The topic of drugs and horses encompasses the study of various pharmacological agents used in equine medicine for therapeutic purposes. This includes the administration of medications for pain management, disease treatment, and performance enhancement. The pharmacokinetics and pharmacodynamics of drugs in horses are key areas of research, as they determine the absorption, distribution, metabolism, and excretion of these substances. Additionally, the topic covers the detection and regulation of substances in competitive equestrian sports to ensure fair play and animal welfare. This page compiles peer-reviewed research studies and scholarly articles that explore the effects, safety, and regulatory aspects of drug use in equine health and performance.
Rubio-Martínez LM, López-Sanromán J, Cruz AM, Santos M, Andrés MS, Román FS.To evaluate clinical variables, regional concentrations, and pharmacokinetics of vancomycin in the synovial fluid of distal forelimb joints of horses after IV regional limb perfusion. Methods: 6 horses. Methods: Vancomycin was administered via IV regional limb perfusion to the distal portion of the forelimbs of anesthetized horses. Drug (300 mg of vancomycin hydrochloride in 60 mL of saline [0.9% NaCl] solution) was infused into 1 forelimb, whereas the contralateral limb served as a control and was perfused with 60 mL of saline solution. Solutions were injected into the lateral digital vein af...
Lasne F, Popot MA, Varlet-Marie E, Martin L, Martin JA, Bonnaire Y, Audran M, de Ceaurriz J.A direct detection method for anti-doping control of recombinant human erythropoietin (rHuEPO) abuse in racehorses is proposed. This method involves screening of plasma (or serum) by an enzyme-linked immunosorbent assay specific for human EPO and confirmation in urine samples by characterization of the urinary EPO isoelectric profile. This method was tested on horses that were administered epoetin alpha (rHuEPO) and the hyper-glycosylated form of this drug (darbepoetin alpha).
Scotty NC, Evans TJ, Giuliano E, Johnson PJ, Rottinghaus GE, Fothergill AW, Cutler TJ.Lufenuron is a benzoylphenyl urea-derived insecticide that has been recently introduced as a novel treatment for fungal infections in horses. The purposes of this study were to determine (1) the in vitro efficacy of lufenuron against Aspergillus and Fusarium spp. and (2) the ability of lufenuron to reach efficacious blood concentrations after PO administration in horses. Fungal colonies isolated from diseased equine corneas were tested against lufenuron solutions up to 700 microg/mL. Twenty-one adult horses received 1 of 3 PO lufenuron treatment regimens: 5 mg/kg body weight (BW) q24h for 3 da...
Lester GD, Smith RL, Robertson ID.To compare the effects of oral administration of omeprazole and ranitidine on gastric squamous ulceration in Thoroughbreds in race training. Methods: Modified crossover study. Methods: 60 Thoroughbreds in race training with gastric squamous mucosal ulceration. Methods: Horses were randomly allocated into 3 groups. Group 1 received no treatment for 28 days followed by administration of omeprazole (4 mg/kg [1.8 mg/lb], PO, once daily) for 28 days; group 2 received omeprazole (4 mg/kg, PO, once daily) for 28 days followed by no treatment for 28 days; and group 3 received ranitidine (6.6 mg/kg [3....
Slocombe JO.Aims of this study with 43 equids naturally infected with Anoplocephala perfoliata in two dose titration trials were to document (i) the usefulness of a critical test with a 48 h treatment to necropsy period, (ii) efficacy of an oral paste of 0.5-2.0 mg praziquantel/kg body weight, and (iii) when after treatment would fecal egg counts provide best estimates of the tapeworm's prevalence in a herd. All feces passed by an equid after treatment and collected in successive 12 h batches were examined for tapeworms. At necropsy, tapeworms were identified as attached to the mucosa or unattached. Tapew...
Davis JL, Salmon JH, Papich MG.To determine the pharmacokinetics of itraconazole after IV or oral administration of a solution or capsules to horses and to examine disposition of itraconazole in the interstitial fluid (ISF), aqueous humor, and polymorphonuclear leukocytes after oral administration of the solution. Methods: 6 healthy horses. Methods: Horses were administered itraconazole solution (5 mg/kg) by nasogastric tube, and samples of plasma, ISF, aqueous humor, and leukocytes were obtained. Horses were then administered itraconazole capsules (5 mg/kg), and plasma was obtained. Three horses were administered itraconaz...
