Retrospective evaluation of leflunomide as an adjunctive therapy in dogs with non-associative immune-mediated thrombocytopenia: 20 cases (2008-2021).

OBJECTIVE: To describe leflunomide as an adjunctive therapy in the treatment of non-associative immune-mediated thrombocytopenia. MATERIALS AND METHODS: A retrospective study of dogs with a diagnosis of non-associative immune-mediated thrombocytopenia treated with leflunomide March 2008 to September 2021 was conducted. Data collected included signalment, clinical signs, physical examination findings and diagnostic testing performed. Medications administered, duration of hospital stay, time to platelet concentration >150×109/L and adverse events during leflunomide therapy were recorded. Relapses within a year of diagnosis were reported. RESULTS: A total of 20 client-owned dogs met inclusion criteria. Nineteen of 20 dogs (95%) achieved a platelet concentration >150×109/L with leflunomide and prednisone combination therapy and four dogs (21.1%) relapsed during treatment or shortly after treatment. Adverse effects included diarrhoea (n=5), mild lymphopenia (n=9) and mild intermittent anaemia (n=1). A single dog developed hepatotoxicity presumed to be secondary to leflunomide therapy that resolved after drug discontinuation. One dog was treated for aspiration pneumonia during treatment. Two dogs were euthanased while receiving leflunomide. CLINICAL SIGNIFICANCE: Length of hospitalisation, time to platelet recovery, treatment response and relapse rate were comparable with alternative treatment protocols. Most adverse effects did not require leflunomide dose adjustment; however, two dogs died while undergoing leflunomide treatment and there is compelling evidence that one of these dogs experienced fatal infection secondary to immune-suppression. Hepatotoxicity remains a known complication of leflunomide treatment and serial biochemistry testing is recommended.

Cocaine's effects on speech sound discriminations and reaction times in baboons.

Three adult baboons were trained using a psychophysical procedure to discriminate between different synthetic vowel sounds [symbol: see text]. Baboons pressed and held a lever down to produce a pulsed train of a single reference vowel that served as the standard stimulus. Animals were trained to release the lever only when this standard vowel sound changed to one of the four remaining comparison vowels. A lever release within 1.5 s of this change in vowel sounds was defined as a correct detection of the change from the standard vowel to one of the comparison vowels, and was reinforced. All baboons readily learned the vowel discriminations and detected vowel changes at the 90-100% correct performance level. Acute IM administration of cocaine prior to test sessions (0.00032-3.2 mg/kg) produced dose-dependent decrements in vowel discriminability. At the same time, cocaine shortened lever release latencies (reaction times) to the vowel stimuli in two of three baboons. The cocaine-induced decrements in vowel discriminability were correlated with the degree to which frequency differences occurred among the different vowels in that lower vowel discriminability scores were found for those vowels with smaller spectral differences from the standard vowel. Further, false alarm rates were not systematically affected by cocaine, indicating that the cocaine-induced decrements in vowel discrimination accuracy occurred in the absence of systematic changes in the reliability of the baboons' discrimination performances.

Acute and chronic nicotine effects on multiple-schedule behavior: oral and SC routes.

For rats responding on a 3 h FI 4 min FR 20 schedule of food reinforcement, presession SC nicotine doses (0.1-0.8 mg/kg) produced depression in all responding followed by stimulation of FI responding that was dependent upon both time and dose. With daily presession 0.8 mg/kg SC nicotine injections for 9 days, no tolerance to the depressive or stimulatory effects of nicotine occurred. When nicotine solutions were orally self-administered by presession exposure to 3 h of schedule-induced polydipsia, the subsequent FR responding was unaffected, but the degree of FI response stimulation and its duration occurred in a dose-related fashion (1.18-4.10 mg/kg). Prolonged daily sessions of oral nicotine self-administration provide a technique for investigating the effects of chronic exposure to nicotine. The postingestive effects of nicotine reveal stimulatory effects that last for at least 3 h.

Effects of cocaine on simple reaction times and sensory thresholds in baboons.

