Tapetal effect of an azalide antibiotic following oral administration in beagle dogs.

An azalide antibiotic (CP-62,993) was administered at 100 mg/kg by oral gavage once daily for 35 consecutive days to 3 normal Beagle dogs (tapetal) and 3 Beagle dogs lacking a clinically apparent ocular tapetum (atapetal). The total dose delivered was approximately 100-fold the recommended clinical dose. Bilateral ophthalmoscopic changes were observed in the treated tapetal dogs on Day 36, consisting of mild to moderate tapetal decoloration with loss of the normal color change at the junction with the nontapetal fundus and muting of reflectivity of the normally highly reflective tapetum; treated atapetal and all control tapetal and atapetal dogs had no ophthalmoscopic changes. Microscopic examination of ocular tissue revealed rudimentary tapetal cell layers in the correct location in untreated, clinically atapetal eyes. Tapetal cells from treated tapetal and atapetal dogs were swollen and vacuolated, and contained intracytoplasmic, electron-dense debris but no recognizable tapetal rodlets. Lysosomal lamellar bodies were observed in the retinal ganglion cells of both treated groups and were neither enhanced nor reduced by the presence of a functional tapetum. Necrosis and inflammation were not observed in any ocular tissue. The altered ophthalmoscopic appearance of treated tapetal dogs was not influenced by the retinal changes because any effect on retinal transparency would have been seen in treated atapetal dogs. The decoloration and muting of reflectivity observed clinically in the tapetal fundus of dogs following prolonged exposure to high levels of CP-62,993 result from unique changes within the ocular tapetum itself and cannot be interpreted to be of consequence to nontapetal species including humans.

Regional brain blood flow in swine following T-2 toxin administration.

Three groups of swine (6/group) were used to assess alterations in regional brain blood flow induced by T-2 toxin. One group served as vehicle (70% ethanol) control, and groups were dosed intravascularly with T-2 toxin at 0.6 or 2.4 mg/kg body weight. Cerebral, cerebellar, and brain stem blood flows were evaluated at 0 h (predosing) and at 90-min intervals for 6 h postdosing. Fifteen-micron diameter radionuclide labeled microspheres were used to determine blood flow. Hemodynamic variables were determined at the same time points. The infusion of T-2 toxin resulted in dose-dependent reductions in both cardiac index and mean arterial pressure, accompanied by significant increases in heart rate. In animals given the lower dose of T-2 toxin, significant reductions in blood flow were evident in the cerebrums and cerebellum but not in the brain stem. Reductions in blood flow to all regions of the brain were evident in those animals given 2.4 mg T-2 toxin/kg. Brain blood flow was less severely compromised than was cardiac output, suggesting intact local autoregulation.

Distribution of blood flow to the gastrointestinal tract of swine during T-2 toxin-induced shock.

Swine (6 per group) were used to study gastrointestinal blood flow during T-2 toxin-induced shock. Low- and high-dose groups were given T-2 toxin at 0.6 or 2.4 mg/kg via the pulmonary artery; controls were given the ethanol vehicle. Radiolabeled microspheres were administered into the left atrium to assess organ blood flow predosing and at 90-min intervals for 6 hr. Gastric blood flow decreased in both T-2 groups, and at 6 hr the high-dose group's value was 17% of the predose value. In the low-dose group, the lowest gastric blood flow (30% of predose) was observed 3 hr postdosing. Small-intestinal blood flow of the control group declined to 64% of the predose value. In the high-dose group, small-intestinal blood flow at 3 hr was 174% of predose, followed by a reduction to 62% at 6 hr, coinciding with a severe decline in cardiac output. Small-intestinal blood flow of the low-dose group was 159% of predose at 1.5 hr, then declined to the control value. The high-dose group's large-intestinal blood flow increased to 177% of predose at 3 hr, then declined to 66% at 6 hr. The low-dose group's large-intestinal blood flow increased to 200% of the predose value. The severe decline in gastric blood flow is probably related to the development in swine (given high doses of T-2 toxin) of a grossly bright red gastric fundus, with histologic evidence of vascular congestion and mucosal deterioration.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of a general therapeutic protocol for the treatment of acute T-2 toxicosis in swine.

T-2 toxin, a trichothecene mycotoxin suspected of being used as a chemical warfare agent, was administered iv to swine at a dose of 3.6 mg/kg body weight (iv LD50 approximately 1.2 mg/kg). Four different therapeutic protocols were assessed for their efficacy in the treatment of the resultant acute T-2 toxicosis syndrome. One therapeutic protocol included the combined use of metoclopramide, activated charcoal, magnesium sulfate, dexamethasone sodium phosphate, sodium bicarbonate and normal saline. The other 3 protocols utilized the same agents less 1 of the following: the combination of activated charcoal and magnesium sulfate, sodium bicarbonate, or normal saline. All 4 treatment groups showed improved survival times compared to a positive T-2 control group. Within the limits of the study, it would appear that the removal of activated charcoal and magnesium sulfate was most detrimental to the T-2 toxin-dosed swine.

Systemic distribution of blood flow during T-2 toxin induced shock in swine.

Three groups of swine (6 per group) were used to determine hemodynamic and blood flow alterations induced by T-2 toxin. Two groups were dosed at 0.6 or 2.4 mg/kg T-2 toxin, and one group served as a vehicle control (70% ethanol). Organ blood flow was determined at 0 hr (predosing) and at 90-min intervals for 6 hr postdosing using 15-micron diameter radionuclide labeled microspheres injected into the left atrium. Hemodynamic parameters were obtained at the same time points. The infusion of T-2 toxin resulted in reductions in cardiac output. This trend appeared to reverse itself in the low dose animals after 3 hr, whereas in the high dose group, cardiac output continued to decline. Mean aortic pressure (MAP) declined in a dose dependent fashion which tended to parallel the reduction observed in cardiac output. Heart rate was increased in both groups treated with T-2 toxin. Blood flow, to the brain, heart, and kidneys decreased following exposure to the toxin. The relative percentage of cardiac output received by these organs, however, was maintained despite the drop in blood flow. Pancreatic and splenic blood flows were the most severely compromised as a result of T-2 toxicosis. Consequently, the percentage of cardiac output going to the pancreas and spleen was dramatically reduced. Adrenal, hepatic, and total gastrointestinal blood flows increased or did not change from control values. As a result, the percentage of cardiac output supplying these organs increased.

Experimental T-2 toxicosis in swine. I. Changes in cardiac output, aortic mean pressure, catecholamines, 6-keto-PGF1 alpha, thromboxane B2, and acid-base parameters.

T-2 toxin given as a single intravascular dose to swine produced a shock syndrome. Dosages of 0.6 or 4.8 mg/kg were administered to different groups of swine. Shock was characterized by reductions in cardiac output and blood pressure, and increased plasma concentrations of epinephrine, norepinephrine, thromboxane B2, 6-keto PGF1 alpha, and lactate. Total peripheral resistance was unchanged in the high-dose group but decreased in the low-dose group. Pulmonary vascular resistance increased in both groups. Decreases occurred in arterial pH and arterial oxygen partial pressure. No alterations occurred in plasma concentrations of histamine or serotonin.