Pharmacokinetics of a recombinant bovine growth hormone and pituitary bovine growth hormone in lactating dairy cows.

The disposition of pituitary-derived bovine growth hormone (pbST) and of a recombinant bovine growth hormone (rbST) produced by Lilly (somidobove, USAN) were compared after an intravenous bolus administration (36.69 micrograms/kg for pbST and 35 micrograms/kg for rbST) to eight lactating cows in a crossover study. It was shown that dose-dependent parameters (volume of distribution, clearance) were significantly different between the two test articles. The steady mean state volume of distribution (.10 +/- .018 vs .12 +/- .015 L/kg) and clearance (.119 +/- .012 vs .143 +/- .011 L.kg-1.h-1) were lower for the pbST than for the somidobove. In contrast, the mean (+/- SD) residence times were not different for the two test articles (50.0 +/- 8.6 vs 46.9 +/- 5.9 min for pbST and somidobove, respectively). The origin of the difference is unclear, but it cannot be explained by the slight difference between the administered dose of the two test articles (< 5%) because the actual dose rate was used to calculate all dose-dependent parameters.

Pulsatile secretion of LH in the ram: a re-evaluation using a discrete deconvolution analysis.

The purpose of the present experiment was to characterize LH secretion pulsatility in rams by analysing the instantaneous secretion rate profile obtained by deconvoluting the plasma concentration profile. Plasma LH concentration profiles were obtained by collecting blood samples every 6 min for 24 h during two different sessions separated by an interval of 15 days. Individual kinetic parameters of ovine LH (oLH) were determined following i.v. injection of oLH. By deconvoluting the plasma concentration profile, it was shown that a pulse has an effective duration of only 20.41 +/- 7.69 (S.D.) min whereas the mean duration estimated from measurement of plasma concentrations was 61.00 +/- 15.16 min. The number of pulses was similar before and after deconvolution (7.80 +/- 1.99 vs 9.70 +/- 3.44 pulses/24 h respectively). Using deconvolution the calculated production rate was 2.26 +/- 0.94 micrograms/kg per 24 h, about 50% of this production being located in the pulses. Statistical analysis of pulsatility revealed that pulse occurrence was a nonperiodic event and that the amplitude of LH pulses and the associated amount of LH released were correlated with the duration of the preceding quiescence period, but had no statistically significant influence on the duration of the following quiescence period.

Vitamin E kinetics after intraperitoneal administration of DL-alpha-tocopherol and DL-alpha-tocopherol acetate in sheep.

The disposition of radiotocopherol after intraperitoneal administration of 14C-labelled-DL-alpha-tocopherol (1 microCi/kg bw, dose 1) and 3H-labelled-DL-alpha-tocopherol (4 microCi/kg bw dose 4) and of D-alpha-tocopherol, after intraperitoneal administration of DL-alpha-tocopherol acetate (100 mg/kg bw) was investigated in sheep. Plasma samples were taken at regular intervals after dosing and assayed for radioactivity and D-alpha-tocopherol. Plasma profiles were modelized using a compartmental approach and the input entry rate (for radioactivity) was identified using a numerical deconvolution method. Based on plasma specific activity (dose 1 and dose 4) and D-alpha-tocopherol plasma concentration (unlabelled alpha-tocopherol acetate), half-lives were not significantly different (99.6 +/- 28.3 h, 121.3 +/- 38.5 h and 75.0 +/- 49.75 h after dose 1, dose 4 and unlabelled alpha-tocopherol respectively). The times to reach maximal plasma concentrations were similar for the 3 test articles (mean values ranging from 21.5 to 26.7 h). The only significant difference was observed for the apparent volume of distribution (with respect to bioavailability) which was much larger for the unlabelled test article. Deconvolution study of plasma specific activity showed: i), that the maximal input rate was reached only after a short delay (3 to 12 h); ii), that half of the activity was absorbed after a delay of 38.13 +/- 16.76 h (dose 1) and 44.3 +/- 6.50 h (dose 4); and iii), that 90% of the activity was absorbed after 151.2 +/- 27.3 h (dose 1) and 162.3 +/- 11.2 (dose 4). It is concluded that the intraperitoneal route is of interest for alpha-tocopherol administration, but that more information is required to determine the exact process of absorption.

Spiramycin concentrations in plasma and genital-tract secretions after intravenous administration in the ewe.

