Acute 4-aminopyridine seizures increase the regional cerebral blood flow in the thalamus and neocortex, but not in the entire allocortex of the mouse brain.

Systemic injections of 4-aminopyridine precipitate epileptiform generalized seizures characterized mainly by shivering of the body, tail movements and tonic-clonic convulsions in rats and mice. However, only few details are known as concerns which brain regions are possibly affected and stimulated by the compound. The aim of the present study was to investigate the changes in regional cerebral blood flow in mice by using the lipophilic compound technetium-99m-hexamethyl-propyleneamineoxime (99mTc-HMPAO). Whilst the uptake of 99mTc-HMPAO was increased significantly in the neocortex and thalamus following the induction of acute 4-aminopyridine seizures, no such changes were observed in the allocortex of the mice. The increases in uptake in the neocortex and thalamus were completely prevented by carbamazepine (which abolished the symptoms of the seizure, too). The primary involvement of the neocortex and thalamus points to the importance of thalamocortical circuits in the precipitation and maintenance of experimental 4-aminopyridine convulsions.

On substance abuse in Kuwait (1992-1997). Evidence from toxicological screening of patients.

PURPOSE: To assess preference for different psychoactive substances and time trends in Kuwait. METHODS: Analysis of urine and blood samples of specimens sent by attending physicians to the only public health reference laboratory for toxicological screening in the country. RESULTS: A total of 28,548 tests were performed on 3781 samples. Cannabinoids were positive in 40% of the tested samples, opiates in 24%, ethanol in 10%, and amphetamines in 5%. Elevated concentrations of methadone, cocaine, and phencyclidine did not exceed 0.1%. About 40% of samples was positive for benzodiazepines, but their therapeutic use obscures the informativeness of this finding. There was a significant increase in the proportion of positive results for ethanol, amphetamines, and benzodiazepines. IMPLICATIONS: It is high time to implement a modern and comprehensive preventive and control program. The tendency to blame the Iraqi invasion for drug addiction has hampered efforts to recognise and address the problem in its entirety.

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. Autoradiograms 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 exemplified by CsA.

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 subcutaneously 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 microCi 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 I-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 I-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 comparable with the histopathological findings in which the organs showed varying degrees of tissue degeneration. It is concluded that the lipophilic radiopharmaceutical, I-125 HIPDM, can be used as an effective screening agent to study multiorgan toxicity due to CsA.

The effect of cyclosporine-A on labeling blood cells with radiopharmaceuticals.

The effect of cyclosporine-A (CsA) on the labeling efficiencies of red blood cells with reduced 99mTcO4-; leukocytes and platelets with 111In oxine was studied. Blood was used from rats treated with CsA (30 mg/kg body weight) for 28 consecutive days and from control rats. For 99mTc labeling of RBCs, blood was obtained from individual rats and in vitro labeling technique was used. For leukocyte and platelet labeling, blood was pooled from 5 rats either treated with CsA or control. Leukocytes/platelets were labeled with 111In oxine using routine techniques. The labeling efficiency for 99mTc RBCs was 83.42 +/- 0.83% (CsA treated) and 84.85 +/- 0.62% (control); 111In-oxine leukocytes was 38.5 +/- 1.75% (CsA treated) and 42.5 +/- 3.53% (control); and for 111In-oxine platelets, it was 74.0 +/- 2.5% (CsA treated) and 78.0 +/- 1.41% (control). Comparison of the results indicate that there is no difference between the percent labeling efficiencies of 99mTc RBCs, 111In-oxine leukocytes, and 111In-oxine platelets for CsA-treated and control rats. Hence, CsA does not interfere with the labeling process of blood cells with radiopharmaceuticals.

Is cyclosporine toxic to the heart?

Cardiotoxicity caused by cyclosporine was studied in experimental rats by the uptake of radiopharmaceuticals (technetium 99m-labeled pyrophosphate and indium 111-labeled antimyosin) and histologic examination of heart tissues. A dose of 50 mg/kg (body weight) of cyclosporine and an equal volume of vehicle (cremophor-EL) were injected into the rats subcutaneously for 7 or 11 consecutive days. A statistically significant difference (p < 0.05) was noted between the uptake of the radiopharmaceuticals in the hearts of cyclosporine-treated rats compared to the control rats. For 99mTc pyrophosphate, the cardiac uptake ratios of cyclosporine-treated rats to control rats were 2.13 and 4.08 for 7-day and 11-day treatment periods, respectively. For 111In antimyosin, the ratios were greater than 2 for both 7-day and 11-day treatment periods. Histologically, vacuoles were found in single or focal groups of myocytes with interstitial edema in the hearts of cyclosporine-treated rats compared to the control rats. The results of both the uptake of the radiopharmaceuticals and the histologic evidence indicate cell injury in the hearts of cyclosporine-treated rats. Cyclosporine therefore seems to be toxic to the heart tissue.

