparations of [99mTc]MAG3 and was 22% of total for [131I]OIH. There were no significant differences among the substances.

Biodistribution and excretion of 125I ioversol in conscious dogs.

Radiolabeled ioversol was injected intravenously into two male and two female beagle dogs (6.7 to 10.4 kg) at two dose levels each (0.2 and 1.0 g I/kg). Blood levels of radioactivity were monitored at 2, 5, 10, 20, 40, 60, 90, and 120 minutes and at one and two days. Urine and feces were collected in metabolism cages for two days, at the end of which the dogs were killed and organs or tissues (kidneys, liver, spleen, lungs, thyroid glands, heart, gonads, and muscle) were sampled. Radioactivity in tissues and excreta was assayed. Biexponential disappearance of radioactivity from blood was observed in three of four dogs at each dose level. Distribution half-lives averaged 2.5 to 3.5 minutes. Elimination half-lives averaged 51 to 54 minutes. Volumes of distribution averaged 25% to 27% of body weight. No organ retention was evident at 48 hours. Recovery of ioversol in urine and feces averaged 86% to 88% of the administered dose, of which all but a few percent was recovered in urine. On chromatographic assay, ioversol accounted for an average of 103% to 109% of radioiodine, suggesting, within the experimental limits of the assay, that ioversol is excreted unchanged. No dose-related differences were evident in any of these measures. The pharmacokinetics and biodistribution of ioversol are consistent with those of other extracellularly distributed iodinated contrast agents that are excreted by the kidney.

Hemodynamic effects of ioversol in the dog and rat.

The hemodynamic effects of selectively administered ioversol were examined in the dog and rat. At concentrations ranging from 32% to 37% I, wt/vol, ioversol was compared with nonionic (iohexol, iopamidol) and ionic (diatrizoate) contrast media for cardiovascular responses following injections into the femoral vein, right and left coronary arteries, left ventricle, and the pulmonary and femoral arteries of the dog, and into the carotid artery of the rat. Regardless of the intravascular route of injection, ioversol generally caused minimal effects on the heart rate, minimal to moderate decreases in myocardial contractility, left ventricular pressure, mean arterial pressure, pulmonary vascular resistance, and systemic vascular resistance. These effects of ioversol were comparable to those of iohexol and iopamidol, and were relatively less profound than those of diatrizoate. Under experimental conditions injections of ioversol exerted hemodynamic effects comparable to those of other nonionic agents, yet relatively diminished as compared with a representative high-osmolality ionic contrast agent. These results suggest that the nonionic contrast agent, ioversol, should be well tolerated in patients following injections via similar intravascular routes.

Differential interaction between stressors and chronic amphetamine or phencyclidine upon operant behavior in the rat.

Three types of stress were examined for their effects upon fixed-ratio 15 (FR-15) operant behavior in Sprague-Dawley rats before and after chronic dextroamphetamine to determine if cumulated drug could interact with stress to produce a state of behavioral toxicity. Six daily s.c. injections of saline were given to rats following 30 min behavioral sessions. Thirty minutes of exposure to a cold environment (7 degrees C) or to electric footshock (2mA for 0.5 sec, 1 shock/min) had no significant effect upon FR-15 behaviour beginning 15 min afterward. Five daily s.c. injections of 2.5 mg dextroamphetamine/kg after behavioral sessions suppressed behavior during the following days an average of 12%. Rats were again stressed twenty-two hours after the sixth injection. Footshock further suppressed behavior to 26% of the unstressed, chronic amphetamine-treated control group. Cold exposure failed to suppress behavior significantly below control levels. A similar experiment employing cold water exposure (15 degrees C for 2 min) as the stressor showed that, although, this stressor suppressed FR-15 behavior to 53% of the previous day's rates and reduced body temperature 2.1 degree C, chronic amphetamine failed to interact with the cold water stress to suppress behavior further. In a third experiment, 4.5 mg phencyclidine/kg, s.c., given after 30-min FR-15 sessions for six days, failed to interact with the footshock stress to cause behavioral suppression different from control treatment. While stress can interact with chronic treatment with lipophilic drugs, the quality of the stress, and the physical and pharmacologic properties of the drug are important determinants of the outcome upon conditioned behavior.

Phencyclidine retards autoshaping at a dose which does not suppress the required response.

Four groups of five food-deprived hooded Long-Evans rats were injected subcutaneously with saline (vehicle) or 2, 4 or 8 mg phencyclidine (PCP) hydrochloride/kg fifteen minutes before being placed for the first time into operant chambers modified to detect exploratory behaviors. Rearing was found to be more sensitive to disruption by phencyclidine than was unconditioned level touching (a measure of floor-level exploratory activities). In an autoshaping session immediately following, the group of animals given the low dose of PCP made as many lever-touch responses as the group given saline, but consumed fewer of the food pellets delivered. In addition, none of the animals in the low-dose group showed within-session shortening of the latency to respond which was observed in four of five control animals. The two other groups given higher doses of PCP demonstrated dose-related decrements in responding as well as a reduction in food pellet consumption during the first session of autoshaping. Over the next two daily autoshaping sessions, performance improved in those groups initially suppressed. Performance converged in all group by the third autoshaping session.