Uterine infections are associated with reduced fertility in ruminant species. Spiramycin is a macrolide antibiotic potentially active against most of the microorganisms isolated from secretions of infected genital tracts. The present work investigated the ability of systemically administered spiramycin to enter genital secretions, by determining the disposition kinetics of the antibiotic in both plasma and uterine genital secretions. Five healthy ovariectomized ewes were given a single intravenous (i.v.) injection of spiramycin, at a dose of 20 mg/kg. Plasma and genital secretion samples were collected at predetermined intervals for 5 days post-injection. Blood was collected from the jugular vein while mucus was obtained by inserting polyurethane sponges into the vagina. The spiramycin concentration peak in genital-tract secretions was obtained 2.53 +/- 0.63 h after the i.v. administration. The mean residence time was significantly longer (P less than 0.01) in the mucus (18.31 +/- 3.24 h) than in plasma (6.99 +/- 2.53 h). An average mucus to plasma ratio of 7.87 +/- 3.00 was calculated from the area under concentration-time curves covering the period under study. These data indicate that after systemic administration to ewes, spiramycin is rapidly found in genital-tract secretions, at concentrations which are sufficiently high and persistent to suggest its use in the treatment of post-partum uterine infections.

Instantaneous secretion rate of growth hormone in lambs: relationships with sleep, food intake, and posture.

Relationships among sleep, feeding behavior, posture, and GH secretion were investigated in two groups of ruminant lambs in January (n = 6) and May (n = 3). Lambs were placed in individual cages and fed ad libitum. Behavioral features were obtained from continuous polygraphic recording. Blood was collected from undisturbed sheep every 3 min for 24 h via an indwelling catheter connected to a peristaltic pump. One month after the sampling session, ovine GH (oGH) was iv administered to evaluate oGH kinetic parameters. From GH plasma concentrations and oGH kinetic parameters, the instantaneous secretion rate of GH was reconstituted using a numerical deconvolution method. All lambs exhibited normal behavioral patterns. The clearance of oGH was similar for the two groups, and the daily production rates of GH were estimated at 14.60 +/- 7.99 micrograms/kg.24 h in January and 10.57 +/- 5.21 micrograms/kg.24 h in May. Analysis of concentration profiles indicate an episodic pattern of GH secretion into plasma. The mean number of peaks was 16.22 +/- 4.47/24 h, and the mean duration was 47.2 +/- 12.8 min for the nine sheep. When instantaneous secretion rates were taken into account, the number of identified peaks was similar, but the mean duration was reduced (32.9 +/- 9.8 min for the nine sheep). Significant relationships were not found between GH plasma concentration profiles and the state of vigilance, food behavior, or posture. Conversely, when the instantaneous secretion rates were taken into account, the highest GH production rate was detected during rest, i.e. slow wave sleep and rapid eye movement sleep, absence of food intake or rumination, and lying down. It is emphasized that the use of GH instantaneous secretion rate instead of GH concentration is of importance when evaluating the relationships between GH dynamics and short duration events. It is concluded that the influence of vigilance on GH secretion, which has already been demonstrated in humans, is likely to exist in other species.

Fenprostalene in cattle: Evaluation of oxytocic effects in ovariectomized cows and abortion potential in a 100-day pregnant cow.

Four ovariectomized cows were used to compare the uterotonic (oxytocic) properties of the prostaglandins F2alpha analogue fenprostalene to cloprostenol and PGF2alpha-tromethamine salt (dinoprost). Uterine activity was measured by electromyography with the duration and magnitude of activity quantified by microcomputer. The administration of 1 mg of fenprostalene to estradiol primed animals significantly increased uterine motility for approximately 19 h. This was significantly longer than the duration observed for either cloprostenol (500 mug, i.m., 8.9 h) or dinoprost (25 mg, i.m., 7.7 h). However, the level of activity was similar for the 3 compounds tested, with postinjection levels of oxytocic effect averaging 369 % for treated animals compared to 100 % for controls. Therefore, the difference in effects for the three prostaglandins may be due more to pharmacokinetic properties rather than to different potencies of the three compounds. In addition, a pregnant cow (100 d gestation) was treated with fenprostalene (1 mg, s.c.). Fenprostalene treatment resulted in unchanged uterine activity for a 6-h period, followed by a four-fold increase in genital tract activity which lasted for 12 h. Thereafter, activity was inhibited for one day, followed by a sharp increase in uterine activity leading to abortion within 66 to 72 h after fenprostalene injection. The placenta was expelled 7 days after treatment.

In vivo pharmacological characterization of alpha adrenergic receptors in sheep myometrium and their physiological meaning.

Utero-cervical responsiveness to alpha-adrenergic receptor stimulation was electromyographically evaluated in vivo in adult ovariectomized ewes. Spontaneous motility and drug-induced changes were quantified with a microcomputer. Our results suggested that the two activity patterns previously described on the ovine genital tract could be respectively controlled by alpha-2 and alpha-1 adrenergic mechanisms. Alpha-2 receptors could be assigned to a chronotropic function by activating a hypothetical zone triggering the outbreak of discrete episodes of motility (regular activity); this function is apparent at the cervix even in the absence of estrogen priming. On the other hand, alpha-1 receptors could be assigned to an inotropic function, regulating mainly the magnitude of estrogen-dependent utero-cervical motility (irregular activity).

