Acetylcholine-induced contractions in the porcine internal mammary artery: possible role of muscarinic receptors

The effect of acetylcholine on the isolated, non-precontracted, porcine internal mammary artery (IMA) was investigated. Acetylcholine induced concentration-dependent contractions of non-precontracted IMA rings with denuded endothelium (pEC50 = 5.80 +/- 0.04) and was without effect on arterial segments with intact endothelium. The muscarinic receptor antagonists atropine, pirenzepine, methoctramine and p-fluoro-hexahydro-sila-diphenidol (pFHHSiD) antagonized the response to acetylcholine. The constrained pA2 values were 10.14, 7.74, 7.34 and 10.5, respectively. It is concluded that acetylcholine induces concentration-dependent contractions of porcine internal mammary artery rings on basal tone and that this contractile effect is probably due to direct cholinergic stimulation of smooth muscle cells, maybe including activation of muscarinic M1 receptors.     

Characterization of muscarinic receptor subtype mediating contraction and relaxation in equine coronary artery in vitro

In coronary arterial rings isolated from horses, 10-^-8-10^-6 mol/l acetylcholine (ACh) induced concentration-dependent contractions which were potentiated by the removal of endothelium and by pretreatment with I,-nitro-arginine (LNAG) or methylene blue (MB). Relatively lower concentrations of Ach 10-¹⁴-10-⁸ mol/l) induced relaxation when the coronary rings were contracted by phenylephrine (PE). ACh-induced contractions in the coronary rings without endothelium were competitively inhibited by each muscarinic subtype selective antagonist in the following order of potency: 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) > pirenzepine ≥ parafluoro-hexahydrosiladiphenidol (pFHHSiD) > methoctramine. ACh-induced relaxation in the rings with endothelium was inhibited by LNAG or MB, and by each selective antagonist in the following order of potency: 4-DAMP < pFHHSiD ≥ pirenzepine ≥ methoctramine. These results suggest that the ACh-induced contraction and relaxation in equine coronary arteries are mediated mainly by an M₃-receptor located on the smooth muscle cells and endothelial cells, respectively, and that the stimulation of the M₃-receptor on the endothelial cells liberates nitric oxide.     

Effects of a selective and a nonselective muscarinic cholinergic antagonist on heart rate and intestinal motility in dogs

The effects of methoctramine, a cardioselective muscarinic cholinergic antagonist, on heart rate and small intestinal motor activity were compared to those of the nonselective competitive muscarinic antagonist, atropine. Methoctramine or atropine, 6, 10, 30, 60 μg/kg, or sterile isotonic saline, was administered intravenously to six conscious dogs in cross-over studies. Methoctramine administration caused dose-dependent tachycardia without affecting intestinal motility, while atropine administration caused dose-dependent tachycardia accompanied by significant reductions in small intestinal motility. Additionally, methoctramine did not inhibit intestinal smooth muscle contractile activity initiated by the muscarinic agonist bethanechol, while atropine inhibited bethanechol-induced contractile activity in a dose-dependent manner. Calculated dosages of methoctramine and atropine required to produce a 50% increase in heart rate over baseline were 35.1 ± 5.3 and 39.5 ± 6.2 μg/kg, respectively. This dosage of atropine caused a 93 ± 13.9% reduction in intestinal motility. These findings suggest that selective muscarinic antagonists may be useful drugs for those veterinary patients in which nonselective muscarinic antagonists have the potential to produce untoward effects on intestinal motility.     

Endothelium-dependent relaxation of canine uterine artery in response to acetylcholine: the possible involvement of alternative pathways

