[Dosage regimen calculation of "intravenous injection+intravenous infusion" for two compartment model drugs].
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Microfilaremia, immune responses, and pathology were compared in ferrets infected with 100 third-stage larvae of Brugia malayi (subperiodic strain) or injected intravenously with 10(6) microfilariae. Ferrets (Mustela putorius furo) inoculated with third-stage larvae typically became patent during the third month after infection, with a mean patency of 123 +/- 25 (SE) days. Ferrets injected intravenously with microfilariae exhibited a relatively constant microfilaremia for 3-4 weeks and usually cleared microfilariae before the fourth month. Ferrets that cleared microfilariae after intravenous injection of microfilariae or after infection with third-stage larvae failed to become patent or became amicrofilaremic within 3 weeks after a challenge intravenous injection of 10(6) microfilariae. Clearance of circulating microfilariae was associated with eosinophilia and serum antibody specific for the microfilarial sheath in ferrets injected with microfilariae and in most ferrets infected with third-stage larvae. Ferrets infected with third-stage larvae and necropsied after clearance of microfilariae had tissue inflammatory reactions to microfilariae characteristic of occult filariasis (tropical eosinophilia) in man; these ferrets exhibited immediate cutaneous hypersensitivity and circulating reaginic antibody to antigens of microfilariae. In ferrets necropsied following two intravenous injections of microfilariae, the majority of ferrets examined within 10 days after clearance of microfilariae had visible liver lesions to microfilariae identical to those of the ferrets infected with third-stage larvae; immediate cutaneous hypersensitivity and reaginic antibody were not consistently detected in ferrets injected with microfilariae. Sera from ferrets that had cleared circulating microfilariae were transferred passively into ferrets made microfilaremic by intravenous injection of microfilariae. Sera with microfilarial sheath-reactive IgG antibody titers (greater than or equal to 1:200) and microfilarial agglutination titers (greater than or equal to 1:40) rapidly cleared injected microfilariae (less than 24 hr); this serum also cleared or greatly reduced circulating microfilariae established by an infection with third-stage larvae; only the IgG-containing fraction of the sera was active in immune clearance. Sera that cleared microfilariae of B. malayi did not clear circulating microfilariae of Dirofilaria immitis or prevent recurrence of circulating microfilariae of B. malayi in ferrets infected with adult filariae.(ABSTRACT TRUNCATED AT 400 WORDS)
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The tissue distribution of daunorubicin (DNR) was investigated in rabbits after 5 mg/kg DNR i.v. bolus injection or 4 h infusion of 5 mg/kg either as free drug or as a complex with DNA. After i.v. bolus, the highest DNR concentration was observed in lungs and kidneys, a lower concentration in heart and spleen and the least in the liver. The DNR biotransformation to daunorubicinol (DNR-ol) and aglycones was most active in kidneys and liver, while heart, lungs and spleen metabolized DNR to a lower extent. The DNR tissue elimination half-life varied from 4.5 to 8.7 h, whereas concentrations of DNR-ol remained elevated for a longer period of time. After 4 h infusion, the only difference when compared with i.v. bolus consisted of a 3-fold lower initial DNR concentration in heart and lungs. No striking difference could be observed after free versus complexed drug infusion except for a somewhat lower DNR concentration in heart and lungs for the complexed drug.
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The early phase of diaplacental transfer of diazepam was studied in 39 women given the drug as a basic anaesthetic for operative vaginal delivery indicated by prolonged second stage of labour (9 cases), breech delivery (19 cases) and intrauterine hypoxia (11 cases). A total dose of 30 mg diazepam (Valium Roche) was injected intravenously over a period of 15 sec umbilical cord blood was collected immediately after delivery. Diazepam was extracted with diethyl ether and determined by gas chromatography. The concentration of diazepam in cord blood increased from greater than 5-250 ng/ml at 57-60 seconds to 48-1861 ng/ml at 90-100 seconds after completion of the intravenous injection. Thereafter a plateau seemed to be reached but the interindividual variation was still great with values ranging from 45-3034 ng/ml up to 360 seconds. Judged by Apgar score and the clinical course the neonates seemed to be unaffected by the medication administered to the mother.
Clinical and morphologic features are described in two patients known to have repeatedly injected intravenously talc-containing drugs intended for oral use. In one patient severe pulmonary hypertension developed; the talc granulomas in him were located predominantly within the pulmonary arteries. The second patient had normal pulmonary arterial pressures, and the talc granulomas in him were located predominantly in the pulmonary interstitium. Of 19 previously described patients with pulmonary talc granulomas, 12 had morphologic evidence of pulmonary hypertension (in three of severe degree); in each, talc granulomas were located predominantly within the pulmonary arteries. In those without signs of pulmonary hypertension, granulomas were located predominantly in the pulmonary interstitium. Why there are differences in the distribution of the talc granulomas is unclear. It is clear, however, as demonstrated by one of our patients, that severe pulmonary hypertension may be a consequence of intravenous injection of drugs intended for oral use.
