Plasma and urinary concentrations of trimetoquinol by LC-MS-MS following intravenous and intra-tracheal administration to horses with heaves.

Trimetoquinol (TMQ) is a very potent and fast acting bronchodilator in horses with heaves. This study assessed the plasma and urinary concentrations of TMQ in horses with heaves following administration via the intravenous (IV, 0.2 microg/kg) and intra-tracheal (IT, 2 microg/kg) routes. TMQ was administered to six horses affected with heaves (RAO - Recurrent Airway Obstruction, used interchangeably) by the above routes and plasma and urine samples collected and stored at -20 degrees C until analyzed. Solid Phase Extraction (SPE) of TMQ was followed by highly sensitive ESI(+)-LC-MS-MS (ElectroSpray Ionization, positive mode - Liquid Chromatography - Mass Spectrometry - Mass Spectrometry); with a Limit of Detection (LOD) estimated at 1 pg/mL. Following IV administration, TMQ plasma levels peaked at 1 min at 707 pg/mL, and at 9 min at 306 pg/mL following IT administration. Our results show that TMQ plasma concentrations decline rapidly following IV administration, which is consistent with the fast onset and short duration of TMQ effect that was observed in our previous studies. On the other hand, IT administration showed a very unique plasma concentration pattern. From a regulatory standpoint, the current available TMQ ELISA kit was also used in an attempt to detect TMQ from the plasma and urine samples. We report that the ELISA kit was unable to detect TMQ from any of the samples generated in these studies.

Trimetoquinol: bronchodilator effects in horses with heaves following aerosolised and oral administration.

REASON FOR PERFORMING STUDY: The bronchodilator effects of trimetoquinol (TMQ) have been studied when administered i.v. or intratracheally, but not in an aerosolised form. OBJECTIVES: To define the relationship between the therapeutic and adverse responses (therapeutic index) of TMQ when administered as an aerosol or by the oral route. METHODS: Increasing doses of TMQ were administered to horses with heaves as an aerosol and by the oral route. Dose ranged 100-1000 microg/horse for aerosolised TMQ and from 6-60 microg/kg bwt for the oral route. Airway and cardiac effects were assessed by measurement of maximal change in pleural pressure (deltaPplmax) and heart rate (HR), respectively. Side effects of sweating, agitation and muscle trembling were scored subjectively. Duration of action of aerosolised (1000 pg/horse) and oral (6-60 microg/kg bwt) TMQ was evaluated over 6 h. RESULTS: Aerosol administration of TMQ caused dose-dependent bronchodilation but did not change HR or cause other observable side effects. When 1000 microg/horse was administered via aerosol, TMQ produced a 2-phase bronchodilation; an immediate effect lasting up to 30 min and a second phase between 2 and 4 h. Oral TMQ was therapeutically ineffective. CONCLUSION: Aerosol administration of TMQ is a safe and effective method of producing bronchodilation in horses.

Intravenous and intratracheal administration of trimetoquinol, a fast-acting short-lived bronchodilator in horses with 'heaves'.

REASON FOR PERFORMING STUDY: Trimetoquinol (TMQ) is a potent beta-adrenoceptor agonist bronchodilator used in human medicine but has not been evaluated for potential use as a therapeutic agent for horses with 'heaves'. OBJECTIVES: To assess the pharmacodynamics of TMQ in horses with 'heaves' to determine potential therapeutic effects. METHODS: Increasing doses of TMQ were administered to horses with 'heaves' by i.v. and intratracheal (i.t.) routes. Doses ranged 0.001-0.2 microg/kg bwt i.v. and 0.01-2 microg/kg bwt i.t. Cardiac and airways effects were assessed by measurement of heart rate (HR) and maximal change in pleural pressure (deltaPplmax), respectively. Side effects of sweating, agitation and muscle trembling were scored subjectively. Duration of action to i.v. (0.2 microg/kg bwt) and i.t. (2 microg/kg bwt) TMQ was evaluated over 6 h. RESULTS: Intravenous TMQ was an exceptionally potent cardiac stimulant. Heart rate increased at 0.01 microg/kg bwt, and was still increasing after administration of highest dose, 0.2 microg/kg bwt. Airway bronchodilation, measured as a decrease in deltaPplmax, also commenced at 0.01 microg/kg bwt. By the i.t. route, TMQ was 50-100-fold less potent than by i.v. Side effects included sweating, agitation and muscle trembling. Overall, the onset of HR and bronchodilator effects was rapid, within about 3 min, but effects were over at 2 h. CONCLUSION: When administered i.v. and i.t., TMQ is a highly potent cardiac stimulant and a modest bronchodilator. It may not be an appropriate pharmacological agent by i.v. and i.t. routes for the alleviation of signs in horses with 'heaves'. Further studies of TMQ by oral and aerosol routes are necessary. POTENTIAL RELEVANCE: In horses, TMQ is a fast-acting bronchodilator with a short duration of action. It could be used as a rescue agent during an episode of 'heaves'. The i.v. and i.t. administration of TMQ is associated with side effects, similar to those reported for all other beta-agonists. However, other routes, such as aerosol and oral, may prove useful and safe for the alleviation of bronchoconstriction typical of 'heaves'.