The effect of acetylcholine on the isolated, pre-contracted, uterine artery of non-pregnant dog was investigated. Acetylcholine-induced concentration-dependent relaxation of isolated canine uterine artery with endothelium (pEC50 = 6.48 +/-0.01, n = 37) and was without effect on arterial segments denuded of endothelium. Indomethacin, 4-aminopyridine (10-5 m) and pre-contraction with K+-rich Krebs-Ringer bicarbonate solution had no effect on acetylcholine-induced relaxation. NG-nitro-l-arginine (l-NOARG) (10-5 m) inhibited relaxation evoked by acetylcholine. Indomethacin applied with l-NOARG led to further inhibition of acetylcholine-induced relaxation. In the presence of both l-NOARG and indomethacin, 4-aminopiridine did not provoke further inhibition of acetylcholine-induced relaxation of canine uterine artery. It is concluded that the acetylcholine-induced relaxation of canine uterine artery is probably mediated by endothelial production of nitric oxide (NO). However, if NO-synthase is inhibited, acetylcholine-induced vasorelaxation may be, in part, mediated through activation of cyclooxygenase pathway.     

Characterization of bradykinin-induced endothelium-independent contraction in equine basilar artery

We investigated the effect of bradykinin (BK) on isolated equine basilar arterial rings with and without endothelium. BK induced concentration-dependent contraction of resting arterial rings and no relaxation when the rings were precontracted by prostaglandin F_2α. The maximal response and pD₂ value were 161.2 ± 28.1% (to 60 m m KCl-induced contraction) and 8.24 ± 0.25 respectively. The cumulative concentration–response curve for BK was not shifted to the right by des-Arg⁹-[Leu⁸]-BK (a B₁-receptor antagonist), HOE140 (a B₂-receptor antagonist) or NPC567 (another B₂-receptor antagonist). In four of six basilar arteries, NPC567 induced concentration-dependent contraction. Indomethacin (a cyclooxygenase inhibitor), nordihydroguaiaretic acid (a lipoxygenase inhibitor), quinacrine (a phospholipase A₂ inhibitor), tetrodotoxin (a selective blocker of Na⁺ channels), guanethidine (a nor-adrenergic neuron blocking drug), phentolamine (an α-adrenoceptor antagonist), Nω-nitro- l -arginine ( l -NNA, a nitric oxide (NO) synthase inhibitor) and endothelial denudation did not affect the BK-induced contraction. l -NNA and indomethacin induced contraction and relaxation under resting vascular tone respectively. These results suggest that endothelial cells are not involved in BK-induced contraction and that the contraction is not mediated via activation of known B₁ and B₂ receptors. Arachidonic acid metabolites and neurotransmitters like norepinephrine and NO might not play a role in BK-induced contraction in equine basilar artery.     

Alpha-adrenoceptors in equine digital veins: Evidence for the presence of both alpha1 and alpha2-receptors mediating vasoconstriction

Rings of equine digital vein examined under conditions of isometric tension recording constricted to alpha-adrenoceptor agonists with an order of potency of 5-bromo-6-[2-imidazolin-2-yl-amino]-quinoxaline bitartrate (UK 14304) = noradrenaline > 6-Allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-(4,5-d) azepine (BHT-920) > phenylephrine > dopamine > methoxamine. The maximum force generated was greatest for the non-selective agonist noradrenaline and lowest for the alpha₂-selective agonist BHT-920 with the other agonists between these two extremes. Selective inactivation of alpha₁-adrenoceptors (achieved by treating yohimbine-protected tissues with phenoxybenzamine) reduced the maximum responses of all agonists, the EC₅₀ values of UK 14304, BHT-920 and noradrenaline and increased the EC₅₀ values of phenylephrine and methoxamine. Prazosin (30 n M ) had no inhibitory effect on responses to low concentrations of BHT-920 and UK 14304 and caused competitive inhibition of responses to phenylephrine and noradrenaline giving pK_b values of 8.49 ± 0.18 and 8.23 ± 0.14, respectively. Yohimbine (0.1 μ M ) caused significant competitive inhibition of responses to BHT-920 and noradrenaline with calculated pK_b values of 8.43 ± 0.11 for BHT-920 and 7.43 ± 0.31 for noradrenaline and non-competitive inhibition of responses to UK 14304. 2-[2-methoxy-1,4-benzodioxan-2-yl]-2-imidazoline (RX 821002; 10 n M ) caused competitive inhibition of responses to BHT-920 (pK_b 9.04 ± 0.27) and dopamine (pK_b 8.2 ± 0.2). These data indicate that equine digital veins possess both post-synaptic alpha₁ and alpha₂-adrenoceptors.     

