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Given the potential for long-term inhibition of bone remodeling/healing and detrimental effects to horses in training, bisphosphonates are tightly regulated in horseracing. Hair has proven to be an effective matrix for detection of drug administration to horses and has been particularly effective in detecting drugs for a long period of time post administration. Thus, hair may prove to be a useful matrix for detection of administration of this class of drugs. The objective of the current study was to develop an assay and assess the usefulness of hair as a matrix for long-term detection of clodronate to horses. Seven horses received a single intramuscular administration of 1.8 mg/kg clodronate. Hair samples were collected prior to and up to 6 months post administration. A liquid chromatography-tandem mass spectrometry method was developed and concentrations of clodronate measured in hair samples. The drug was first detected on day 7 in 4/7 horses, and on days 14, 28 and 35 in the remaining three horses. In 4/7 horses, clodronate was still detectable 6 months post administration. Results of this study demonstrate that, although there was significant inter-individual variability in detection times (63 to 180 days) and several intermediate times where the drug could not be detected but was subsequently detected in later timepoints, clodronate administration was detectable in hair for a prolonged period in most of the horses (4/7) studied., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

During the latter half of gestation in mares, there is a complex milieu of pregnanes in peripheral blood. Progesterone concentrations are often assessed by immunoassay during late gestation as a measure of pregnancy well-being; however, interpretation of results is complicated by the numerous cross-reacting pregnanes present in high concentrations during late gestation. Further, many mares are supplemented with an exogenous progestin, altrenogest, which may also cross-react with existing assays and further confound interpretation. The objectives of this study were: 1) to compare differences in pregnane concentrations determined with four immunoassays compared to LC-MS/MS and 2) to assess cross-reactivity observed with the same immunoassays, specifically considering pregnenolone (P5), progesterone (P4), 5α-dihydroprogesterone (DHP), allopregnanolone, and altrenogest. Blood samples from four healthy mares in late gestation were evaluated by immunoassay and by LC-MS/MS. Measured immuno-reactive progesterone (ir-progesterone) concentrations differed (p < 0.0001) between immunoassays, although results were highly correlated (r = 0.85-1.0; p < 0.001). Measured ir-progesterone concentrations by immunoassay were linearly associated (r 2  = 0.68-0.76; p < 0.001) with concentrations of P5, P4, DHP, and allopregnanolone determined by LC-MS/MS. There was no detectable cross-reaction of altrenogest in any immunoassay, but varying degrees of cross-reactivity was observed with other pregnanes analyzed. These data confirm ir-progesterone concentrations during late gestation vary depending upon the assay used and the cross-reactivity to other pregnanes present in late gestation, although the synthetic progestin altrenogest did not affect the results of any immunoassay tested., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To describe the effects of alpha2 -adrenergic receptor antagonists on the pharmacodynamics of sublingual (SL) detomidine in the horse., Study Design: Randomized crossover design., Animals: Nine healthy adult horses with an average age of 7.6 ± 6.5 years., Methods: Four treatment groups were studied: 1) 0.04 mg kg(-1) detomidine SL; 2) 0.04 mg kg(-1) detomidine SL followed 1 hour later by 0.075 mg kg(-1) yohimbine intravenously (IV); 3) 0.04 mg kg(-1) detomidine SL followed 1 hour later by 4 mg kg(-1) tolazoline IV; and 4) 0.04 mg kg(-1) detomidine SL followed 1 hour later by 0.12 mg kg(-1) atipamezole IV. Each horse received all treatments with a minimum of 1 week between treatments. Blood samples were obtained and plasma analyzed for yohimbine, atipamezole and tolazoline concentrations by liquid chromatography-mass spectrometry. Behavioral effects, heart rate and rhythm, glucose, packed cell volume (PCV) and plasma proteins were monitored., Results: Chin-to-ground distance increased following administration of the antagonists, however, this effect was transient, with a return to pre-reversal values as early as 1 hour. Detomidine induced bradycardia and increased incidence of atrioventricular blocks were either transiently or incompletely antagonized by all antagonists. PCV and glucose concentrations increased with tolazoline administration, and atipamezole subjectively increased urination frequency but not volume., Conclusions and Clinical Relevance: At the doses administered in this study, the alpha2 -adrenergic antagonistic effects of tolazoline, yohimbine and atipamezole on cardiac and behavioral effects elicited by SL administration of detomidine are transient and incomplete., (© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.)

