Methodologic considerations for the use of canine in vivo aged biotinylated erythrocytes to study RBC senescence.

Biotinylation of erythrocytes has been developed in rabbits as a tool to retrieve labeled cells following various periods in circulation. This retrieval capability allows biochemical studies to be conducted on red blood cells (RBC) that have aged for desired times in vivo. However, because erythrocyte life span is much shorter in rabbits than in humans, and because cell removal is measurably age-independent in rabbits, we have sought to validate the same protocol in dogs, whose cell life span and age-dependent removal characteristics are similar to humans'. Canine RBC were biotinylated in vivo by infusion of N-hydroxysuccinimidyl biotin dissolved in dimethylacetamide or dimethylsulfoxide. Cell life spans were evaluated using 14C-cyanate labeling followed by scintillation counting or avidin-FITC labeling followed by flow cytometry. Both methods gave identical results. The life span of the biotin-conjugated cells was found to be normal (approximately 110 days), and the stability of the biotin ligand was adequate for efficient retrieval of cells using avidin-coated magnetic beads (magnetic cell sorting [MACS]). From each isolation, approximately 20 microL of packed biotinylated cells of approximately 90% purity (i.e., 10% contamination by unlabeled cells) could be harvested. On average, approximately 60% of the biotinylated cells in any sample could be retrieved. Either multiple isolations or use of larger collection columns will facilitate collection of cell numbers sufficient for biochemical tests. After incorporating several modifications in the previous biotinylation protocol that were required for adaptation to the dog, the methodology can be used to study red cell senescence in an animal that has several pertinent similarities to humans.

Patulin mycotoxicosis in the rat: toxicology, pathology and clinical pathology.

Patulin, a secondary metabolite produced by species of the genera Penicillium and Aspergillus, was administered to male Sprague-Dawley rats, weighing 50-60 g, by the oral, sc and ip routes. The 72-hr LD50 values (in mg/kg weight) were: oral, 55.0; sc, 11.0; ip, 10.0. Mortality was greatest 0-24 hr after administration by the oral and sc routes and 49-72 hr after ip dosing. Gross alterations consisted of gastric and intestinal hyperaemia and distention. Histopathological alterations consisted principally of ulceration and inflammation of the stomach. Patulin was administered orally to rats daily or every other day for 2 wk at doses of 50 or 75% of the oral LD50. Mortality in the treated groups was greater than in controls but was similar for all treated groups. No evidence of cumulative toxicity was found and the gross and histopathological alterations were similar to those found in the LD50 studies. Clinicopathological alterations included metabolic alkalosis with respiratory compensation, oliguria, decreased serum sodium, elevated blood glucose, reduced plasma protein and an elevated total leucocyte count which differential leucocyte counts indicated to be due to neutrophilia. The inflammatory alterations observed in the gastro-intestinal tract may be due to the irritant properties of patulin or to an alteration in the gastro-intestinal flora by the antibiotic activity of patulin.

Citrinin mycotoxicosis in the rabbit: clinicopathological alterations.

Citrinin, a nephrotoxic mycotoxin, was dissolved in 0.5 N-NaOH neutralized with HCl and given in a single oral dose of 120 mg/kg (Trial I) or 80 or 100 mg/kg (Trial II) to male New Zealand white rabbits weighing 2.0-2.7 kg. In Trial I, sequential measurements of clinicopathological parameters were made over a 24-hr period. Azotaemia and metabolic acidosis with haemoconcentration and hypokalaemia developed within 4-12 hr. In Trial II, clinicopathological and urinary parameters were measured daily for 7 days. Increased blood urea nitrogen and serum-creatine levels and decreased creatinine clearance indicated renal failure; these values were most abnormal on days 2-4, returning to normal or near normal by day 7 in rabbits that survived. Urine analysis indicated tubular dysfunction and necrosis with glucosuria, isosthenuria and cylindruria; most urinary parameters were normal by day 7.

Heritability and biochemistry of gangliosidosis in emus (Dromaius novaehollandiae).

