Protection by Desferrioxamine Against Histopathological Changes of the Liver in the Post-Oligaemic Phase of Clinical Haemorrhagic Shock in Dogs: Correlation with Improved Survival Rate and Recovery

Abstract

Haemorrhagic shock was produced in anaesthetized dogs, by rapid arterial bleeding to mean arterial blood pressure 35 mmHg, and maintained oligaemic for 4 h followed by return of withdrawn blood(ROWB). Dogs were observed for 72 h after ROWB for survival and recovery, and, for histopathological (HP) studies on liver, dogs were sacrificed 2 h after ROWB in non-survival experiments. Desferrioxamine mesylate (25 mg/kg) was administered intra-muscularly at 2,3 and 4 h after blood loss in survival experiments and for HP studies the drug was given at 4 h in one group and at 2 h plus 4 h after blood loss in the second group. With the drug given at 3 or 4 h, survival was 70% and 100% while in the 2 h and the untreated groups it was 50%. Recovery was rapid in all the drug treated survivors, few became conscious within 30 min, showed slight activity by 4-6 h, all were almost normally active by 24 and fully so by 72 h after ROWB. All the 5 control survivors remained unconscious/drowsy upto 24 h; 3 were sluggish at 72 h. By group analysis, serum iron elevation during the oligaemic and at the end of the post-oligaemic phase was less in the drug-treated animals. HP changes of shock in the liver studied by light microscopy, were markedly reduced in severity and were less prevalent in the drug-treated dogs. The salutory effects of desferrioxamine may be due to inhibition of iron catalyzed free-radical production and tissue damage, through its strong iron chelating action. It may have a therapeutic advantage in this emergency condition without the disadvantages of toxicity inherent in prolonged use.

Influence of ACTH‐(1–24) on free radical levels in the blood of haemorrhage‐shocked rats: direct ex vivo detection by electron spin resonance spectrometry

“…A large body of indirect evidence suggests that an increased production of oxygen-derived free radicals mediates damage to the cell membrane during haemorrhagic shock (Horton & Borman, 1987;Lee et al, 1987;Bond et al, 1988;Vedder et al, 1988;von Ritter et al, 1988;Lieners et al, 1989;Sanan et al, 1989;Marzi et al, 1990;Fleckenstein et al, 1991; treatment with ACTH-(I-24) (160 pg kg-1). Table 1 Summary of a-phenyl-N-tert-butylnitrone-adduct signal (electron spin resonance) intensity (arbitrary units ml-' whole blood) in haemorrhage-shocked rats before and after i.v treatment with saline (1 ml kg-'), Values represent the mean+s.e.…”

“…Severe haemorrhagic shock may be viewed as whole body ischaemia, and is characterized by inadequate perfusion of tissues, altered cell membrane permeability and subsequent cellular dysfunction (Baue et al, 1971;1973;Horton & Tuggle, 1983). A large body of indirect evidence suggests that an increased production of oxygen-derived free radicals mediates damage to the cell membrane during haemorrhagic shock (Horton & Borman, 1987;Lee et al, 1987;Bond et al, 1988;Vedder et al, 1988;von Ritter et al, 1988;Lieners et al, 1989;Sanan et al, 1989;Marzi et al, 1990;Fleckenstein et al, 1991; Percentage of surviving animals (at the end of lines) 2 h after treatment with ACTH-(1-24) or after blood reinfusion was statistically different from that of saline-treated controls (P<0.005; Fisher's test). 1 Summary of a-phenyl-N-tert-butylnitrone-adduct signal (electron spin resonance) intensity (arbitrary units ml-' whole blood) in haemorrhage-shocked rats before and after i.v treatment with saline (1 ml kg-'), Values represent the mean+s.e.…”

Effects of inhibitors of the activity of poly (ADP‐ribose) synthetase on the organ injury and dysfunction caused by haemorrhagic shock

“…The overproduction of ROS in haemorrhagic shock leads to a considerable oxidant stress as indicated by lipid peroxidation (Fleckenstein et al ., 1991; Hamano et al ., 1993) as well as the consumption of the endogenous antioxidant, vitamin E (Fleckenstein et al ., 1991). Interventions which reduce the generation or the effects of ROS exert beneficial effects in a variety of models of haemorrhagic shock (Allan et al ., 1986; Sanan et al ., 1989; Mannion et al ., 1994; Daughters et al ., 1996; Simon et al ., 1996; Fan et al ., 1998; Mota‐Filipe et al ., 1999).…”

Development of an Intravenous Desferrioxamine Mesylate Treatment Protocol for Swine: Monitoring of Desferrioxamine and Metabolites by High-Performance Liquid Chromatography

“…It has also been used to treat acute iron toxicity seen most often in children [10]. The efficacy of DFO mesylate treat ment of other disorders is currently under investigation for the following: as a treat ment for rheumatoid disease where evidence suggests that iron participates in the patho genesis of the disease [11,12], as an agent in leukemia chemotherapy [13,14], in isch emia-reperfusion injury [15][16][17] and as an immunosuppressive agent to prevent autoreactive and rejection processes involving T lymphocytes [13,18] where iron is consid ered essential for DNA synthesis.…”