Effect of cyclosporin A on bile flow in experimental animals using technetium-99m EHIDA.

The effect of cyclosporin A (CyA) on bile flow was studied in experimental rabbits by radionuclide imaging and measurement of bilirubin levels. The rabbits were dosed intravenously with 15 mg/kg CyA for 4 consecutive days. Each rabbit served as its own control. The rabbits were injected IV with technetium (Tc)-99m EHIDA, and dynamic images were obtained prior to and 1, 4, 8, and 15 days after CyA treatment. There was no difference in half-times of blood clearance in control and CyA-treated rabbits. There were differences in the half-times of liver curve and bilirubin measurements between control and 4-day treated rabbits. By the 15th day after CyA treatment both the radionuclide findings and bilirubin levels became normal. The results suggest that CyA causes intrahepatic cholestasis and demonstrate evidence of reversibility of CyA's toxic effect on bile flow after treatment is discontinued.

The use of 125I-HIPDM for studying tissue response due to toxic effects of cyclosporin-A in rats.

125I-HIPDM was used to study the response of various tissues in cyclosporin-A, CyA, treated and control rats. The rats were given 50 mg/kg of CyA for 7 consecutive days. The liver, kidney and heart showed significant increase while the spleen had a pronounced decrease in the uptake of 125I-HIPDM in CyA treated compared to control rats. This difference in the uptake of 125I-HIPDM between CyA treated and control rats is assumed to be the tissue response to toxic effects of CyA. The results indicate that CyA is toxic to liver, kidney, spleen and probably heart. There was no difference in the uptake of 125I-HIPDM in the lung and brain of CyA treated and control rats. This lack of difference is assumed to indicate that CyA does not adversely affect the lung and brain.

Evaluation of the sorbent suspension reciprocating dialyser in the treatment of overdose of paracetamol and phenobarbitone.

Poisoning with paracetamol (acetaminophen) and phenobarbitone is a common occurrence in the United States and Europe. The removal efficiency of these drugs by a sorbent suspension reciprocating dialyser (SSRD) has been investigated. The SSRD is a parallel plate dialyser with a reciprocating blood flow and free mobile sorbent suspension composed of charcoal and zeolites. This arrangement provided a system with minimal sorbent saturation. High performance liquid chromatography was used for the quantification of the drugs in aqueous and serum fluids. The in-vitro removal efficiency of the dialyser was studied by dialysing a large volume of the drug in solution for 12 to 16 h. The removal efficiency remained relatively constant up to 10 h of dialysis. The in-vivo dialysis studies were performed using normal dogs. Large doses of the drugs were administered orally or intravenously to achieve high blood levels. The clearance values obtained from these studies were comparable with, or in excess of, the values reported in the literature for conventional dialysers. The major advantage of the SSRD is the ability of the unit to be used for prolonged dialysis and to provide a system with minimal sorbent saturation due to mixing and interchange of sorbent granules next to the membrane surface.

A comparison of antibiotics consumption and bacterial resistance patterns in Kuwait and Sweden.

The total utilization of antimicrobial drugs, expressed as DDD/1000 inhibitants/day, was 19 in Kuwait and 15 in Sweden. Aminoglycosides, tetracyclines and trimethoprim/sulphonamide were used more in Kuwait than in Sweden. The utilization of cephalosporins, however, was more prevalent in Sweden than in Kuwait. Hospital use of aminoglycosides was more pronounced in Kuwait than in Sweden, whereas trimethoprim/sulphonamide was less utilized in Kuwait. The overall consumption of antimicrobial drugs expressed as DDD/500 hospital beds, was highest in one of the Swedish hospitals where, for example, the consumption of tetracyclines was 15-fold higher than that in the comparable Kuwaiti hospital. Regarding bacterial resistance patterns, the large use of aminoglycosides and ampicillin was reflected in a higher resistance frequency among the Kuwaiti isolates. Resistance frequencies for trimethoprim/sulphonamide was also relatively much higher in Kuwait than in Sweden. In this case there was, however, no simple correlation to utilization figures, which are lower for the Kuwaiti hospital than for the Swedish. Resistance to chloramphenicol was prevalent in both countries, in spite of the very limited use of this drug.