The progeny of two emu breeder pairs, which had a history of producing offspring with gangliosidosis, were monitored for 15 mo. DNA fingerprinting revealed that individuals in each breeder pair were not related to each other. One breeder pair had 13 progeny that reached or exceeded the age of 1 mo, and six of these progeny developed gangliosidosis. The mean age at which these affected emus were euthanatized, with distinct neurologic disease, or died was 5.7 mo. The second emu pair had 13 progeny, seven of which developed gangliosidosis, with a mean age of euthanasia/death of 4.6 mo. Affected emus died or were euthanatized from 2 to 8 mo of age. The primary clinical sign in the affected emus was mild to severe ataxia. Severe hemorrhage into the body cavity or the muscles of the thigh was noted in 8 of 13 of the affected emus. Brain ganglioside levels were evaluated in six of the affected emus and six controls. Significant increases (P < 0.05) in gangliosides GM1 and GM3 were noted, with 2.3- and 4.9-fold increases in these two gangliosides, respectively, in affected emus. Furthermore, the diseased emu brains contained ganglioside GM2, whereas this monosialoganglioside was undetectable in the brains of normal controls. Total mean brain ganglioside sialic acid in affected emus was increased 3.3-fold in comparison with controls. Serum chemistries revealed elevated cholesterol and decreased uric acid levels in affected emus. Gangliosidosis in emus is an inherited disease process that, in the current study, caused 50% mortality in the progeny of two emu breeder pairs. The elimination of this lethal gene from emu breeder stock is essential for the long-term economic viability of the United States emu industry.

Ultracentrifugal and electrophoretic characteristics of the plasma lipoproteins of miniature schnauzer dogs with idiopathic hyperlipoproteinemia.

To better characterize the idiopathic hyperlipoproteinemia of Miniature Schnauzer dogs, the plasma lipoproteins of 20 Miniature Schnauzers (MS) and 11 dogs of other breeds (DOB) were evaluated by ultracentrifugation, electrophoresis, and biochemical tests. Seventeen MS were healthy; 3 had diabetes mellitus. Plasma from 6 of 17 healthy and all 3 diabetic MS was visibly lipemic. Lipemia was slight to marked in healthy lipemic MS, and marked in diabetic ones. All DOB had clear plasma; 8 were healthy and 3 had diabetes. All healthy lipemic MS and diabetic lipemic MS had hypertriglyceridemia associated with excess very low density lipoproteins. Chylomicronemia was present in 4 of 6 healthy lipemic MS and all 3 diabetic lipemic MS. Lipoproteins with ultracentrifugal and electrophoretic characteristics of normal low density lipoprotein were lacking in 4 of 6 healthy lipemic MS. The lipoprotein patterns of 4 of 11 healthy nonlipemic MS were characterized by mild hypertriglyceridemia associated with increased very low density lipoproteins and a lack of lipoproteins with characteristics of normal low density lipoproteins. Lipoprotein patterns of diabetic DOB closely resembled those of healthy DOB; those of diabetic lipemic MS resembled those of markedly lipemic healthy lipemic MS. In conclusion, the hyperlipoproteinemia of Miniature Schnauzers is characterized by increased very low density lipoproteins with or without accompanying chylomicronemia; some affected dogs may have decreased low density lipoproteins.

Plasma granulocyte colony-stimulating factor concentrations in neutropenic, parvoviral enteritis-infected puppies.

We evaluated the temporal relationship between neutrophil numbers and plasma granulocyte colony-stimulating factor (G-CSF) concentrations in dogs infected with canine parvovirus, a common infectious cause of neutropenia. G-CSF is produced in response to neutropenia, infection, or inflammation, and results in the production and release of neutrophils from the bone marrow. Adequate numbers of functional neutrophils are necessary for protection from infection, and the timely production of G-CSF is a crucial response to certain diseases. The relationship between peripheral neutrophil numbers and plasma G-CSF concentrations during the course of an infectious disease characterized by neutropenia has not been described previously in dogs. Eight mixed-breed puppies were given an oronasal challenge with canine parvovirus, and peripheral neutrophil numbers as well as plasma G-CSF concentrations were measured daily. G-CSF was not detectable in plasma of any dog before the onset of neutropenia, but G-CSF became detectable just after the onset of neutropenia in the 7 dogs that developed clinical illness. Neutropenia persisted or worsened for at least 2 days after plasma G-CSF became detectable in all 7 dogs. Neutrophil nadir, the highest plasma G-CSF concentrations, and the most severe clinical illness occurred concurrently in most dogs. Although 1 dog died while still neutropenic, plasma G-CSF concentrations declined before resolution of neutropenia in the other 6 dogs, and were again below the limits of detection in 5 of the 6 dogs at the time of resolution.

Isoamylases in clinically normal dogs.