A method for the detection and quantitation of 35 endogenous steroids in equine serum was developed and validated. Androgens, estrogens, progestins and their metabolites potentially present in serum were simultaneously monitored in one method using on-line sample extraction by turbulent flow chromatography (TFC) on a 2-dimensional liquid chromatography system and detected on a triple-stage quadrupole mass spectrometer by electrospray ionization. Analytes were detected and quantitated by single-reaction monitoring or selected-ion monitoring. Limits of detection (range 0.025-10 ng mL(-1)) and quantitation (range 0.125-25 ng mL(-1)) along with recovery and matrix effects were determined for each analyte. Inter- and intra-day accuracy and precision was assessed for with the majority of analytes having %CV less than 20% and accuracy within 20% of the expected concentrations. Eight of the 35 analytes were unable to meet these guidelines across all of the quality control concentrations monitored for each analyte. This method was used to determine the endogenous steroid profiles of Thoroughbred horses and has been modified for use in non-human primates and cell culture., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: To describe the pharmacokinetics of detomidine and yohimbine when administered in combination., Study Design: Randomized crossover design., Animals: Nine healthy adult horses aged 9 ± 4 years and weighing of 561 ± 56 kg., Methods: Three dose regimens were employed in the current study. 1) 0.03 mg kg(-1) detomidine IV (D), 2) 0.2 mg kg(-1) yohimbine IV (Y) and 3) 0.03 mg kg(-1) detomidine IV followed 15 minutes later by 0.2 mg kg(-1) yohimbine IV (DY). Each horse received all three dose regimens with a minimum of 1 week in between subsequent regimens. Blood samples were obtained and plasma analyzed for detomidine and yohimbine concentrations by liquid chromatography-mass spectrometry. Data were analyzed using both non-compartmental and compartmental analysis., Results: The maximum measured detomidine concentrations were 76.0 and 129.9 ng mL(-1) for the D and DY treatments, respectively. Systemic clearance and volume of distribution of detomidine were not significantly different for either treatment. There was a significant increase in the maximum measured yohimbine plasma concentrations from Y (173.9 ng mL(-1)) to DY (289.8 ng mL(-1)). Both the Cl and V(d) for yohimbine were significantly less (6.8 mL minute(-1) kg(-1) (Cl) and 1.7 L kg(-1) (V(d) )) for the DY as compared to the Y treatments (13.9 mL minute(-1) kg(-1) (Cl) and 2.7 L kg(-1) (V(d))). Plasma concentrations were below the limit of quantitation (0.05 and 0.5 ng mL(-1)) by 18 hours for both detomidine and yohimbine., Conclusion and Clinical Relevance: The Cl and V(d) of yohimbine were affected by prior administration of detomidine. The elimination half life of yohimbine remained unaffected when administered subsequent to detomidine. However, the increased plasma concentrations in the presence of detomidine has the potential to cause untoward effects and therefore further studies to assess the physiologic effects of this combination of drugs are warranted., (© 2012 The Authors. Veterinary Anaesthesia and Analgesia. © 2012 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.)