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A case of a 16 year old male who injected intravenously metallic mercury is presented. The patient was admitted to the hospital due to slightly elevated fever and hemoptysis. Both symptoms presented themselves 18 months following intravenous injection of metallic mercury. Radiological examination disclosed fine metallic interstitial shadowing in the lung parenchyma. Metallic shadows were also present in the subcutaneous region of the cubital fossa. CT scans and USG examination disclosed similar deposition of metal in the liver, kidneys, lymph nodes and heart. The mercury serum and urine levels exceeded the normal values by hundreds. Encountered diagnostic problems are presented, also prognosis basing on data from literature is discussed.
When adenovirus vectors are injected intravenously, they are quickly taken up by Kupffer cells in the liver. We report that this causes rapid necrosis of Kupffer cells in mice at doses of 10(11) particles/kg or higher. By 10 min after intravenous vector injection, Kupffer cells were permeable to propidium iodide and trypan blue. This coincided with a sharp rise in serum lactate dehydrogenase. Ultrastructural examination showed degeneration of Kupffer cells, including complete disappearance of chromatin by 1 h. After an initial intravenous injection of vector, dead Kupffer cells were unable to take up a second dose of vector, and hepatic transgene expression from the second dose was augmented. Death of Kupffer cells did not affect serum levels of IL-6 or IL-12. There was no immediate change in the number of Kupffer cells in the liver, but a significant decline was found by 4 h after injection of vector. Interestingly, substantial numbers of vector-containing Kupffer cells were found in pulmonary capillaries, indicating that they had been swept out of the liver. Together these results show that an intravenous injection of adenovirus vector causes synchronous and surprisingly rapid Kupffer cell death.
Survival of rats exposed to 100% oxygen was increased from 69.5 +/- 1.5 to 118.1 +/- 9.9 h (mean +/- SEM, P less than 0.05) when liposomes containing catalase and superoxide dismutase were injected intravenously before and during exposure. The increased survival time in 100% oxygen was also associated with significantly less fluid in the pleural cavity. Rats injected with catalase- and superoxide dismutase-containing liposomes, which had increased survival in 100% oxygen, had increased lung wet weight upon autopsy compared with saline-injected controls (2.9 +/- 0.2 g/lung vs. 4.8 +/- 0.4 g/lung, mean +/- SE, P less than 0.05). Intravenous injection of control liposomes along with catalase and superoxide dismutase in the suspending buffer decreased the mean pleural effusion volume 89% and had no significant effect on survival time. Lung catalase and superoxide dismutase activities were increased 3.1- and 1.7-fold, respectively, 2 h after a single intravenous injection of liposomes containing catalase or superoxide dismutase. Superoxide dismutase activity was also significantly greater than controls in both air- and 100% oxygen-exposed rat lungs, when enzyme activity was assayed 24 h after cessation of injection of control and oxygen-exposed rats with enzyme-containing liposomes every 12 h for 36 h. Free superoxide dismutase and catalase injected intravenously in the absence of liposomes did not increase corresponding lung enzyme activities, affect pleural effusion volume, lung wet weight, or extend the mean survival time of rats exposed to 100% oxygen. The clearance of liposome-augmented 125I-labeled catalase from lung and plasma obeyed first order kinetics according to a one-compartment model. When clearance of liposome-augmented catalase activity or radioactivity were the parameters used for pharmacokinetic studies, the half-life of augmented lung catalase was 1.9 and 2.6 h, respectively. The half-life of liposome-entrapped catalase and superoxide dismutase activity in the circulation was 2.5 and 4 h, respectively, while intravenously injected catalase and superoxide dismutase had a circulation half-life of 23 and 6 min, respectively.
Intravenous injections of the quaternary dipyridlium salt paraquat (14C-labelled) dissolved in solutions of low tonicity result in a high uptake in the erythrocytes and concomitantly also in the spleen (red pulp), the latter being probably due to phagocytosis of paraquat-containing erythrocytes by the reticuloendothelial system. Higher tonicities of the injected solutions result in a low uptake and the same applies to oral, intraperitoneal and subcutaneous injections. Paraquat was present in the erythrocytes in a non-metabolized form without being bound to membranes or proteins. The uptake in the erythrocytes was not influenced by alterations of the pH or by the preparation of a charge-transfer complex with serotonin in the injection solutions. Chemical alterations of the paraquat in the injection solutions could not be detected. In vitro the uptake of paraquat in the erythrocytes was higher in the haemolysed (and then reconstituted by adding sodium chloride) erythrocyte-ghosts than in the non-haemolysed erythrocytes, as shown by incubations at various tonicities. It is proposed that the intravenous injections of paraquat in hypotonic solutions temporarily alter the membranes of the erythrocytes in the blood-stream and make them permeable to paraquat, possibly, as judged from the in vitro experiments, only during a short period of partial haemolysis. The distribution studies also showed a retention of paraquat in the lungs. In addition paraquat was accumulated in the melanin of the tissues.