Isoenzymes of canine serum amylase were evaluated by electrophoresis on cellulose acetate membranes in a discontinuous buffer system. Two isoamylase groups were identified in the serum of clinically normal dogs. Most of the serum amylase activity was the more cathodal isoamylase. The anodal isoamylase was rarely observed in serum from normal dogs and, when present, accounted for little of the enzymatic activity. Amylase activities of various tissues were determined and isoenzymes were identified. The anodal isoenzyme was found in the pancreas and uterus. The cathodal isoamylase had its origin mainly from the intestinal tract. Activities of other tissues were not greater than was serum amylase activity. Effects of feeding upon total serum amylase activity and isoenzyme composition also were examined over a period of 5 minutes to 7 hours. Feeding did not markedly alter the serum amylase activity.

Induction of lesions of selenium-vitamin E deficiency in weanling swine fed silver, cobalt, tellurium, zinc, cadmium, and vanadium.

Forty-two weanling pigs were allotted to 7 groups and fed (for 10 weeks) a commercial ration that was adequate in selenium and vitamin E (Se-E) content, either alone or with supplements of Ag (3,000 mg/kg of feed, as acetate), Co (500 mg/kg, as chloride), Te (500 mg/kg, as tetrachloride), Zn (3,000 mg/kg, as sulfate), Cd (500 mg/kg, as sulfate), or V (200 mg/kg, as vanadate). The pigs fed the Ag supplement died after 25 to 39 days and had lesions characteristic of Se-E deficiency with accumulations of serous transudates in body cavities and hepatic and cardiac necrosis. In the pigs fed the Ag supplement, there was high hepatic Se content terminally; blood glutathione peroxidase (GSH-Px) activity decreased to low levels several weeks before the pigs died with lesions of Se-E deficiency. Macroscopic lesions of Se-E deficiency were not found in pigs fed Co, Te, Zn, Cd, or V. However, evidence of Se-E deficiency, as indicated by microscopically detected necrosis of cardiac and skeletal muscle, was present in 50% to 65% of the pigs fed Co or Te and occasionally in pigs fed Zn, Cd, and V supplements. The pigs fed Te had marked decrease of blood GSH-Px activity over the last 6 weeks of the feeding period. No consistently abnormal values for blood GSH-Px activity or terminal hepatic Se content were observed in pigs fed Co, Zn, Cd, or V. The pigs fed the Zn supplement grew as rapidly as the control pigs. Evidence of V toxicosis was observed as severe growth suppression, mortality, and marked enteritis and cystitis (with accompanying hydroureter in 1 pig).

Induction of lesions of selenium-vitamin E deficiency in ducklings fed silver, copper, cobalt, tellurium, cadmium, or zinc: protection by selenium or vitamin E supplements.

In 3 experiments, 684 newly hatched White Pekin ducklings were fed (for 15 to 28 days) a commercial starter mash that was adequate in selenium and vitamin E (Se-E) content, either alone or with supplements of Ag (3,000 mg/kg of feed, as acetate), Cu (1,500 mg/kg, as sulfate), Co (200 or 500 mg/kg, as chloride), Te (500 mg/kg, as tetrachloride), Cd (100 or 500 mg/kg, as sulfate), Zn (3,000 or 6,000 mg/kg, as sulfate), or V (100 mg/kg, as vanadate). The ducklings fed Ag, Cu, Co, Te, Cd, and Zn frequently developed lesions characteristic of Se-E deficiency, such as necrosis of skeletal and cardiac muscle and of smooth muscle of the gizzard and intestine. Complete protection from the muscle lesions produced by Cu, Co, Te, Cd, and Zn supplements was provided by vitamin E (200 IU of alpha-tocopherol acetate/kg) and Se (2 mg/kg, as selenite). Ducklings fed Ag were protected by supplements of vitamin E and partial protection was achieved by Se addition. The birds fed excessive Zn developed pancreatic necrosis and fibrosis that was not prevented by supplements of Se or vitamin E. Terminally, blood glutathione peroxidase activity was low and hepatic Se concentration was increased in the ducklings fed Ag. However, neither blood glutathione peroxidase activity nor hepatic Se concentrations was consistently abnormal in ducklings fed other trace elements, although lesions of Se-E deficiency were often present in these animals.

Effects of acute pancreatitis on circulating lipids in dogs.