Objective: To describe the pharmacodynamics and pharmacokinetics following an intravenous (IV) bolus dose of medetomidine in the horse., Study Design: Prospective experimental trial., Animals: Eight, mature healthy horses age 11.7 ± 4.6 (mean ± SD) years, weighing 557 ± 54 kg., Methods: Medetomidine (10 μg kg(-1) ) was administered IV. Blood was sampled at fixed time points from before drug administration to 48 hours post administration. Behavioral, physiological and biochemical data were obtained at predetermined time points from 0 minutes to 24 hours post administration. An algometer was also used to measure threshold responses to noxious stimuli. Medetomidine concentrations were determined by liquid chromatography-Mass Spectrometry and used for calculation of pharmacokinetic parameters using noncompartmental and compartmental analysis., Results: Pharmacokinetic analysis estimated that medetomidine peaked (8.86 ± 3.87 ng mL(-1) ) at 6.4 ± 2.7 minutes following administration and was last detected at 165 ± 77 minutes post administration. Medetomidine had a clearance of 39.6 ± 14.6 mL kg(-1) minute(-1) and a volume of distribution of 1854 ± 565 mL kg(-1). The elimination half-life was 29.1 ± 12.5 minutes. Glucose concentration reached a maximum of 176 ± 46 mg dL(-1) approximately 1 hour post administration. Decreased heart rate, respiratory rate, borborygmi, packed cell volume, and total protein concentration were observed following administration. Horses lowered their heads from 107 ± 12 to 20 ± 10 cm within 10 minutes of drug administration and gradually returned to normal. Horse mobility decreased after drug administration. An increased mechanical threshold was present from 10 to 45 minutes and horses were less responsive to sound., Conclusion and Clinical Relevance: Behavioral and physiological effects following intravenous administration positively correlate with pharmacokinetic profiles from plasma medetomidine concentrations. Glucose concentration gradually transiently increased following medetomidine administration. The analgesic effect of the drug appeared to have a very short duration., (© 2011 The Authors. Veterinary Anaesthesia and Analgesia. © 2011 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.)

Objective: To characterize the hemodynamic effects of dexmedetomidine in isoflurane-anesthetized cats., Study Design: Prospective experimental study., Animals: Six healthy adult female cats weighing 4.6 ± 0.8 kg., Methods: Dexmedetomidine was administered intravenously using target-controlled infusions to maintain nine plasma concentrations between 0 and 20 ng mL(-1) in isoflurane-anesthetized cats. The isoflurane concentration was adjusted for each dexmedetomidine concentration to maintain the equivalent of 1.25 times the minimum alveolar concentration, based on a previous study. Heart rate, systemic and pulmonary arterial pressures, central venous pressure, pulmonary artery occlusion pressure, body temperature, and cardiac output were measured at each target plasma dexmedetomidine concentration. Additional variables were calculated. Arterial and mixed-venous blood samples were collected for blood gas, pH, and (on arterial blood only) electrolyte, glucose and lactate analysis. Plasma dexmedetomidine concentration was determined for each target. Pharmacodynamic models were fitted to the data., Results: Heart rate, arterial pH, arterial bicarbonate concentration, mixed-venous PO(2) , mixed-venous pH, mixed-venous hemoglobin oxygen saturation, cardiac index, stroke index, and venous admixture decreased following dexmedetomidine administration. Arterial blood pressure, central venous pressure, pulmonary arterial pressure, pulmonary arterial occlusion pressure, packed cell volume, PaO(2) , PaCO(2) , arterial hemoglobin concentration, mixed-venous PCO(2) , mixed-venous hemoglobin concentration, ionized calcium concentration, glucose concentration, rate-pressure product, systemic and pulmonary vascular resistance indices, left ventricular stroke work index, arterial oxygen concentration, and oxygen extraction increased following dexmedetomidine administration. Most variables changed in a dexmedetomidine concentration-dependent manner., Conclusion and Clinical Relevance: The use of dexmedetomidine as an anesthetic adjunct is expected to produce greater negative hemodynamic effects than a higher, equipotent concentration of isoflurane alone., (© 2011 The Authors. Veterinary Anaesthesia and Analgesia. © 2011 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.)