The in vivo activity of murine Lyt-2+ cytolytic T lymphocyte clones was assessed in a tumor allograft model system. Mice that had been sublethally irradiated 16 h previously were injected intraperitoneally with 131I-IUdR-labeled tumor cells. Simultaneously, various doses of four cytolytic T cell clones were injected intravenously and the mice monitored for tumor cell elimination by whole-body counting tecniques. These four clones had been selected on the basis of their ability to proliferate in response to alloantigens in the absence of added T cell growth factor(s). With two of the four clones tested, rapid elimination of tumor cells within the peritoneal cavity was observed, as early as 48 h after intravenous injection of the cloned T cells.
BACKGROUND: The purpose of this study was to determine whether murine mesenchymal stem cells (MSC) are able to home to the viable myocardium when injected intravenously and attenuate cardiac dysfunction and ventricular remodeling associated with myocardial infarction. METHODS AND RESULTS: Murine bone marrow cells were negatively selected for lineage markers and adherent MSC differentiated into adipocytes and osteocytes following treatment in culture. Two weeks after coronary occlusion that resulted in a permanent transmural infarct we observed a significant drop in LV systolic pressure, dP/dt(max), dP/dt(min), ESPVR and E(max) and a significant increase in end-diastolic volume in vivo. Femoral vein injection of MSC 1 h after occlusion attenuated the cardiac dysfunction without altering infarct size, or end-diastolic volume. Injected MSC pre-labeled with fluorescent paramagnetic microspheres were observed scattered in noninfarcted regions of the myocardium. Flow cytometry of whole heart digests after intravenous injection of MSC labeled with either fluorescent microspheres or fluorescent PKH26 dye demonstrated that infarcted hearts from mice that received MSC injections contained significantly more cells that integrated into the heart (20x) than those from uninfarcted controls. CONCLUSION: We conclude that intravenously injected MSC were able to home to viable myocardium and preserve systolic function by 2 weeks following ligation. The preserved contractility is likely an MSC-mediated paracrine response since infarct morphology was unchanged and labeled cells observed at two weeks exhibited the same characteristics as the injected MSC. These data underscore the importance of using MSC as a potential therapeutic intervention in preserving cardiac function following infarction.
The aim of this study was to evaluate the role of endothelin and endothelin ETA receptor in the early cerebral vasoconstriction following subarachnoid hemorrhage (SAH) in the rat. SAH induced by injection of autologous blood in the cisterna magna reduced by 22 to 38% cerebral blood flow (CBF) measured with radioactive microspheres at 30, 60 and 120 min after SAH. The cyclic pentapeptide BQ-123, a selective antagonist of the ETA receptor, injected intravenously (3 mg/kg) had no effect on this decrease in CBF. However, intracisternal BQ-123 (10 nmol) completely prevented the decrease in CBF at 60 and 120 min after SAH. These results suggest that BQ-123 does not cross the blood-brain barrier, but demonstrate that endothelin acting on ETA receptor plays a role in the pathogenesis of cerebral vasoconstriction in this rat model of SAH.
We have identified a novel means of reducing the risk of decompression sickness (DCS) in rats. A substantial reduction in DCS, from 55% in untreated animals to 24% in animals injected intravenously with a hydrogenase of bacterial origin, was documented for animals breathing a mixture of oxygen and hydrogen. However, this reduction was clearly not a function of metabolic elimination of H2; injections of proteins lacking hydrogenase activity also elicited a lower DCS incidence, and animals breathing hyperbaric helium had the same protective advantage as animals breathing H2. The reduction in DCS risk was shown to be caused by intravenous injection of a foreign protein. The magnitude of the effect varied: two foreign proteins tested did not induce a statistically significant response. We speculated that the foreign protein elicited an immune reaction pre-dive, which diminished the subsequent response of the immune system in DCS. Identifying the underlying mechanism may be important to understanding the pathophysiology of this malady, and may ultimately lead to a therapy applied pre-decompression for reducing DCS risk in human diving.
To compare the distribution of cis-diamminedichloroplatinum (II) (CDDP) on scintigraphic images between intra-arterial injection with lipiodol and intravenous injection, we obtained serial scintigraphic images using radiolabeled CDDP (Pt-195m CDDP), which had a high specific activity (7.4 x 10(6) Bq [200 microCi]/mg-CDDP), in the rabbit VX-2 tumor system. A dose of 9.25 x 10(6) Bq (250 microCi) of Pt-195m CDDP was injected at one shot via an ear vein, while 7.4 x 10(6) Bq (200 microCi of Pt-195m CDDP mixed with 1 ml of lipiodol was injected at one shot via a saphenous artery. Mean pixel count, which was corrected for the total dose injected, in the arterially injected tumor always exceeded than that in the intravenously injected tumor. Pt-195m CDDP uptake by the rabbit tumor at 2 hr was 7.8% of the total injected dose with intravenous injection and 16.0% with intra-arterial injection. These data suggest that intra-arterial injection with lipiodol is a more useful method to increase CDDP uptake by tumors than intra-venous injection.