Effects of acute pancreatitis on circulating lipids in dogs were evaluated by comparing the serum cholesterol and triglyceride concentrations and plasma lipoprotein electrophoretic patterns of 4 dogs with experimentally induced pancreatitis (EIP), 2 (healthy) sham-operated control (SOC) dogs, and 4 dogs with naturally acquired pancreatitis (NAP) with the concentrations and patterns of 23 healthy, nonoperated control (HNC) dogs. Blood samples were collected once from HNC dogs, 1 to 3 times during the course of the disease in dogs with NAP, and prior to and at 6, 12, 24, 48, 72, and 96 hours after induction of pancreatitis in dogs with EIP or after the sham operation in the SOC dogs. The dogs with EIP did not have turbid serum and did not develop hypercholesterolemia or hypertriglyceridemia. Three of the dogs with NAP had turbid serum and hypertriglyceridemia, and 3 had hypercholesterolemia. The electrophoretic tracings of HNC dogs had predominant alpha-1 peaks and small beta peaks; 2 of the HNC dogs also had small alpha-2 peaks. The tracings of dogs with EIP were similar to those of HNC dogs until 48 to 72 hours after induction of pancreatitis, when dogs with EIP developed increased beta lipoproteins, decreased alpha-1 lipoproteins, and movement of lipoproteins into the alpha-2 zone. The tracings of SOC dogs were similar to those of HNC dogs at all times. Compared with HNC dogs, dogs with NAP all had increased beta lipoproteins, and 2 had decreased alpha-2 lipoproteins. Two dogs with NAP had additional lipoprotein alterations, unlike any seen in dogs with EIP.

Evaluation of a spectrophotometric method for canine serum lipase determination.

The British antilewisite butyrate-dithionitrobenzoate (BALB-DTNB) spectrophotometric serum lipase assay was evaluated for precision, accuracy, and diagnostic usefulness in analyzing canine sera. Sera samples from clinically healthy dogs, dogs with experimentally induced pancreatitis, and dogs with spontaneous pancreatitis were analyzed. A titrimetric method of serum lipase determination was used for comparison. Although the BALB-DTNB method was not found to be precise or accurate for determining the lipase activity of canine serum samples, it seemed to be at least as diagnostically useful as the titrimetric procedure. The small sample size requirement and the speed of analysis of the BALB-DTNB procedure are advantages of this method over the titrimetric method, and thus, its use in place of the titrimetric method is justified. A laboratory reference range of 3 to 37 IU/L was determined for canine serum.

Support of an anephric dog for 54 days with ambulatory peritoneal dialysis and a newly designed peritoneal catheter.

A bilaterally nephrectomized dog was successfully supported with peritoneal dialysis for 54 days, using a radically new design of access catheter and a human dialysis schedule designated as continuous ambulatory peritoneal dialysis. The dog remained active and alert with a stabilized blood urea nitrogen of 30 to 40 mg/dl and a serum creatinine concentration of 4 to 6.5 mg/dl. Problems encountered with the peritoneal dialysis included the propensity for developing peritonitis, anorexia, and a significant plasma protein loss in the dialysate fluid as result of leakage across the peritoneum. Protein loss coupled with anorexia produced a catabolic state, and the animal was euthanatized because of this, at postnephrectomy day 54. The development of a new catheter design alleviated the drainage problems of the straight tube Tenckhoff catheter. Its use coupled with the continuous ambulatory peritoneal dialysis schedule and detailed management techniques allowed using the anephric dog as a model of uremia. In addition, peritoneal dialysis could be a viable treatment for animals presenting with acute reversible anuric or oliguric renal failure where conservative medical management with fluids and diuretics has failed to give clinical improvement.

Effects of dexamethasone on endotoxin shock in the anesthetized pony: hematologic, blood gas, and coagulation changes.