Anti-Müllerian hormone (AMH), a member of the transforming growth factor β superfamily of growth and differentiation factors, is expressed in granulosa cells of preantral and small antral ovarian follicles. In humans, AMH appeared to regulate recruitment and growth of small ovarian follicles. Furthermore, circulating AMH concentrations were elevated in women with granulosa-cell tumors (GCT). In the horse, GCTs are the most common tumor of the ovary, and a variety of endocrine assays have been used to diagnose presumptive GCTs. The objectives of the present study were to validate a heterologous enzyme immunoassay for determination of serum AMH in the horse, and to determine concentrations of AMH in the blood of mares during the estrous cycle, pregnancy, and in mares with granulosa-cell tumors. Mares with normal estrous cycles (n = 6) and pregnant mares (n = 6) had blood samples collected throughout one interovulatory period and monthly throughout gestation, respectively. Mares diagnosed with GCT had blood samples taken before (n = 11) and after ovariectomy (n = 5). Tumors were sectioned and fixed for immunohistochemistry and snap frozen for immunoblot analyses and RT-qPCR. In normal cyclic mares and in pregnant mares, there was no effect of cycle stage or month of gestation on serum AMH concentrations. In GCT mares, serum concentrations of AMH (1901.4 ± 1144.6 ng/mL) were higher than those in cyclic (0.96 ± 0.08 ng/mL) or pregnant (0.72 ± 0.05 ng/mL) mares and decreased after tumor removal. Both AMH and AMH receptor (AMHR2) immunolabeling and expression were detected by immunohistochemistry in the tumor and cyst fluid obtained from mares with GCTs. Therefore, we concluded that AMH was a useful biomarker for detection of granulosa-cell tumors in mares., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To characterize cardiovascular, respiratory and biochemical effects and recovery behavior associated with a 3-hour continuous infusion of a micellar microemulsion propofol formulation in horses., Study Design: Prospective experimental trial., Animals: Six healthy adult horses, 9 +/- 2 years old and weighing 557 +/- 14 kg., Methods: All horses received xylazine (1 mg kg(-1), IV) 5 minutes prior to anesthetic induction. Each horse was anesthetized on two occasions with a 5% micellar microemulsion propofol formulation (2 mg kg(-1), IV); first as a single bolus (phase I) and then as a 3-hour continuous infusion (phase II). Propofol pharmacokinetics were obtained from phase I and used to determine the starting infusion rates in phase II. Anesthetic induction and recovery characteristics were quantitatively and qualitatively assessed. Cardiovascular, respiratory and biochemical parameters were monitored during anesthesia and recovery., Results: Induction quality varied, ranging from good to poor. Standing and overall recovery quality scores were consistently excellent in phase I but more variability was observed among horses in phase II. Heart rate (HR) and mean arterial pressure (MAP) were adequately maintained but marked hypoventilation developed. There were only minimal changes in blood biochemical analytes following anesthesia., Conclusions and Clinical Relevance: The micellar microemulsion propofol formulation, administered as a 3-hour continuous infusion, showed similar results compared to those previously described with a commercially available propofol preparation. However, based on present findings, use of propofol as a primary anesthetic in horses for prolonged periods of anesthesia requires further study to determine the limits of safety and clinical applicability.

Background: To define the pharmacokinetic profile of propofol 5% microemulsion formulation in horses., Methods: First, propofol was administered as bolus injection (2 mg kg(-1)) to six xylazine-sedated horses. Secondly, after sedation and bolus injection, propofol was maintained with continuous infusion for 3 h [8.1 (sd 3.2) mg kg(-1) h(-1)] to the same six horses. Thirdly, in two horses, a commercial propofol was used for comparison. Response to noxious stimulation was used to evaluate analgesia. Venous blood samples were obtained to measure propofol plasma concentration using liquid chromatography-mass spectrometry analysis. The plasma concentrations were related to the anaesthesia characteristics to determine the ED(50)., Results: The pharmacokinetic profile of propofol is best characterized by a non-compartmental model. The mean (confidence interval) for area under plasma concentration-time curve, elimination half-life, mean residence time, and clearance was 41 min microg ml(-1) (+/-7.7), 44.8 min (+/-21.3), 13.7 min (+/-3.2), and 45.8 ml min(-1) kg(-1) (+/-6.5), respectively. Linear regression analysis showed a correlation between plasma concentration and infusion rate (r(2)=0.47). Most propofol infusion rates did not inhibit the response to noxious stimulation and rates above 11.9 mg kg(-1) h(-1) caused involuntary muscle contractions. Better recoveries were associated with lower propofol plasma concentrations. Propofol plasma concentration frequently increased when horses woke from anaesthesia., Conclusions: Caution is warranted when propofol is used for continuous infusion due to variable kinetics, myoclonal activity, poor analgesia, and less desirable recovery quality.