Peroni JF, Moore JN, Noschka E, Grafton ME, Aceves-Avila M, Lewis SJ, Robertson TP.Equine laminitis is a crippling condition associated with a variety of systemic diseases. Although it is apparent that the prodromal stages of laminitis involve microvascular dysfunction, little is known regarding the physiology of this vasculature. The aim of the present study was to determine the relative responses of equine laminar arteries and veins to the vasoconstrictor agonists phenylephrine (1 nM-10 microM), 5-HT (1 nM-10 microM), PGF2alpha (1 nM-100 microM), and endothelin-1 (1 pM-1 microM). We have determined that laminar veins were more sensitive, with respect to the concentration o...
Mills PC, Cross SE.Commercial formulations of non-steroidal anti-inflammatory drugs (NSAIDs) are developed for human use but the extent to which they will pass through equine skin is unknown. Skin was harvested from five Thoroughbred geldings from the thorax, groin and leg (dorsal metacarpal) regions and frozen (-20 degrees C) until required. Two grams of methylsalicylate (MeSa) gel was applied to defrosted full-thickness samples in diffusion cells and the penetration of MeSa and its active metabolite, salicylate (Sa), through skin samples were measured over 24 h. Significantly higher (P < or = 0.02) total sa...
Schwarzwald CC, Bonagura JD, Luis-Fuentes V.Quinidine is effective for treatment of atrial fibrillation (AF) in horses, but often accelerates ventricular response rate. Diltiazem effectively controls heart rate response to AF in other species. This investigation determined the effects of diltiazem on cardiac rate and rhythm, left ventricular (LV) function, central hemodynamics, and peripheral blood flow in normal, standing, nonsedated horses. A dose-finding study was performed. Afterward, 8 healthy horses were treated with diltiazem IV every 30 minutes to achieve cumulative dosages of 0 (saline control), 1, 1.5, and 2 mg/kg. Plasma dilt...
Davis JL, Salmon JH, Papich MG.The purpose of this study was to determine the pharmacokinetics and tissue fluid distribution of cephalexin in the adult horse following oral and i.v. administration. Cephalexin hydrate (10 mg/kg) was administered to horses i.v. and plasma samples were collected. Following a washout period, cephalexin (30 mg/kg) was administered intragastrically. Plasma, interstitial fluid (ISF) aqueous humor, and urine samples were collected. All samples were analyzed by high-pressure liquid chromatography (HPLC). Following i.v. administration, cephalexin had a plasma half-life (t(1/2)) of 2.02 h and volume o...
Adams AR, Haines GR, Brown MP, Gronwall R, Merritt K.Pharmacokinetics of difloxacin and its distribution within the body fluids and endometrium of 6 mares were studied after intragastric (IG) administration of 5 individual doses. Difloxacin concentrations were serially measured in serum, urine, peritoneal fluid, synovial fluid, cerebrospinal fluid, and endometrium over 120 h. Bacterial susceptibility to difloxacin was determined for 174 equine pathogens over a 7-month period. Maximum serum concentration (Cmax) was 2.25 +/- 0.70 microg/mL at 3.12 +/- 2.63 h and Cmax after the 5th dose was 2.41 +/- 0.86 microg/mL at 97.86 +/- 1.45 h. The mean elim...
Gilmour MA, Clarke CR, Macallister CG, Dedeo JM, Caudell DL, Morton RJ, Pugh M.To investigate intraocular penetration of orally administered doxycycline in the normal equine eye and to compare intraocular and serum doxycycline concentrations. Procedures Six mares were administered doxycycline at 10 mg/kg every 12 h by nasogastric tube for 5 days. Blood, aqueous, and vitreous samples were collected on days 1 and 5. All samples were assayed for doxycycline concentrations. Aqueous and vitreous samples were also assayed for protein quantitation. Results: Doxycycline was rapidly absorbed after the first dose (T(max) value of 1.42 +/- 1.28 h); and elimination of doxycycline oc...