Affinity of detomidine, medetomidine and xylazine for alpha-2 adrenergic receptor subtypes

α₂-Adrenergic receptor agonists are widely used in veterinary medicine as sedative/hypnotic agents. Four pharmacological subtypes of the α₂-adrenergic receptor (A, B, C and D) have been identified based primarily on differences in affinity for several drugs. The purpose of this study was to examine the affinities of the sedative agents, xylazine, detomidine and medetomidine at the four α₂-adrenergic receptor subtypes. Saturation and inhibition binding curves were performed in membranes of tissues containing only one subtype of a₂-adrenergic receptor. The K_D for the α₂-adrenergic receptor radioligand, [³H]-MK-912, in HT29 cells (α_2A-), neonatal rat lung (α_2B-), OK cells (α_2C-) and PC12 cells transfected with RG20 (α_2D-) were 0.38 ± 0.08 n m , 0.70 ± 0.5 n m , 0.07 ± 0.02 n m and 0.87 ± 0.03 n m , respectively. Detomidine and medetomidine had approximately a 100 fold higher affinity for all the α₂-adrenergic receptors compared to xylazine but neither agonist displayed selectivity for the α₂-adrenergic receptor subtypes. These data suggest that available sedative/hypnotic α₂-adrenergic receptor agonists can not discriminate between the four known α₂-adrenergic receptor subtypes.     

Functional characterization of post-junctional adrenergic receptor subtypes in bovine intra-mammary arteries

We examined the functional role of adrenergic receptor subtypes (ARs) in bovine intra-mammary arteries (IMAs), 1.5–2.5 mm internal diameter. Norepinephrine (NE) and phenylephrine (PE) produced concentration-dependent increases in tone in segments maintained at a previously determined optimal basal tension in vitro . The sensitivity of the tissue to NE and PE, based on -log molar ED_50s was 6.87 ± 0.17 and 7.05 ± 0.35, respectively. In addition a Schild analysis yielded antagonist affinities for the receptor mediating contractile responses to NE (pA2 value) of 10.46 ± 0.85 for prazosin and 6.29 ± 0.18 for yohimbine. These data indicate a dominance of functional alpha 1 (α₁) over alpha 2 (α₂)-ARs in this tissue. Based on the inhibitory effects of chloroethylclonidine (CEC) on PE responses and the further reduction in sensitivity when nifedipine was added to the CEC, also in the presence of PE, we conclude that there is more than one α₁-AR subtype, with a predominant role for α_1B-ARs in phenylephrine responses. Stimulation of beta (β)-ARs, resulted in relatively small reductions in tone (the highest magnitude of response was 25.94 ± 6.46% of the papaverine maximum at 3×10⁻⁶ M isoproterenol); in addition, propranolol did not significantly alter tissue sensitivity to NE. Additional characterization of functional autonomic receptor populations in this circulatory bed will form a basis for future studies on circulatory dynamics in the mammary gland.     

Effects of muscarinic receptor antagonists on acetylcholine-induced contractions of jejunal smooth muscle in horses

This study investigated the effects of a muscarinic type 1 (M(1)), 2 (M(2)), and 3 (M(3)) antagonists (4-DAMP, pirenzepine, and methoctramine, respectively) on acetylcholine (Ach)-induced contractions of longitudinal jejunal muscle strips of horses. Strips were irrigated with Krebs-Henseleit solution gassed with 95% O(2) and 5% CO(2), and the developed tension in response to Ach was recorded before and after incubation with increasing concentrations of 4-DAMP (10(-8)-10(-6) M), pirenzepine (10(-6)-10(-4) M), and methoctramine (10(-5)-10(-3) M). When competitive antagonism was characterized, the affinity constant (pA(2)) was calculated by Schild plots. A parallel rightward shift in the concentration-response curves was observed after 4-DAMP and pirenzepine. Methoctramine presented a dual effect on the concentration-response curves: lower concentrations induced a parallel rightward shift without altering the maximum intensity of contraction (E(max)), while the highest concentration increased slope of the concentration-response curve and increased E(max). The pA(2) for 4-DAMP and pirenzepine was 9.18 and 7.13, respectively. Acetylcholine-induced contractions of longitudinal jejunal smooth muscle are mediated mainly via M(3) receptors. The complex role of M(2) receptors in jejunal smooth muscle contractions was evident because methoctramine potentiated the contractile response to higher doses of Ach.     