Delayed effects of amphetamine or phencyclidine: interaction of food deprivation, stress and dose.

Tritium-labelled phencyclidine (PCP) hydrochloride (12 mg/kg) was injected SC for six consecutive days into two groups of eight male rats maintained at 85% of their initial free-feeding weights. Eight days after the last injection, electric footshock raised fat levels of PCP 28% over nonshocked controls, and lowered blood levels 18%, but did not alter brain levels of the drug significantly. Thus, application of an acute stressor does result in redistribution of tissue stores of phencyclidine as predicted in the literature; however, the direction of the redistributions was to fat, rather than to brain. To explore the relation of a long-term stressor (one that eliminates adipose tissue as a sink for mobilized PCP), exploratory behavior was evaluated in male rats during six days of food deprivation commencing after six daily injections of PCP HCl (2 or 4 mg/kg, SC). Exploratory behavior of the 4 mg/kg dose group was abruptly altered, compared to saline controls, at six days of food deprivation, when the rats' body weights were about 70% of initial weights and when body fat would be severely reduced or depleted. To assess replicability and generalizability of this phenomenon, PCP HCl (4 or 8 mg/kg, SC) or dextroamphetamine sulfate (3.2 or 6.4 mg/kg, SC) was injected into male rats for six days and food deprivation followed afterward for nine consecutive days, or until similar body weight reductions as in the first experiment were achieved. Again, exploratory behavior was altered in comparison to saline controls in phencyclidine-treated rats (at the 4 mg/kg dose level) when rats reached about 70% of initial weights.(ABSTRACT TRUNCATED AT 250 WORDS)

Food deprivation alters behavioral and plasma corticosterone responses to phencyclidine in rats.

Phencyclidine (PCP) sensitivity of rats, whose body weights were maintained at 70% of free-feeding controls, was compared to drug sensitivity of the controls in terms of unconditioned (exploratory) behavior and plasma corticosterone levels. Low doses of PCP HCl [0 (saline vehicle), 0.3 or 0.9 mg/kg, SC] were given to food-deprived rats and to free-feeding controls 15 minutes before measuring unconditioned behavior for 90 minutes; then PCP in brain and corticosterone in plasma were assayed. An additional group (0.43 mg/kg) was established from the reduced-weight rats in order to compare with free-feeding rats given 0.3 mg/kg, the same absolute dose-a circumstance reflecting "street" usage in which doses are not adjusted for body weight differences among users. These low doses of PCP altered exploratory behaviors, but there did not appear to be an interaction between food-deprivational status and drug, with the possible exception of an altered effect of PCP upon habituation in the lighter animals. PCP elevated plasma corticosterone levels over saline controls only in the reduced-weight rats. The drug, possibly reflecting a tranquilizing action of the lowest dose, reduced corticosterone levels in free-feeding controls. Brain levels of drug were directly related to dose, and were elevated in the food-deprived animals 26-30% over those at the same per-weight dose levels in the free-feeding rats, in spite of being given lower absolute amounts of drug. In the 0.43 mg/kg reduced-weight dose group, given the same absolute dose as the 0.3 mg/kg free-feeding group, brain levels were doubled over the latter group, and exploratory behavior was correspondingly different from the free-feeding group.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of diuretics on urinary general base catalytic activity and cyclophosphamide-induced bladder toxicity.

The influence of diuretics on the induction of bladder toxicity by cyclophosphamide was investigated in rats. Following ip administration, about 3.5% of the cyclophosphamide was excreted as 4-hydroxycyclophosphamide. This amount was found to be compatible with the view that the urotoxic effects of cyclophosphamide are caused by the acrolein generated in the urine from 4-hydroxycyclophosphamide, the primary metabolite of cyclophosphamide. In situ, acrolein was more potent than 4-hydroperoxycyclophosphamide with regard to producing an increase in bladder weight; phosphoramide mustard was essentially without urotoxic activity. The urotoxic potency of 4-hydroperoxycyclophosphamide, but not that of acrolein, increased as the pH and/or the phosphate concentration of the infusion medium increased. This was as expected in view of the knowledge that release of acrolein from 4-hydroxycyclophosphamide or 4-hydroperoxycyclophosphamide is facilitated by the presence of general base catalysts, eg, phosphate and bicarbonate, and that the rate at which this reaction proceeds in the presence of these catalysts increases as their concentration and the pH increases. In vivo, diuretics that acidified the urine, eg, ammonium chloride and furosemide, prevented the increase in bladder weight ordinarily elicited by the dose of cyclophosphamide used in these experiments. In contrast, a diuretic, acetazolamide, that markedly increased urinary bicarbonate concentration and alkalinized the urine, did not. None of the diuretics altered the systemic metabolism and urinary excretion of cyclophosphamide nor did they alter the systemic action, as judged by spleen weight, of cyclophosphamide. These observations demonstrate that the pH of the urine and the urinary concentration of general base catalysts greatly influence the urotoxic potential of oxazaphosphorines such as cyclophosphamide. They indicate that while the use of acidifying diuretics is likely to be beneficial in minimizing oxazaphosphorine-induced bladder toxicity, the use of alkalinizing diuretics may not be helpful.