Sasaki N, Okamura K, Yamada H.To examine the effects of various doses of mosapride, a 5-hydroxytryptamine 4 receptor agonist, on motility of the small intestine and cecum in horses by use of electrical activity and to determine the dose that provides the optimal response. Methods: 6 healthy adult Thoroughbreds. Methods: Electrical activity of the small intestine and cecum was recorded before and after mosapride administration by use of an electrogastrograph. Mosapride (0.5, 1, 1.5, and 2 mg/kg) was dissolved in 200 mL of water and administered orally to horses through a nasogastric tube. Three hours after drug administrati...
Westermann CM, Laan TT, van Nieuwstadt RA, Bull S, Fink-Gremmels J.To determine whether treatment of horses with antitussive agents before bronchoalveolar lavage (BAL) reduces the frequency and intensity of the cough reflex during BAL. Methods: 8 healthy horses. Methods: Standard BAL was performed on each horse weekly for 6 weeks. Detomidine was used as a general sedative, and various antitussive agents were evaluated for their suitability to suppress undesirable coughing. Treatments administered prior to BAL consisted of saline (0.9% NaCl) solution (control treatment), codeine, butorphanol tartrate, glycopyrrolate, lidocaine hydrochloride (final concentratio...
Reepmeyer JC, Brower JF, Ye H.Equilin-3-sulfate and delta8,9-dehydroestrone-3-sulfate are two isomers found in equine conjugated estrogens that differ in structure only by the position of a double bond in the steroid B-ring. These geometric isomers were not resolved on a C18 column during the analysis of conjugated estrogen drug products by LC-MS using acetonitrile-ammonium acetate buffer as the mobile phase. While no separations of these two isomers were observed on C18 or other alkyl-bonded silica based phases using a variety of mobile phase conditions, partial separations were achieved on phenyl bonded silica phases wit...
Orsini JA, Moate PJ, Boston RC, Norman T, Engiles J, Benson CE, Poppenga R.In two studies, six healthy adult horses were given imipenem-cilastatin by slow intravenous (i.v.) infusion at an imipenem dosage of 10 mg/kg (study 1) and 20 mg/kg (study 2). The same horses were used in each dosage schedule, with a 2-week washout period between studies. In each dosage group, serial blood and synovial fluid samples were collected for 6 h after completion of the infusion. HPLC was used to determine the imipenem concentration in all samples. Imipenem was well tolerated by all horses at both dosages; no adverse effects were noted during the study period or during the 24-hour pos...
Müntener CR, Gassner B, Demuth DC, Althaus FR, Zwahlen R.We received 62 reports of suspected adverse events (SARs) for the year 2004. Their number and repartition according to affected animals and active substances were comparable with the previous year. The distributors or manufacturers submitted most of the declarations, but the proportion submitted by practicing veterinarians is slowly growing. 72% of the declarations dealt with adverse reactions in small animals (cats and dogs), followed by cattle and horses. Antiparasitics, anti-inflammatory drugs and immunologicals were the most frequently mentioned therapeutic classes, which are listed here a...
van Hoogmoed LM, Boscan PL.Although potent analgesics, opioids decrease intestinal activity, leading to ileus in many species. N-methylnaltrexone (MNTX), an opioid antagonist which does not cross the blood-brain barrier and antagonises the morphine effect on the intestine, directly stimulates motility and restores function without affecting analgesic properties. While its use has been reported in human subjects, there is no information with regard to its usage in the horse. Objective: To determine whether MNTX has an effect on contractile activity of the equine jejunum and pelvic flexure. Methods: Using circular smooth ...
Ryan CA, Sanchez LC, Giguère S, Vickroy T.Proton pump inhibitors (PPIs) are a mainstay of treatment for acid-related ulceration in man and horses. Currently, only an oral preparation of omeprazole is approved for use in horses in the USA. Intravenous administration of a PPI would provide a useful therapeutic alternative for those foals in which oral medication is not feasible. Objective: To investigate the pharmacokinetics and pharmacodynamics of pantoprazole following i.v. or intragastric administration in healthy neonatal foals. Methods: Seven healthy foals age 6-12 days at the start of the study were evaluated. Treatments included ...
Sykes BW, Furr MO.The pathophysiology of endotoxaemia, a leading cause of death in the horse, is beginning to be understood in greater detail. Endotoxin may be absorbed into the systemic circulation in a number of different ways: most commonly the body's normal defense mechanisms are disrupted or bypassed, or the normal clearance mechanisms overwhelmed. Following this wide-spread effects are observed, although the most significant are seen in the cardiovascular system. Fever, arterial hypoxaemia and signs of abdominal pain are also common. With increased understanding of the disease new therapeutic agents have ...