The effects of chronic, daily administration of cocaine on auditory and visual reaction times and thresholds were studied in baboons. Single intramuscular injections of cocaine hydrochloride (0.1 to 5.6 mg/kg) were given once daily for periods of 10 to 25 days, and were followed immediately by psychophysical tests designed to assess cocaine's effects on simple reaction times as on auditory and visual threshold functions. Consistent reductions in reaction times were frequently observed over the cocaine dose range of 0.32 to 1.0 mg/kg; at higher doses, either decreases or increases in reaction times were observed, depending upon the animal. Lowered reaction times generally occurred immediately following the 1st day's cocaine injection, and continued through all subsequent days during the dose administration period, suggesting little development of tolerance or sensitivity to these reaction-time effects. Reaction-time decreases showed a U-shaped dose-effect function. The greatest decreases in reaction times occurred from 0.32 to 1.0 mg/kg, and produced an average reaction-time decrease of 10 to 12%. Concurrently measured auditory and visual thresholds showed no systematic changes as a function of cocaine dose. Pausing was observed during performance of the psychophysical tasks, with the length of total session pause times being directly related to cocaine dose.

Effects of cocaine on sensory motor function in baboons.

The effects of cocaine on auditory and visual threshold functions and reaction times were studied in baboons. Single IM injections of cocaine HCl (0.001-1.0 mg/kg) were administered once or twice weekly and were followed immediately by psychophysical tests designed to assess cocaine's effects on sensory thresholds and reaction times. Consistent reductions in reaction times were observed in the cocaine dose range of 0.032-0.32 mg/kg. Reaction times were decreased by 5-8% at the more effective cocaine doses. Concurrently measured auditory and visual threshold sensitivities showed no systematic changes at any of the cocaine doses studied.

General activity in baboons measured with a computerized, lightweight piezoelectric motion sensor: effects of drugs.

A small, 1-oz activity-monitoring device is described for measuring motor activity continuously for periods of up to 42 days. The monitor employs a piezoelectric sensor that detects extremely small accelerations induced by movements. The monitor can be placed on collars or harnesses (e.g., for rabbits, cats, dogs, nonhuman primates, etc.). The use of the monitor is described within numerous laboratories studying the behavioral pharmacology of drugs in individually caged laboratory baboons. Patterns of daily activity were reliably recorded over periods of several months, and reflected the normal activity patterns of animals. The activity monitor recorded reliable, drug-induced changes in general activity that paralleled the known effects of the same drugs on learned behaviors. Low doses of the stimulants cocaine and d-amphetamine both increased general activity. Marked reductions in general activity were observed following both the administration of delta-9-tetrahydrocannabinol and an antihypertensive drug combination of diuretic and verapamil.

Acute ethanol effects on sensory/motor function in baboons with a history of chronic ethanol ingestion.

Baboons with a history of chronic, daily ethanol ingestion were subsequently studied under conditions that assessed the effects of acute oral self-administration of ethanol on auditory and visual threshold functions and reaction times. During the post-chronic experiment reported herein, the animals consumed specific amounts of ethanol twice weekly (0.1, 0.32, 1.0 or 1.3 g/kg), following which they immediately performed psychophysical tests designed to assess ethanol's effects on sensory thresholds and reaction times. Clear, dose-related increases in reaction times were observed following ethanol doses greater than 0.32 g/kg. Trends within individual threshold functions were consistent with systematic changes in auditory and visual threshold sensitivities of 1-3 dB at the high ethanol doses. Reaction time increases ranged from 25 to 180 ms above baseline levels at the highest dose (a 15% average increase). These general findings however, were in contrast to data obtained in the same animals under conditions of daily, chronic ethanol administration which characteristically showed greater sensory/motor effects of up to twice the magnitude of those observed with single doses.

Acute opioid administration effects on sensory and motor function in baboons: buprenorphine, morphine, and naloxone.