Secretory profiles and production rate of growth hormone in ruminant lambs.

Secretory profiles and production rates of growth hormone (GH) were determined in 6 ruminant lambs during winter. The mean GH concentrations (3.78 +/- 2.17 ng/ml) calculated were based upon blood sampling obtained every 3 min using a withdrawal pump. Body clearance (0.162 +/- 0.031 1/h/kg) was calculated from bolus intravenous oGH administration. The data were analysed by non-linear regression analysis; a bicompartmental model was selected to describe the data. production rate was 14.6 +/- 7.98 micrograms/kg/24 h. It has been emphasized that the experimental design used gave an accurate estimate of GH production rate.

Direction of uterine contractions during estrus in ewes: a reevaluation.

In four ewes direction of propagation of uterine contractions was evaluated using an electromyographic technique during 15 entire estrous periods; 120,101 propagations were analyzed. When horns were considered separately 89.9% of all propagations were classified into three main modes: ascending (34.3%), descending (59.85%), and divergent (5.85%). When both horns were analyzed simultaneously, horn's synchronicity was observed in most instances; on this basis, eight modes of propagation were identified of which three accounted for two-thirds of all propagation: synchronous descending (24.9%), reciprocal propagation (descending on one horn and then ascending on contralateral horn) (22.1%), and isolated descending propagation (18.0%). A time-dependent pattern of propagation throughout estrus was clearly identified, the percentage of ascending propagations reaching a minimum (16.5%) and the percentage of descending propagation reaching a maximum (77%) at peak uterine motility level. By considering both direction of uterine propagation and cervical mechanical activity, a new hypothesis concerning two aspects of sperm transport (speed and mechanism) was formulated. It is hypothesized that the high prevalence of descending propagations is important to reduce sperm cell population by selecting the most vigorous spermatozoa; such selection is possible when the mechanical cervical activity is low or absent (cervix open); when cervical mechanical activity is high (cervix closed), it is suggested that both descending and ascending propagations participate in sperm transport by back and forth motion of luminal fluid within the uterine lumen.

Activity of the genital tract and plasma levels of oxytocin and cortisol at the time of mating in the ewe.

Experiments were conducted in the ewe to determine the effects of mating on the activity of the genital tract and on blood levels of oxytocin and cortisol. The activity of the uterus and cervix was recorded by electromyography, oxytocin was measured by radioimmunoassay, and cortisol by high performance liquid chromatography. Mating itself did not increase circulating oxytocin or cortisol; uterine motility remained unchanged during and after copulation but the cervix was significantly stimulated during teasing and after copulation. It is suggested that increased cervical activity resulting from adrenergic mechanisms may facilitate the generation of a cervical reserve of spermatozoa.

Relative oxytocic properties of fenprostalene compared with cloprostenol, prostaglandin F2 alpha, and oxytocin in the ovariectomized ewe.

The oxytocic effect of a prostaglandin F2 alpha analogue, fenprostalene, was assessed in 4 ovariectomized ewes fitted with electrodes in both uterine horns and in the cervix. In the absence of estradiol priming, significant motility changes were not elicited by fenprostalene. Conversely, when ewes were primed with 17-beta-estradiol, fenprostalene markedly increased the electrical activity in the uterus and cervix. After a single subcutaneous fenprostalene administration (5 micrograms/kg), activity values remained about twice that of the control values during 8.52 +/- 3.31 hours. When the same dosage was administered IM, similar post-injection activity values were obtained, but only during 5.88 +/- 0.72 hours. Oxytocic effects of fenprostalene were far longer than those elicited by a single IM administration of 50 micrograms of prostaglandin F2 alpha (tham salt)/kg (0.91 +/- 0.32 hours) or by a single IM administration of 1 microgram of cloprostenol/kg (1.88 +/- 0.81 hours). Using the dose-effect relationship curve obtained from the same ewes by continuous IV infusions of oxytocin (OXT), the postinjection activity values reached after a single subcutaneous administration of fenprostalene were equivalent to those of an IV infusion of OXT at an average dose of 4.09 ImU of OXT/kg/hr for 6 to 13 hours, according to the values of the particular ewe concerned. These long-lasting oxytocic properties, in addition to its luteolytic capabilities, would make fenprostalene a suitable drug for promoting effective evacuation of the uterus when required in daily veterinary practice.