Equine coronary artery responds to 5-hydroxytryptamine with relaxation in vitro

Isolated equine coronary arteries responded to 5-hydroxytryptamine (5-HT) with relaxations in both endothelium-dependent and endothelium-independent mechanisms. Experiments were designed to characterize the 5-HT receptor sub type mediating these relaxations. Both 5-HT and alpha-methyl-5-HT (α-Me-5- HT; 5-HT₂ agonist) produced concentration-dependent relaxations in equine coronary arteries precontracted with a thromboxane A₂ derivative (0N011113). The degree of the maximal relaxation induced by α t-Me-5-HT was about one-half of that induced by 5-HT. In the coronary arteries without endothelium, α -Me-5-HT produced no relaxation, but 5-HT caused relaxation, which was inhibited by a 5-HT₁ antagonist (methysergide, mianserin and methiothepin), but was inhibited neither by ketanserin (5-HT₂ antagonist) nor by MDL72222 (5-HT₃ antagonist). In the coronary arteries with endothelium, however, the relaxation induced by α -Me-5-HT was inhibited by ketanserin, L-nitro-arginine (NO synthase inhibitor) and methylene blue (soluble guanylate cyclase inhibitor). These results suggest that the relaxation induced by 5-HT in equine coronary arteries depends mainly on the stimulation of both 5-HTi receptor subtype on smooth muscle cells directly, and 5-HT₂ receptor subtype on endothelial cells indirectly by liberating endothe-lium-derived NO.     

Pharmacokinetics of a new long acting endectocide formulation containing 2.25% ivermectin and 1.25% abamectin in cattle

The objective of this study was to determine the kinetic parameters of a new formulation that contained 2.25% ivermectin combined with 1.25% abamectin in bovine plasma. The results for 2.25% ivermectin: C _max (37.11 ng/mL ± 7.42), T _max (16 days ± 5.29), T _1/2 (44.62 days ± 53.89), AUC (928.2 ng·day/mL ± 153.83) and MRT (36.73 days ± 33.64), and for 1.25% abamectin: C _max (28.70 ng/mL ± 9.54), T _max (14 days ± 4.04), T _1/2 (15.40 days ± 11.43), AUC (618.05 ng·day/mL ± 80.27) and MRT (20.79 days ± 8.43) suggest that this combination of 2.25% ivermectin + 1.25% abamectin possesses properties that give this pharmaceutical formula a longer activity time than two of the commercial products tested (1% ivermectin and 1% abamectin), and showed similarity to 3.15% ivermectin.     

Characterization of vasodilatory adenosine receptors in equine digital veins

Isolated equine digital veins (EDVs) which had been denuded of their endothelium were used to study adenosine receptors causing vasodilation. When the blood vessel wall tension was raised with the thromboxanemimetic, U44069 (30 n m ), the order of vasodilator potency of adenosine receptor agonists was: 5'-N-ethylcarboxamidoadenosine (NECA) > 2- p -(2-carboxyethyl)phenyl amino-5'-N-ethylcarboxamido-adenosine (CGS 21680) > 5'-N-methylcarboxamido-adenosine (MECA) > > N⁶-cyclohexyladenosine (CHA) > N⁶-cyclopentyladenosine (CPA) > N⁶–2-(4-Aminophenyl)ethyladenosine (APNEA) > adenosine. Removal of the endothelium had no significant effect on the responses to NECA. The adenosine receptor antagonists, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; A₁-selective) and xanthine amine cogener (XAC; non-selective antagonist) inhibited responses to NECA and CHA in a competitive manner and XAC proved to be 8–25 times more potent than DPCPX against both agonists. These data support the presence of A₂ adenosine receptors in EDVs, located on the vascular smooth muscle cells, which are most likely to be of the A_2A-adenosine receptor subtype. A direct comparison between the potency and efficacy of NECA and adenosine as vasodilators of EDV and equine digital arteries was made and both agonists proved to be significantly more potent and efficacious as vasodilators of EDVs. These data suggest that adenosine may be an important local mediator regulating blood flow through the digital circulation and that its generation under hypoxic conditions would lead to selective venodilation.     