The effects of acute administration of the opioid compounds buprenorphine, morphine, and naloxone were studied on auditory and visual threshold functions and reaction time performances in baboons. Baboons were trained in a reaction time procedure to hold a lever depressed, and release the lever when a signal was presented. Auditory and visual signals were employed in separate sessions. Drug was administered 30min prior to testing. Dose-related increases in visual and auditory thresholds were observed following buprenorphine, with visual thresholds being somewhat more drug-sensitive. Buprenorphine also increased reaction times to both high-intensity and low-intensity stimuli. High doses of morphine increased reaction times to high-intensity auditory and low-intensity visual stimuli; thresholds for both modalities were unaffected by any dose of morphine. Naloxone produced no consistent effects on thresholds or reaction times. False alarm rates were not significantly changed by buprenorphine, morphine, or naloxone.

Cocaine and food as reinforcers: effects of reinforcer magnitude and response requirement under second-order fixed-ratio and progressive-ratio schedules.

Reinforcer magnitude and fixed-ratio requirement were varied under two second-order schedules. Under one, the first sequence of a fixed number of responses completed after the lapse of a 10-min fixed interval produced reinforcement. Under the second, a second-order progressive-ratio schedule, the fixed number of responses increased after each reinforcement. Either cocaine (0 to 300 micrograms/kg/inj) or food (0 to 5,700 mg/delivery) reinforcers were delivered. Under some conditions, a 2-s illumination of stimulus lights occurred on completion of each ratio sequence. Under the second-order schedule, as cocaine dose or amount of food increased, rates of responding increased; at the highest values, rates of responding decreased. Increases in the ratio requirement from 10 to 170 responses minimally decreased overall response rates. Under the second-order progressive-ratio schedule, increases in dose of cocaine or amount of food increased rates of responding; at the highest amounts of food, rates of responding decreased but response rates at the highest dose of cocaine remained relatively high. The highest ratio requirement that was completed (breaking point) depended on the dose of cocaine but was less dependent on the amount of food. Removing brief-stimulus presentations had a greater effect on completion of ratio requirements with cocaine compared to food.

Methohexital and cocaine self-administration under fixed-ratio and second-order schedules.

Behavior maintained by either cocaine or methohexital was compared under two different schedules of drug delivery. Under a fixed-ratio 10 schedule, each tenth response produced an injection and responding was characterized by pauses alternating with high rates that were sustained until the drug injection. Under a second-order schedule, each tenth response produced a brief visual stimulus, and the first sequence of ten responses emitted after the lapse of a ten-minute interval produced the stimulus and the drug injection. Responding under the second-order schedule was characterized by an overall positive acceleration in responding that consisted of fixed-ratio response patterns terminating in the presentation of a brief stimulus. Under either schedule, each drug maintained maximal rates of responding at intermediate doses. In most respects, rates and patterns of responding depended more on the schedule of drug delivery than on the particular drug maintaining responding.

Delay or rate of food delivery as determiners of response rate.

PIGEONS WERE CONFRONTED WITH TWO KEYS: a green food key and a white changeover key. Food became available for a peck to the green key after variable intervals of time (mean = 113 seconds). A single peck on the changeover key changed the color of the food key to red for a fixed period of time during which the timing of the variable-interval schedule in green was suspended and the switching option eliminated and after which the conditions associated with green were reinstated. In Experiment 1 a single food presentation was obtainable during each red-key period after a minimum delay timed from the switch. This delay and the duration of the red-key period were held constant during a condition but varied between conditions (delay = 2.5, 7.5, 15, or 30 seconds; red-period duration = 30, 60, 120, 240, or 480 seconds). In Experiment 2 additional food presentations were scheduled during a 240-second red-key period with the delay to the first food delivery held constant at 30 seconds, and the delays to later food deliveries varied over conditions. Considering the data from both experiments, the rate of switching to red was a decreasing function of the delay to the first food, the delay to the second food, and perhaps the delay to the third food after a switch. There was no clear evidence that the rate of food in the red-key period made an independent contribution. The ordering of response rates among conditions was consistent with the view that each food presentation after a response adds an incremental effect to the rate of the response and that each food presentation's contribution is a decreasing function of its delay timed from the response.