The effects of dexamethasone (1 mg/kg of body weight) on hematologic, blood gas, and blood coagulation values in anesthetized ponies during endotoxin-induced shock were evaluated. Fifteen ponies were assigned to 3 groups of 5 ponies each: group 1, anesthetized nontreated and dexamethasone-treated controls; group 2, endotoxin, nontreated; group 3, endotoxin, dexamethasone treated. The hematologic changes in this endotoxin shock model included leukopenia and hemoconcentration. Significant hematologic effects were not seen in ponies after administration of dexamethasone. However, dexamethasone treatment resulted in an increased trend in total WBC counts and neutrophils. The blood gas changes reflected a respiratory component resulting from anesthesia and a greater metabolic component from the endotoxemia. The plasma lactate increase was significantly (P less than 0.05) less in ponies treated with dexamethasone, compared with plasma lactate in non-treated ponies. During endotoxin shock, the changes observed in the blood coagulation values included a significant (P less than 0.05) prolongation of the activated partial thromboplastin time and thrombin time and an insignificant prolongation of the prothrombin time. Dexamethasone treatment prevented prolongation of thrombin time and permitted only a mild prolongation of activated partial thromboplastin time. Seemingly, corticosteroids are useful in the treatment of clinical endotoxin shock in horses as indicated by their desirable effects on total WBC, neutrophils, cellular metabolism, and blood coagulation.

Endotoxin-induced change in hemograms, plasma enzymes, and blood chemical values in anesthetized ponies: effects of flunixin meglumine.

A study was made of flunixin meglumine (FM), an analgesic agent with antiprostaglandin activity, in the management of endotoxin-induced changes in ponies. Three groups of 5 ponies each were used: A--controls, B--nontreated ponies with endotoxin-induced shock, and C--ponies with endotoxin-induced shock treated with FM. Shock was induced in anesthetized ponies with IV injections of Escherichia coli endotoxin. Disruption of glucose homeostasis, insulin levels, hemograms, aerobic metabolism, and cell damage as indicated by plasma enzymes were observed. Treatment with FM (5 minutes) after shock was induced did not prevent general tissue damage as indicated by plasma enzymes, but separation of creatine phosphokinase into its 3 isoenzymes revealed a significant increase in the amount of the creatine phosphokinase isoenzyme bb in group B ponies, but not in FM-treated ponies (group C). The source of this isoenzyme is believed to be brain tissue. Acidosis as indicated by lactic acid and venous pH was less in FM-treated ponies than in nontreated (group B) ponies. Blood glucose and insulin concentrations changed in both groups B and C (endotoxin-induced shock), but the patterns of change were different. The only effect of FM on hematologic values was a significant decrease in blood platelet counts. The results of these experiments indicate that FM improved cellular metabolism and reduced brain damage. These effects were believed to be the result of the maintenance of mean arterial blood pressure and enhanced perfusion of vital organs by preventing extensive vasodilation in the gastrointestinal tract.

Hemoperitoneum secondary to traumatic rupture of an adrenal tumor in a dog.

Hemoperitoneum secondary to traumatic rupture of an adrenocortical adenocarcinoma was diagnosed in a 10-year-old male dog. Immediate surgical attention was required to remove the tumor and to control hemorrhage. The dog appeared to develop transient hypoadrenocorticism after surgery, but recovered with short-term exogenous corticosteroid administration. At 6 months after surgery, the dog was clinically normal.

Ionized and total magnesium concentrations in blood from dogs with naturally acquired parvoviral enteritis.

OBJECTIVE: To determine whether pretreatment total and ionized blood magnesium concentrations were associated with outcome for dogs with parvoviral enteritis and whether ionized magnesium concentration was related to total magnesium concentration or other laboratory values. DESIGN: Prospective cohort study. ANIMALS: 61 healthy dogs and 72 dogs with parvoviral enteritis. PROCEDURE: Total, ionized, and pH-normalized ionized magnesium concentrations, ionized and pH-normalized ionized calcium concentrations, pH, sodium and potassium concentrations, and Hct were measured prior to treatment. chi 2 Analyses were used to test for associations between outcome and age and between outcome and treatment with antiendotoxin antibody. Pearson's correlation coefficients were calculated to determine whether ionized magnesium concentration was linearly associated with other laboratory values. RESULTS: Total and ionized magnesium concentrations were not significantly different between healthy dogs and dogs with parvoviral enteritis or between dogs surviving and those not surviving parvoviral enteritis. The only laboratory value strongly correlated with ionized magnesium concentration was pH-normalized ionized magnesium concentration. Of the factors tested, none were significantly associated with outcome, except that dogs 16 weeks old or less treated with antiendotoxin antibody were significantly more likely to die than were dogs 16 weeks old or less that were not treated with antiendotoxin antibody. CLINICAL IMPLICATIONS: Total and ionized blood magnesium concentrations cannot be used to consistently predict outcome for dogs with parvoviral enteritis. Antiendotoxin antibody should be used with caution in dogs 16 weeks old or less.