Derossi R, Miguel GL, Frazílio FO, Nunes DB, Kassab TA.Bupivacaine is available as a racemic mixture of its enantiomers, d-bupivacaine and l-bupivacaine (LB). The aim of this randomized, double-blind study was to investigate the clinical efficacy and safety of S(-)-bupivacaine compared with standard racemic bupivacaine (RB) in horses under caudal epidural analgesia. Two treatments were administered to each horse, with a 2-week interval between subsequent treatments. Treatment 1 consisted of 0.5% LB at a dose of 0.06 mg/kg of body weight, and treatment 2 consisted of 0.5% RB at a dose of 0.06 mg/kg of body weight. Epidural injections were given in ...
Beretta C, Garavaglia G, Cavalli M.We report on the inhibitory activity of the NSAIDs meloxicam, carprofen, phenylbutazone and flunixin, on blood cyclooxygenases in the horse using in vitro enzyme-linked assays. As expected, comparison of IC50 indicated that meloxicam and carprofen are more selective inhibitors of COX-2 than phenylbutazone and flunixin; meloxicam was the most advantageous for horses of four NSAIDs examined. However at IC80, phenylbutazone (+134.4%) and flunixin (+29.7%) had greater COX-2 selectivity than at IC50, and meloxicam (-41.2%) and carprofen (-12.9%) had lower COX-2 selectivity than at IC50. We therefor...
McClure SR, White GW, Sifferman RL, Bernard W, Doucet MY, Vrins A, Holste JE, Fleishman C, Alva R, Cramer LG.To determine the minimal effective dosage of omeprazole oral paste for the prevention of naturally occurring ulcers in horses starting race training. Methods: Prospective study. Methods: 175 horses. Methods: Horses in the dose selection portion of the study were sham dose treated or received 1 mg (0.45 mg/lb) or 2 mg (0.9 mg/lb) of omeprazole/kg, PO, every 24 hours for 28 days or 4 mg of omeprazole/kg (1.8 mg/lb; loading dose), PO, every 24 hours for 4 days, then 1 or 2 mg of omeprazole/kg, PO, every 24 hours for 24 days. Horses in the dose confirmation portion of the study were sham dose trea...
Anderson D, Kollias-Baker C, Colahan P, Keene RO, Lynn RC, Hepler DI.The liposomal cream formulation of diclofenac, an NSAID, is an effective, safe, and convenient way to treat localized areas of inflammation in horses. The results of this study reveal urinary and serum concentrations of diclofenac following topical administration of 1% liposomal diclofenac cream for 10 days at the labeled dose and at 2X and 4X the labeled dose. These results demonstrate the slow absorption and elimination of 1% liposomal diclofenac cream and may be useful when estimating the withdrawal time needed before a competition in order to prevent an inadvertent positive drug test.
Steffey EP, Woliner MJ, Puschner B, Galey FD.To quantitate the effects of desflurane and mode of ventilation on cardiovascular and respiratory functions and identify changes in selected clinicopathologic variables and serum fluoride values associated with desflurane anesthesia in horses. Methods: 6 healthy adult horses. Methods: Horses were anesthetized on 2 occasions: first, to determine the minimum alveolar concentration (MAC) of desflurane in O2 and second, to characterize cardiopulmonary and clinicopathologic responses to 1X, 1.5X, and 1.75X desflurane MAC during both controlled and spontaneous ventilation. Results: Mean +/- SEM MAC ...
Sánchez Bruni SF, Fusé LA, Moreno L, Saumell CA, Alvarez LI, Fiel C, McKellar QA, Lanusse CE.The study of novel pharmacological strategies to control parasitism in horses is required since many parasite species have developed resistance to anthelmintic drugs. Objective: To evaluate the effects of piperonyl butoxide (PB) (a metabolic inhibitor) on the plasma availability and enantiomeric behaviour of oxfendazole (OFZ) given orally to horses, and to compare the clinical efficacy of OFZ given either alone or co-administered with PB in naturally parasitised horses. Methods: Fifteen naturally parasitised crossbred male ponies were allocated into 3 groups (n = 5) and treated orally as follo...