Comparison of Two Doses of the GnRH Antagonist, Acyline, for Pregnancy Termination in Bitches

Gonadotropin-releasing hormone (GnRH) antagonists are particularly useful when a rapid inhibitory effect on the gonadal axis is required. The aim of this study was to test the efficacy and clinical safety of a low and high dose of the third generation GnRH antagonist, acyline, on pregnancy termination in female dogs. The effect of the antagonist on the progesterone (P₄) serum concentration was also described. Twenty-one mid-pregnant bitches were randomly assigned to a single subcutaneous (SC) dose of a placebo (PLACE; n = 7), a low (ACY-L; 110 μg/kg; n = 6) or high (ACY-H; 330 μg/kg; n = 8) dose of acyline. The animals were followed up for 15 days. All ACY treated but no placebo-treated animals terminated their pregnancy by abortion (p < 0.01). The ACY-L and ACY-H groups interrupted their pregnancy 7 ± 1.9 and 6.4 ± 1.3   days after treatment, respectively (p = 0.7). A significant interaction between treatment and day was found (p < 0.01) for P₄ serum concentrations when PLACE was compared with both ACY groups. No difference was found for this hormone between both ACY groups (p > 0.05) where P₄ diminished throughout the study. The decreasing rate varied among animals and was closely related to the time of abortion when P₄ reached basal concentrations. In PLACE animals, gestation progressed normally and P₄ did not change throughout the study (p > 0.05). None of the bitches presented side effects. It was concluded that acyline safely terminated mid-pregnancy by permanently decreasing P₄ serum concentrations.     

Femtomolar bradykinin-induced relaxation of isolated bovine coronary arteries, mediated by endothelium-derived nitric oxide

We reported previously that bradykinin induces endothelium-dependent relaxation at nanomolar (n M ) concentrations in isolated bovine coronary arteries with an intact endothelium. Recently we have found that in the presence of 10 μ m indomethacin, femtomolar (f M ) concentrations of bradykinin induce endothelium-dependent relaxation in some bovine coronary arteries (≈ 10% of the coronary arteries examined). The present study was designed to characterize the relaxation induced by f M bradykinin. Relaxation was completely abolished by repeated application of f M bradykinin, by 100 μ m N^ω- nitro- l - arginine methyl ester and by 10 μ m methylene blue. Relaxation induced by n M bradykinin was partly affected by these treatments. Relaxation induced by both concentrations of bradykinin was inhibited by a B₂-kinin receptor antagonist, [Thi^5,8, D-Phe⁷]-bradykinin, in a concentration-dependent manner, but not by a B₁-kinin receptor antagonist, des-Arg⁹, [Leu⁸]-bradykinin. In the presence of 10 μ m captopril, an angiotensin-converting enzyme (ACE) inhibitor, all coronary arteries examined in this experiment showed endothelium-dependent relaxation to f M bradykinin. These results show that some bovine coronary arteries relax in response to f M bradykinin, and this response is mediated predominantly by the release of nitric oxide via stimulation of endothelial B₂-kinin receptors. The relaxation may be dependent on ACE activity.     