Substantial gaps exist in our knowledge of the metabolic clearance of therapeutic agents in horses. Accordingly, a cytochrome P450 monooxygenase in the 2C family was cloned from an equine liver, sequenced and expressed in a baculovirus expression system. Catalytic activities of the recombinant protein were measured with a number of substrates. The protein, assigned CYP2C92, displayed optimal catalytic activity with diclofenac using molar ratios of CYP2C92 to NADPH CYP450 reductase of 1:18. Addition of cytochrome b(5) to diclofenac incubations had no significant effect on metabolic turnover. CYP2C92 catalyzed diclofenac metabolism was 20-fold slower than the human counterpart, CYP2C9. CYP2C92 demonstrated comparable tolbutamide and (S)-warfarin hydroxylase activity compared to CYP2C9, upon addition of b(5) to the reactions. The results of this study demonstrate substantial interspecies differences in metabolism of substrates by CYP2C orthologues in the horse and human and support the need to fully characterize this enzyme system in equids.

Objective: To characterize the pharmacokinetics of fentanyl and the tolerance of foals to the drug following a single application of a commercially available transdermal system (TS)., Study Design: Prospective experimental study., Animals: Six (two male, four female) foals aged 4-8 days, weighing 56-74 kg., Methods: After placement of a jugular sampling catheter, one fentanyl TS (FTS) containing 10.2 mg fentanyl, released at 100 microg hour(-1), was applied for 72 hours. Blood samples were withdrawn over the course of 90 hours for fentanyl plasma analysis. Before and after the study, weight, complete blood count and blood chemistry values were obtained. During the study, tolerance and safety were monitored by physical examination and assessment of behavior., Results: Fentanyl was detected as early as 20 minutes after FTS placement. Peak plasma concentrations were variable (0.1-28.7 ng mL(-1)), were reached after 14.3 +/- 7.6 hours (mean +/- SD), and returned to baseline concentrations 12 hours after FTS removal. All foals satisfactorily tolerated the FTS application and no significant adverse effects were observed. Rectal temperature increased above 38.5 degrees C (max. 39.0 degrees C) in all foals, although this did not correlate with fentanyl plasma concentrations. Results of hematological and biochemical analyses were within reference ranges., Conclusion and Clinical Relevance: Our data show that 100 microg hour(-1) fentanyl administered by an FTS results in time-related but variable plasma concentrations in foals. The FTS was easy to apply and was well tolerated.

Objective: To compare the density and binding characteristics of opioid receptor subtypes in horse, rat, and guinea pig cerebral cortex and cerebellum., Study Design: Prospective receptor binding study., Animals: Whole brains were obtained from four neurologically normal adult horses during necropsy. Rat and guinea pig brains were obtained commercially., Methods: The cerebellum and cerebral cortex were dissected from each brain, and tissue homogenates prepared. A radioligand binding technique with the highly selective ligands [(3)H]-DAMGO, [(3)H]-U69593, and [(3)H]-DPDPE was used to identify the mu- (mu), kappa- (kappa) and delta- (delta) opioid receptors, respectively. Competitive binding assays were performed with these ligands and varying concentrations of one of multiple unlabeled ligands., Results: While there were marked species differences in relative densities of opioid receptors, all radioligands interacted with their binding sites with high, nanomolar affinity in both the cerebral cortex and cerebellum. In the horse cerebral cortex, the percentages of total opioid binding sites for the mu-, kappa- and delta-receptors were 71%, 14% and 15%, respectively. In the rat and guinea pig cerebral cortex, the corresponding values were 56% mu-, 4% kappa- and 40% delta-receptors, and 25% mu-, 37% kappa- and 38% delta-receptors, respectively. In horse and guinea pig cerebellum, the binding was 37% mu-, 59% kappa- and 4% delta-receptors, and 15% mu-, 76% kappa- and 10% delta-receptors, respectively. For competitive analysis, all competitors of the mu-, kappa- and delta-receptors completely displaced [(3)H]-DAMGO, [(3)H]-U69593, and [(3)H]-DPDPE and had inhibitory constants in the nanomolar range., Conclusion and Clinical Relevance: Horses used in this study had a greater density of mu-receptors in the cerebral cortex compared with rats and guinea pigs but without further characterization of the functional role of these receptors it is impossible to determine the clinical significance of these data.