Atwal OS, McDonell W.The pulmonary intravascular macrophages (PIMs) of equines contain a unique electron-dense surface coat that is predominantly composed of lipoproteins. A single exposure of inhalatory halothane causes mobilization of the surface coat into the endocytotic system of the PIMs, followed by expansion of the Golgi apparatus and its enrichment with acid phosphatase. Simultaneously, the cells of the lymphocytic series show hyperplasia in the form of mitotic changes inside the microvascular compartment of the lung. Halothane is known to cause acute and chronic hepatotoxicity because of its biotransforma...
Yu NH, Ho EN, Leung DK, Wan TS.Anabolic steroids have the capability of improving athletic performance and are banned substances in the Olympic games as well as in horseracing and equestrian competitions. The control of their abuse in racehorses is traditionally performed by detecting the presence of anabolic steroids and/or their metabolite(s) in urine samples using gas chromatography-mass spectrometry (GC-MS). However, this approach usually requires tedious sample processing and chemical derivatisation steps and could be very insensitive in detecting certain steroids. This paper describes a high performance liquid chromat...
McKinney AR, Suann CJ, Stenhouse AM.A method has been developed for the detection of modafinil and its major metabolite, modafinil acid, in equine urine by solid-phase extraction and positive ion electrospray ionisation liquid chromatography/mass spectrometry. The method has been applied to the analysis of equine urine samples obtained after the oral administration of modafinil. Modafinil acid was the major component in the urine, and was detected up to 4 days post-administration. Unchanged modafinil was present at substantially lower concentrations, and was detected for only 24 hours.
Beaudry F, Lavoie JP, Vachon P.A rapid and selective method has been developed for the determination of theophylline in horse serum by LC-ESI/MS/MS. The analytical method includes a protein precipitation extraction for sample preparation, liquid chromatography separation technique and ionspray tandem mass spectrometry. The drug was extracted from serum using a protein precipitation with acetonitrile and the supernatants were analyzed using an LC-ESI/MS/MS instrument. The chromatography was performed using a 50 x 2.1 mm C(8) analytical column and an isocratic mobile phase composes of 60:40 acetonitrile-0.5% formic acid in wa...
Aleman M, Davis E, Knych H, Guedes A, Smith F, Madigan JE.Intrathecal lidocaine hydrochloride under general anesthesia has been used as an alternative method of euthanasia in equids. Carnivore, scavenger, and even human consumption of horse meat from carcasses have been anecdotally reported in rural areas after this method of euthanasia. The presence of drug residues in horse meat has not been investigated. Objective: To investigate if drug residues are found in horse tissues and determine their concentrations. Methods: Of 11 horses requiring euthanasia for medical reasons. Methods: Prospective descriptive study. Horses were anesthetized with total I...
Rumpler MJ, Colahan P, Sams RA.A simple LC/MSMS method has been developed and fully validated to determine concentrations and characterize the concentration vs. time course of methocarbamol (MCBL) and guaifenesin (GGE) in plasma after a single intravenous dose and multiple oral dose administrations of MCBL to conditioned Thoroughbred horses. The plasma concentration-time profiles for MCBL after a single intravenous dose of 15 mg/kg of MCBL were best described by a three-compartment model. Mean extrapolated peak (C0 ) plasma concentrations were 23.2 (± 5.93) μg/mL. Terminal half-life, volume of distribution at steady-state...
Yamashita K, Yonezawa K, Izumisawa Y, Kotani T.The antagonistic effects of atipamezole (20, 40, 60, 80, and 100 micrograms/kg i.v.) on medetomidine (10 micrograms/kg i.v.)-induced sedation were evaluated in horses. Although 20 and 40 micrograms/kg of atipamezole were not sufficient to reverse the sedation, 60 micrograms/kg did effectively reverse the sedation. Atipamezole at 80 micrograms/kg was more potent, and significantly shortened the duration of sedation without any apparent side effects, but a higher dose of 100 micrograms/kg was not more effective than 80 micrograms/kg. The possible use of atipamezole as a reversal agent may enhanc...
Hubenov H, Bakalov D, Krastev S, Yanev S, Haritova A, Lashev L.The objective of the study was to evaluate the pharmacokinetics of tobramycin in plasma and urine in the horse (n = 7) after intravenous administration of a dose of 4 mg/kg b.w. Plasma tobramycin concentrations were assayed microbiologically and by means of HPLC analyses. Pharmacokinetic parameters, calculated on the basis of concentrations determined with the microbiological assay were not statistically different from those obtained when data from HPLC analysis were used, but the microbiological assay was more sensitive in the detection of low plasma and urine values. The values of the total ...
