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A number of drugs have been used to treat asphyxia in new-born calves and the aim of the current study was to investigate the effect of commonly-used stimulant drugs on ventilation, arterial blood gas and acid base variables. A group (n=18) of new-born (3-15 h old) calves were treated in a randomised sequence with doxapram (40 mg, IV), lobeline (5mg, IV) or prethcamide (5 mL, consisting of 375 mg crotethamide and 375 mg cropropamide, buccally). Blood and spirometric measurements, using an ultrasonic spirometer, were collected prior to and 1, 5, 15, 30, 60, 90 min after administration of each drug. Doxapram caused a significant increase in the respiratory rate, peak inspiratory and expiratory flow and minute volume (V(min)) during the 90-min post-treatment study period, although maximum values occurred 1 min after treatment. The V(min) increased from 13.8 ± 5.0 L to 28.5 ± 12.3 L. Prethcamide, but not lobeline, also caused significant increases in inspiratory and expiratory volumes. The effects of doxapram on ventilation were accompanied by an increase in arterial partial pressure of oxygen (P(a)O(2)) (77.7 ± 18.8 mm Hg to 93.2 ± 23.7 mm Hg), a decrease in arterial partial pressure of carbon dioxide (P(a)CO(2)) (42.6 ± 4.9 mm Hg to 33.1 ± 6.6mm Hg), a significant increase in pH and a decrease in bicarbonate concentration and base excess 1 min after treatment. Prethcamide caused a gradual increase in P(a)O(2) and decrease in P(a)CO(2) over 90 min, whereas lobeline had no measurable effect on the investigated variables. Of the three treatments, only doxapram had a distinct stimulatory effect on respiration in healthy neonatal calves and may therefore be useful in the treatment of calf asphyxia.

The respiratory stimulant prethcamide is a mixture of equal parts of crotethamide and cropropamide. A specific and sensitive gas chromatographic method for the determination of crotethamide and cropropamide in horse plasma and urine is described. Both components of prethcamide were extracted from plasma and urine into dichloromethane. The extracts were analyzed by capillary gas chromatography with thermionic detection in the nitrogen-specific detection mode. The lower limits of quantitation were 4.0 ng ml −1 of plasma and 10.0 ng ml −1 of urine. Calibration curves were linear from 2.0–100 ng ml −1 of plasma for both components. Pharmacokinetic parameters for crotethamide and cropropamide after intravenous and oral dosing were estimated by analysis of plasma concentration versus time data. The total plasma clearance of cropropamide was greater than that of crotethamide and both values were greater than 5 ml min −1 kg −1 . Renal clearance values of the two drugs were comparable and were much less than estimates of filtration clearance values in horses, indicating extensive re-absorption of both components from the renal tubules. Both compounds were metabolized by N-demethylation of the [(dimethylamino)-carbonyl]-propyl moiety and these metabolites were excreted in urine. The method was demonstrated to be suitable for detecting illicit administration of prethcamide to competition horses.

A simple and sensitive gas chromatographic method for determination of Prethcamide components (I and II) in whole blood and tissues of rats has been developed. The method was used to study disposition of Prethcamide after oral and intravenous administration (60 mg/kg) to rats. Half-lives were found to be low for both constituent of Prethcamide, reaching 7.3 min and 6.5 min for I and II compounds respectively in the blood. They were longest in both cases in the kidney (9.4 min and 8.3 min).

Summary The effects of Micoren on respiration were studied in 11 patients suffering from acute exacerbations of chronic respiratory disease. pCO2 was normal or slightly raised. Increases in minute volume and falls in pCO2 following intravenous or intramuscular administration were observed in all the patients studied. Intravenous injection acted more rapidly than intramuscular administration but its effects were of shorter duration. Variable effects on the respiratory rate were observed. Side-effects were reported in one patient following intravenous therapy. The clinical value of the drug in the management of acute respiratory failure was not investigated.