An overview of hemostasis.

Hemostasis is a remarkable and a remarkably complex mechanism. It can maintain blood in a fluid state intravascularly but very quickly changes blood to a jellylike mass upon disruption of the vasculature. This review will give a synopsis of the 3 phases of hemostasis: platelet, vascular, and coagulation. Fibrinolysis and control mechanisms of hemostasis will also be covered. In addition, brief descriptions of the clinical and laboratory evaluation of patients and the diagnosis of bleeding disorders will be presented.

Senescence of canine biotinylated erythrocytes: increased autologous immunoglobulin binding occurs on erythrocytes aged in vivo for 104 to 110 days.

We have evaluated senescence related changes in canine red blood cells (RBCs) using the biotinylation system, where RBCs are labeled in vivo with biotin at the beginning of their life span, and retrieved from circulation on immobilized avidin at the end of their life span. This approach avoids the controversial use of density gradient centrifugation to collect presumably old RBCs. Furthermore, the dog is an appropriate model for human RBC senescence because it has a low degree of random RBC loss and a similarly long RBC life span (approximately 110 days). Two dogs had 97% to 100% of their circulating RBCs biotinylated by infusion of N-hydroxysuccinimido biotin (Clontech, Palo Alto, CA; Calbiochem, La Jolla, CA) dissolved in dimethyl sulfoxide. At postbiotinylation days 104 and 107 for one dog and day 110 for the other dog, biotinylated RBCs were isolated by magnetic cell sorting and analyzed for the presence of autologous IgG using 125I-labeled sheep-antidog IgG (SAD IgG). On all 3 days, there were at least three times more SAD IgG molecules per RBC on senescent biotinylated RBCs than on control (unfractionated) RBCs (day 104: 11,677 v 3,399; day 107: 6,710 v 2,115; day 110: 6,042 v 1,838 molecules of SAD IgG per senescent v control RBC). Furthermore, it is unlikely that an immune response to the conjugated biotin had been elicited, because fresh in vitro biotinylated RBCs that were incubated in autologous plasma (taken after exposure to circulating biotinylated RBCs for 113 days) and then exposed to the SAD IgG showed no increase in antibody binding over control (non-biotinylated) RBCs (1,431 v 1,378 cpm/10(8) biotinylated v control RBCs; P > .20). These results suggest that senescence of canine biotinylated RBCs is characterized by binding of autologous IgG and that antibiotin antibodies do not contribute to this process.

Antiviral nucleoside toxicity in canine bone marrow progenitor cells and its relationship to drug permeation.

The most promising nucleoside analogs that are currently undergoing preclinical and clinical testing for anti-HIV activity belong to the dideoxynucleoside group. We have studied the toxicity of 3'-azido,3'-deoxythymidine (AZT), 2',3'-dideoxycytidine (DDC), and 2',3'-dideoxyinosine (DDI) in canine bone marrow progenitor cells in culture. AZT potently inhibited both canine CFU-GM and CFU-E with IC50 values of 2 and 8 mumol/l respectively, while DDC was relatively non-toxic to either progenitor with IC50 of > 200 mumol/l and 80 mumol/l respectively. DDI was mildly toxic to the bone marrow progenitors, with IC50 values of 62 mumol/l for CFU-GM and 70 mumol/l for CFU-E. Dipyridamole, a nucleoside transport inhibitor, did not influence the toxicity of these dideoxynucleosides in either progenitor at concentrations up to 10 mumol/l. Using uridine as the prototype endogenous nucleoside, we have demonstrated that there is a saturable "zero-trans" nucleoside transport system in canine bone marrow mononuclear cells, which is completely inhibited by 1 mumol/l dipyridamole (Ki = 0.02 mumol/l). None of the dideoxynucleosides appeared to be a substrate for this transport system, and dipyridamole did not alter their influx. Permeation of radiolabeled AZT into bone marrow mononuclear cells was slow and non-saturable, while the permeation of DDI was even slower. DDC did not permeate bone marrow cells well, with very little cell accumulation even after 2 hours of equilibration. Our toxicity data from canine bone marrow progenitor cells paralleled the clinical hematotoxicity profiles of these dideoxynucleosides in AIDS patients and suggest that the myelotoxicity of a nucleoside analog is related to its ability to permeate the progenitor cells in question. Canine bone marrow progenitor cultures may serve well as an in vitro model for drug hematotoxicity studies.