[Comparison of the bronchodilating effects of five beta-adrenergic stimulants administered by inhalation to patients with bronchial asthma].

The bronchodilating effects of 5 different beta-adrenergic stimulants, isoproterenol, salbutamol, trimetoquinol, orciprenaline and procaterol were examined in 28 same patients who were in a free period from asthmatic attack. Suitable broncho-constrictive conditions for the comparison of the bronchodilators were produced by having the patients inhale methacholine at the threshold dosage, which had been determined previously for each patient. FEV1 measurements were taken throughout the study. Salbutamol was found to be superior to isoproterenol, trimetoquinol and orciprenaline with respect to bronchodilation and its duration. Procaterol, however, showed a more prolonged effect than salbutamol, although the initial bronchodilation was less remarkable.

Pasaje transplacentario de betamiméticos / Transplacental transfer of 3H - Trimetoquinol

Cuatro grupos de ratas en el dia 19 de la gestación fueron injectadas con 3H-trimetoquinol (Inolin-R) intravenoso en dosis de 4,3 uCi/kg de peso (actividad específica 17.18 mCi/nM). Los 4 grupos de animales fueron sacrificados a diferentes intervalos post-inyección: 5, 15, 30 y 60 minutos respectivamente. Al cabo de dichos tiempos, se estudió la distribución de la droga en los tejidos maternos y fetales: hígado, pulmón, riñón, orina y plasma maternos, placenta, líquido amniótico, sangre e hígado fetales, importantes niveles de radiactividad fueron encontrados a nivel fetal, demostrando el pasaje placentario de la droga (AU)

Pasaje transplacentario de betamiméticos / Transplacental transfer of 3H - Trimetoquinol

Cuatro grupos de ratas en el dia 19 de la gestación fueron injectadas con 3H-trimetoquinol (Inolin-R) intravenoso en dosis de 4,3 uCi/kg de peso (actividad específica 17.18 mCi/nM). Los 4 grupos de animales fueron sacrificados a diferentes intervalos post-inyección: 5, 15, 30 y 60 minutos respectivamente. Al cabo de dichos tiempos, se estudió la distribución de la droga en los tejidos maternos y fetales: hígado, pulmón, riñón, orina y plasma maternos, placenta, líquido amniótico, sangre e hígado fetales, importantes niveles de radiactividad fueron encontrados a nivel fetal, demostrando el pasaje placentario de la droga

A new spirometric parameter in clinical pharmacology.

Several functional parameters can be used to define respiratory dysfunctions. Many of these variables provide specific information about particular physiopathologic phenomena, but they seldom provide a general overview of the ventilatory function. Nevertheless, both pharmacologic and epidemiologic research need functional parameters that precisely specify the respiratory defect. The new parameter we discuss takes into account the variations in volumes as related to flow variations: it is the product of two traditional spirometric parameters (FEV1 X MMEF). This value gives information on the patient's capacity to exhale air from the lungs for a fixed variation of intrathoracic pressure as well as data on the acceleration pattern of the expired volume in 1 s, hence the name, acceleration index (AI). AI was used to predict bronchodilation in two groups of patients with severe airway flow limitations. On the basis of our findings three conclusions can be drawn. This new spirometric parameter provides an inexpensive and rapid means of obtaining a highly sensitive definition of the patient's respiratory dysfunction which is useful in screening patients. Applied to patients with severe airways obstruction, AI can be used to immediately predict the reversibility of air flow limitation and then to define the limits of the activity of bronchodilators. Finally, a basal value of AI below 1.000 l/s-1 indicates the probable irreversibility of the airways obstruction, regardless of drug or route of administration. Such cases suggest a prevailing picture of emphysema rather than reversible bronchospasm.

[Comparative evaluation of the respiratory function and the acid-base equilibrium in patients with chronic bronchopulmonary disease after intravenous administration of 5 beta receptor agonists]. / Valutazione comparativa della funzione respiratoria e dell'equilibrio acido-base, in pazienti broncopneumopatici cronici sottoposti a somministrazione venosa di cinque farmaci beta2-stimolanti.

The Authors studied lung mechanics, acid-base balance parameters, arterial blood pressure and pulse rate in five different groups of chronic obstructive lung disease patients, undergoing e.v. different bronchodilators. The drug were: 1. group: 500 gamma of orciprenalina; 2. group: 500 gamma of idrossi-fenil-orciprenalina; 3. group: 200 gamma of salbutamolo; 4. group: 100 gamma of trimetochinolo; 5. group: 500 gamma of terbutalina. The comparative analysis of bronchodilators, their cardiovascular effects and on acid-base balance indicate that mainly salbutamol and trimetochinol have negligeable adverse effects.