Background: Fentanyl decreases the minimum alveolar concentration (MAC) of inhaled anaesthetics and has been used clinically to reduce the requirements of other anaesthetic drugs in humans and small animals. We hypothesized that i.v. fentanyl would decrease the MAC of isoflurane in horses in a dose-dependent manner., Methods: Following determination of baseline MAC of isoflurane, fentanyl was administered i.v. to target plasma concentrations of 1, 8 and 16 ng ml(-1). Each horse was randomly assigned two of three target concentrations administered in ascending order. Loading and infusion doses for each horse were determined from previously derived individual pharmacokinetic values. Isoflurane MAC determination began 45 min after fentanyl administration at each target fentanyl concentration. Venous blood was collected at fixed intervals during the infusion for measurement of plasma fentanyl concentrations., Results: Mean actual fentanyl plasma concentrations were 0 (baseline), and 0.72 (SD 0.26), 8.43 (3.22), and 13.31 (6.66) ng ml(-1) for the target concentrations of 1, 8 and 16 ng ml(-1), respectively. The corresponding isoflurane MAC values were a baseline of 1.57 (0.23), and 1.51 (0.24), 1.41 (0.23) and 1.37 (0.09)%, respectively. The fentanyl concentrations of 0.72 and 8.43 ng ml(-1) did not significantly alter the MAC of isoflurane, but an 18 (7)% ISO-MAC reduction was observed at the 13.31 ng ml(-1) concentration., Conclusions: These results cautiously encourage further study of fentanyl as an opioid anaesthetic adjunct to inhalant anaesthesia in horses.

Two metabolites of the tranquilizer azaperone were extracted from alkalinized horse urine after treatment with beta-glucuronidase/sulfatase from limpets (Patella vulgata). The metabolites were identified by a combination of independent chemical synthesis and GC/MS and 1H NMR analysis. The metabolites were identified as 1-(fluorophenyl)-4-[4-(5-hydroxy-2-pyridinyl)-1-piperazinyl]-1-butanol, designated as 5'-hydroxy-azaperol, and 1-(fluorophenyl)-4-[4-(5-hydroxy-2-pyridinyl)-1-piperazinyl]-1-butanone, designated as 5'-hydroxyazaperone. A TLC screening test was developed for detecting both metabolites in basic extracts of horse urine treated with beta-glucuronidase/sulfatase. The screening test was used to detect azaperone metabolites in extracts of horse urine collected for 24 h after intravenous administration of azaperone. The administration of azaperone to horses was confirmed by GC/MS identification of 5'-hydroxyazaperone and 5'-hydroxyazaperol from basic extracts of horse urine treated with beta-glucuronidase/sulfatase. The extracted metabolites were treated with bis(trimethylsilyl)acetamide to produce trimethylsilyl (TMS) ether derivatives, and mass spectra and retention times were compared to those of the synthesized metabolites treated in the same manner.

Human immunodeficiency virus type-1 (HIV-1)-infected individuals exhibit functional impairment in various forms of cell-mediated cytotoxicities (CMC) at all stages of disease. The purpose of this study was to determine (i) if peripheral blood mononuclear cells (PBMC) obtained from HIV-1-infected patients could be stimulated in vitro to yield lymphokine-activated killer (LAK) activity; (ii) if non-MHC-restricted gp120-specific CMC could be preserved; and (iii) what effect zidovudine (AZT) would have on LAK activity. Fourteen asymptomatic HIV-1 seropositive adults and five healthy seronegative adults (controls) were evaluated. PBMCs were isolated and incubated in media or supplemented with IL-2 for 4 or 72 hr. Lysis of the NK resistant target cell line, Daudi, was similar for the control and experimental group. The increase in activity after stimulation was elevated to a similar degree in both seronegative and seropositive groups (P less than 0.001). LAK activity was significantly decreased (P = 0.011) when AZT was added to LAK cultures. In addition, virus production may not have been completely inhibited by AZT in LAK cultures. Thus, PBMCs from asymptomatic HIV-1-infected patients could be stimulated to yield LAK activity. However, AZT can impair LAK generation. It is unclear if LAK activation results in virus production that cannot be inhibited by AZT in this system. Further definition in other patient populations is required prior to applying this information to clinical trials.