Schelling CG, Klein LV.A double-blind comparison of carbonated lidocaine and lidocaine hydrochloride in caudal epidural anesthesia was performed in 8 horses. Among 5 horses with successfully paired bilateral caudal epidural blockades, no significant differences in onset time, duration, or sensory blockade were demonstrated. In the present study, carbonated lidocaine did not offer an advantage over the hydrochloride salt for caudal epidural anesthesia in the horse.
Derksen FJ, Olszewski M, Robinson NE, Berney C, Lloyd JW, Hakala J, Matson C, Ruth D.Aerosol administration of bronchodilators to horses is recommended for treatment of certain airway diseases such as 'heaves'. We have developed a novel, hand-held, metered-dose inhaler and we sought to determine the bronchodilator efficacy of the beta 2 adrenoceptor agonist pirbuterol delivered by this device to horses affected with 'heaves'. To induce airway obstruction, 6 heaves-susceptible horses were stabled, bedded on straw and fed hay. When the maximum change in pleural pressure during tidal breathing (delta Pplmax) was greater than 20 cmH2O on 2 consecutive days, pulmonary function was ...
Lehner AF, Stewart J, Dafalla A, Ely KJ, Connerly AL, Jones CN, ElkHoly H, Thompson K, Tobin T, Dirikolu L.Gabapentin [1-(aminomethyl)cyclohexaneacetic acid, Neurontin], is a new anticonvulsant used as adjunctive therapy in the treatment of partial seizures in humans not controlled with standard antiseizure drugs, and it has also been used in veterinary medicine. In performance horses, gabapentin is listed as a class 3 performance-enhancing substance by the Association of Racing Commissioners International, and thus is considered to have the potential to influence the outcome of races. Therefore, we developed and validated a sensitive gas chromatographic-mass spectrometric (GC-MS) method for gabape...
Knych HK, Arthur RM, Kanarr KL, McKemie DS, Kass PH.Methamphetamine is a central and peripheral nervous system stimulant. There is only a single study that describes exposure to and disposition of this compound in horses. The potential for abuse and inadvertent exposure in equine athletes along with the limited data available necessitates further study. The objectives of the current study were to describe drug and metabolite concentrations, develop an analytical method that could be used to regulate its use, and describe selected pharmacodynamic effects. In phase 1, six horses were randomized into three transmucosal dose groups (n = 2/group; ...
Lynn RC, Hepler DI, Kelch WJ, Bertone JJ, Smith BL, Vatistas NJ.A topical 1% diclofenac liposomal cream proved to be safe, easy to use, and effective in reducing equine lameness caused by degenerative joint disease. Diclofenac liposomal cream was shown to reduce lameness as graded by owners and veterinarians, regardless of the severity or chronicity of the clinical condition. Topical application allowed for more convenient administration than oral or injectable agents, and no clinically relevant hematologic or serum biochemical changes were noted. The liposomal cream provided a delivery system for diclofenac, an NSAID, to achieve therapeutic levels locally...
Ingle-Fehr JE, Baxter GM.To quantitate blood flow in the palmar digital artery and dorsal laminae of the hoof in standing, unmedicated, nonsedated horses, and in horses treated with oral isoxsuprine, oral pentoxifylline, and intravenous acetylpromazine as a positive control. Methods: Experimental study; treatments administered in a random cross-over design. Methods: A total of 6 healthy horses selected with at least one nonpigmented forelimb hoof wall and determined to be free of laminitis. Methods: All horses were instrumented with a flow probe placed around one palmar digital artery under general anesthesia and a la...
Gillen AM, Munsterman AS, Reid Hanson R. To report the outcomes of horses with suspected nephrosplenic entrapment (NSE) of the large colon treated by IV phenylephrine administration and exercise with and without trocarization (ie, medical management). Retrospective, observational study. 134 horses. Electronic medical records were searched to identify horses that underwent medical management for suspected NSE at a veterinary teaching hospital between 1995 and 2014. Demographic information, physical and ultrasonographic examination findings, treatment information (including the number of times the treatment was performed and patien...