Doxapram hydrochloride was administered to unrestrained, conscious animals by continuous intravenous infusion. Respiratory stimulant and convulsant doses were recorded and a ratio of these doses was determined for each species under test. Ratios were found to be 38:1 for the cat, 10:1 for the rabbit and 11:1 for both the rat and mouse. In a comparative study, corresponding ratios obtained with ethamivan and prethcamide were notably smaller than those recorded with doxapram hydrochloride. Since the ratios of convulsant to respitory respiratory stimulant, it is concluded that doxapram hydrochloride may have a greater margin of safety in clinical use than either ethamivan or prethcamide.

Crotethamide and cropropamide, both components of the respiratory stimulant prethcamide, are metabolized in humans by demethylation of the [(dimethylamino)-carbonyl]-propyl moiety. The resulting metabolites are characterized by gas chromatography-mass spectrometry of urinary extracts. The use of HCl to prevent losses by volatilization during the evaporation step, combined with methanol as solvent, complicates gas liquid chromatographic analysis of prethcamide. The resulting artifacts are identified.

The effects of the two components of prethcamide (namely crotetamide and cropropamide) upon various behaviors in rats were compared with those of prethcamide itself to see if both were active or not and the kind of joint action shown when they were given in combination. Both crotetamide and cropropamide increase the motor activity of rats, reduce the rate of lever pressing in FR and VI food-reinforced schedules and increase the latency times in a multiple CRF-discrimination schedule. When given in combination the drugs show additive effects upon locomotor activity and FR or VI behaviors but they potentiate each other as regards the effects upon latency times in the multiple schedule. On the other hand, a clear antagonism between the two drugs has been found in the acute toxicity test.

The ventilatory effects of intravenous injections and infusions of prethcamide have been investigated with healthy young adult male volunteers. Ventilatory changes due to the drug were measured at constant inspired Pco2 or constant alveolar Pco2, and in relation to the response to changes in alveolar Pco2. The experiments show that the drug is a mild and somewhat inconstant respiratory stimulant, slow and prolonged in action and liable to give rise to a variety of unpleasant side-effects.

The effect of oral prethcamide (Micoren) (a mixture of two related amides of crotonyl N' butyric acid) was compared with a placebo preparation in 13 patients with established chronic ventilatory failure. Part I of the study comprised a double-blind single cross-over trial with an initial assessment and two further assessments at the end of each period of one month. Prethcamide was taken in 200-mg. doses four times daily. No subjective or objective changes were noted, and in particular the resting Pco(2) showed no change.Part II of the study comprised a double-blind single cross-over trial of the short-term effect of prethcamide compared with placebo in 12 patients in chronic ventilatory failure. Frequent estimations of mixed venous Pco(2) were made with a rebreathing technique for four and a half hours after ingestion of prethcamide or placebo preparation.Following prethcamide a fall in Pco(2) level to a minimum value at 30 minutes of 93% of control values and persisting for about three hours was noted for the group as a whole. The fall represents a lowering by about 4 mm. Hg of the mixed venous Pco(2).It is concluded that, though in patients with chronic ventilatory failure prethcamide may reduce the Pco(2) in the short term, there is no subjective benefit or observable objective change following repeated administrations over a period of one month.

The effects of slow intravenous infusion of three different respiratory stimulants (dimefline, nikethamide and prethcamide) on minute and alveolar ventilation, blood gases and pH were studied in 18 patients with chronic pulmonary emphysema and chronic respiratory failure. For a more accurate assessment of the results of the double blind controlled trial, a factorial design in a Youden square scheme was employed. Respiratory rate, tidal volume, minute ventilation, arterial Po 2 , pH and heart rate failed to show significant changes after the intravenous infusion of the drugs. The other parameters studied (dead space, alveolar ventilation, CO 2 output, Paco 2 ) showed some differences but these were temporally similar for the three drugs. As improvement in respiratory and blood gases data was transient and slight and undesirable side-effects constant, it is concluded that the use of respiratory stimulants in management of chronic respiratory failure cannot be recommended.

Prethcamide was given by slow intravenous injection to five patients while respiratoru minute volume, heart rate, systemic arterial pressure and pulmonary arterial pressure were recorded. No consistent change in pressures or heart rate was observed although an increase in minute volume occurred in every case.