Effect of Sanguinarine on Active Capacity of Isolated Rat Uterine Smooth Muscle in vitro and Its Mechanism

The study was aimed to explore the effects of the sanguinarine on activity of isolated rat uterine smooth muscle in vitro. The effect of the sanguinarine on activity of the isolated myometrium of non-pregnant Sprague-Dawley rats eight weeks old was recorded by BL-420F four channels physiological recorder. Four antagonists, atropine sulfate, ranitidine hydrochloride, propranolol hydrochloride and diphenhydramine hydrochloride were used to study their mechanism, respectively. The results showed that sanguinarine and Yuan hu painkillers markedly inhibited the frequency, amplitude and activity of uterine contractions induced by oxytocin injection (P<0.05). The inhibitory effect of sanguinarine on uterine muscle contractions was blocked after using diphenhydramine hydrochloride (H₁-receptor antagonist) and ranitidine hydrochloride (H₂-receptor antagonist). However, after using atropine sulfate (M-receptor antagonist) and propranolol hydrochloride (β-receptor antagonist), sanguinarine also significantly inhibited the contractions of rat uterine smooth muscle (P<0.05). It was concluded that the effect of sanguinarine on activity of uterine smooth muscle in rats was mainly associated with H₁ receptor or H₂ receptor but not M receptor or β receptor.     

血根碱对大鼠离体子宫平滑肌收缩的影响及其机制研究

试验旨在研究血根碱对大鼠离体子宫平滑肌活动的影响。分离8周龄SD雌性未孕大鼠子宫平滑肌,通过BL-420F生物信号采集系统记录子宫平滑肌收缩频率和收缩幅度,计算子宫平滑肌活力。以硫酸阿托品、盐酸普萘洛尔、盐酸苯海拉明及盐酸雷尼替丁为阻断剂,观察血根碱对子宫平滑肌M、β、H₁、H₂受体的关系,探讨血根碱对子宫平滑肌的作用机制。结果显示,血根碱组和元胡止痛片组对缩宫素所致大鼠离体子宫平滑肌收缩频率、收缩幅度和活力均有显著的抑制作用（P<0.05）;应用H₁受体阻断剂苯海拉明和H₂受体阻断剂雷尼替丁后,血根碱对子宫平滑肌抑制作用基本被阻断,而应用M受体阻断剂阿托品,β受体阻断剂普萘洛尔后,血根碱对子宫平滑肌收缩仍具有显著的抑制作用（P<0.05）。综上所述,血根碱对大鼠子宫平滑肌活力具有显著的抑制作用,可能是通过抑制H₁、H₂受体实现,与M、β受体无关。     

Pharmacokinetics of a single bolus intravenous, intramuscular and subcutaneous dose of disodium fosfomycin in horses

Pharmacokinetic parameters of fosfomycin were determined in horses after the administration of disodium fosfomycin at 10 mg/kg and 20 mg/kg intravenously (IV), intramuscularly (IM) and subcutaneously (SC) each. Serum concentration at time zero (C_S0) was 112.21 ± 1.27 μg/mL and 201.43 ± 1.56 μg/mL for each dose level. Bioavailability after the SC administration was 84 and 86% for the 10 mg/kg and the 20 mg/kg dose respectively. Considering the documented minimum inhibitory concentration (MIC₉₀) range of sensitive bacteria to fosfomycin, the maximum serum concentration (Cmax) obtained (56.14 ± 2.26 μg/mL with 10 mg/kg SC and 72.14 ± 3.04 μg/mL with 20 mg/kg SC) and that fosfomycin is considered a time-dependant antimicrobial, it can be concluded that clinically effective plasma concentrations might be obtained for up to 10 h administering 20 mg/kg SC. An additional predictor of efficacy for this latter dose and route, and considering a 12 h dosing interval, could be area under the curve AUC_0-12/MIC₉₀ ratio which in this case was calculated as 996 for the 10 mg/kg dose and 1260 for the 20 mg/kg dose if dealing with sensitive bacteria. If a more resistant strain is considered, the AUC_0-12/MIC₉₀ ratio was calculated as 15 for the 10 mg/kg dose and 19 for the 20 mg/kg dose.     

An Experimental Model to Study Resistance Index and Systolic/Diastolic Ratio of Uterine Arteries in Adverse Canine Pregnancy Outcome

The aim of this study was to describe the changes in the resistance index (RI) and systolic/diastolic ratio ( S / D ) of the uterine arteries during mid-pregnancy abortion induction in the dog. Sixteen 30–35 day pregnant bitches were randomly assigned to either a pharmacological protocol to interrupt gestation (n = 8) or were used as untreated control group (n = 8). Doppler assessments of uterine arteries blood flow were carried out before the initiation of the protocol and then every other day up to abortion (treated group) or parturition (control group). All treated bitches aborted 6 ± 1.2 days after initiation of the treatment (while none of the non-treated bitches aborted). Pre-treatment RI and S / D did not differ between groups (p > 0.2) while average post-treatment indexes were (mean ± SD): 0.62 ± 0.1 vs 0.53 ± 0.1 (p < 0.01) and 2.96 ± 0.9 vs 2.23 ± 0.3 (p = 0.01), for the treated and non-treated group respectively. Correlations between days to abortion and RI or S / D were 0.75 (p < 0.01) and 0.79 (p < 0.01) and, −0.78 (p < 0.01) and −0.73 (p < 0.01) for the treated and non-treated groups respectively. In the treated group, correlations between serum progesterone (P₄) concentrations and RI and S / D were −0.76 (p < 0.01) and −0.59 (p < 0.01) respectively. It is concluded that, during induction of abortion, RI and S / D of uterine arteries progressively increased while P₄ decreased.     

Pharmacokinetics of pradofloxacin and doxycycline in serum, saliva, and tear fluid of cats after oral administration

The pharmacokinetic properties of pradofloxacin and doxycycline were investigated in serum, saliva, and tear fluid of cats. In a crossover study design, six cats were treated orally with a single dose of pradofloxacin (Veraflox^® Oral Suspension 2.5%) and doxycycline (Ronaxan^® 100 mg) at 5 mg/kg body weight. Following administration, samples of serum, saliva, and tear fluid were taken in regular intervals over a period of 24 h and analysed by turbulent flow chromatography/tandem mass spectrometry. All values are given as mean ± SD. Pradofloxacin reached a mean maximum serum concentration ( C _max) of 1.1 ± 0.5 μg/mL after 1.8 ± 1.3 h ( t _max). In saliva and tear fluid, mean C _max was 6.3 ± 7.0 and 13.4 ± 20.9 μg/mL, respectively, and mean t _max was 0.5 ± 0 and 0.8 ± 0.3 h, respectively. Doxycycline reached a mean C _max in serum of 4.0 ± 0.8 μg/mL after 4.3 ± 3.2 h. Whilst only at two time-points doxycycline concentrations close to the limit of quantification were determined in tear fluid, no detectable levels were found in saliva. The high concentrations of pradofloxacin in saliva and tear fluid are promising to apply pradofloxacin for the treatment of conjunctivitis and upper respiratory tract infections in cats. As doxycycline is barely secreted into these fluids after oral application the mechanisms of its clinical efficacy remain unclear.     

Plasma pharmacokinetics and urine concentrations of meropenem in ewes

The pharmacokinetics of meropenem was studied in five ewes after single i.v. and i.m. dose of 20 mg/kg bw. Meropenem concentrations in plasma and urine were determined using microbiological assay method. A two-compartment open model was best described the decrease of meropenem concentration in plasma after an i.v. injection. The drug was rapidly eliminated with a half-life of elimination ( t _{1/2 β} ) of 0.39 ± 0.30 h. Meropenem showed a small steady-state volume of distribution [ V _d(ss)] 0.055 ± 0.09 L/kg. Following i.m. injection, meropenem was rapidly absorbed with a t _1/2ab of 0.25 ± 0.04 h. The peak plasma concentration ( C _max) was 48.79 ± 8.83  μ g/mL was attained after 0.57 ± 0.13 h ( t _max). The elimination half-life ( t _1/2el) of meropenem was 0.71 ± 0.12 h and the mean residence time ( MRT ) was 1.38 ± 0.26 h. The systemic bioavailability (F) after i.m. injection was 112.67 ± 10.13%. In vitro protein-binding percentage of meropenem in ewe's plasma was 42.80%. The mean urinary recoveries of meropenem over 24 h were 83% and 91% of the administered dose after i.v. and i.m. injections respectively. Thus, meropenem is likely to be efficacious in the eradication of many urinary tract pathogens in sheep.