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Topic:Pharmacology

Pharmacology in horses involves the study and application of drugs and medications to diagnose, treat, and prevent diseases and conditions in equine species. This field encompasses the understanding of pharmacokinetics and pharmacodynamics specific to horses, including how drugs are absorbed, distributed, metabolized, and excreted by the equine body. Commonly studied pharmacological agents in horses include non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, sedatives, and anthelmintics. Research in equine pharmacology focuses on determining appropriate dosages, understanding drug interactions, and minimizing adverse effects. This page compiles peer-reviewed research studies and scholarly articles that investigate the efficacy, safety, and regulatory aspects of pharmacological interventions in equine veterinary practice.
The In Vitro Effect of Ozone Therapy Against Equine Pythium insidiosum.
Journal of equine veterinary science    December 30, 2020   Volume 98 103305 doi: 10.1016/j.jevs.2020.103305
Ferreira JC, Pires RH, Costa GBD, Carrijo BN, Guiotto FG, Rodrigues VS.The goal of the present study was to characterize the antimicrobial action of different ozone (O) presentations against Pythium insidiosum isolated from horses. In experiment 1, P. insidiosum was treated with ozonated distilled water, ozonated sunflower oils with distinct peroxide indexes or O gas (72 μg O mL). In experiment 2, samples were exposed one or three times to oxygen (O) or O gas (72 μg O mL; 30 min/day). In experiment 3, P. insidiosum was treated with different concentrations of O gas (Ø, 32, 52, or 72 μg O mL) for three days (30 min/day). In experiment 4, samples were ex...
Newly isolated lytic bacteriophages for Staphylococcus intermedius, structurally and functionally stabilized in a hydroxyethylcellulose gel containing choline geranate: Potential for transdermal permeation in veterinary phage therapy.
Research in veterinary science    December 24, 2020   Volume 135 42-58 doi: 10.1016/j.rvsc.2020.12.013
Silva EC, Oliveira TJ, Moreli FC, Harada LK, Vila MMDC, Balcão VM.In the present research work, we propose a new antimicrobial treatment for pyoderma via cutaneous permeation of bacteriophage particles conveyed in a hydroxyethylcellulose (HEC) gel integrating ionic liquid as a permeation enhancer. Ionic liquids are highly viscous fluids constituted exclusively by ions, that are usually hydrolytically stable and promote solubilization of amphipathic molecules such as proteins, hence serving as green solvents and promoting the transdermal permeation of biomolecules. In the research effort entertained herein, the synthesis and use of choline geranate for integr...
Effect of Meperidine on Equine Blood Histamine, Tryptase, and Immunoglobulin-E Concentrations.
Frontiers in veterinary science    December 23, 2020   Volume 7 584922 doi: 10.3389/fvets.2020.584922
Trenholme HN, Sakai DM, Berghaus LJ, Hanafi AL, Knych HK, Ryan CA, McHale B, Banovic F, Quandt JE, Barletta M, Reed RA. To evaluate changes in immunological parameters following subcutaneous (SC) and intramuscular (IM) administration of meperidine in horses through quantitative analysis of plasma tryptase, histamine, and IgE levels. Six adult horses were enrolled in a prospective randomized crossover design. Horses were administered one treatment per day, with a seven day washout period: (a) meperidine 1 mg/kg IM, saline 6 mL SC; (b) saline 6 mL IM, meperidine 1 mg/kg SC; (c) saline 6 mL SC, saline 6 mL IM. Blood samples were obtained for plasmatic histamine (baseline, 5, 10, 15, 30, and 60 min) via LC-MS/MS ...
Atrial fibrillation in horses Part 2: Diagnosis, treatment and prognosis.
Veterinary journal (London, England : 1997)    December 22, 2020   Volume 268 105594 doi: 10.1016/j.tvjl.2020.105594
Decloedt A, Van Steenkiste G, Vera L, Buhl R, van Loon G.Atrial fibrillation (AF) is suspected by an irregularly irregular rhythm during auscultation at rest and should be confirmed by electrocardiography. Heart rate monitoring is potentially interesting for AF detection by horse owners, based on the disproportionally high heart rate during exercise or increased heart rate variability. Echocardiography and laboratory analysis are useful to identify underlying cardiac disease. Horses with severe cardiac disease should not undergo cardioversion due to the risk of recurrence. Cardioversion is recommended especially in horses performing high intensity e...
The effects of flumazenil on ventilatory and recovery characteristics in horses following midazolam-ketamine induction and isoflurane anaesthesia.
Equine veterinary journal    December 17, 2020   Volume 53, Issue 6 1257-1267 doi: 10.1111/evj.13391
Douglas H, Hopster K, Cerullo M, Hopster-Iversen C, Stefanovski D, Driessen B.Flumazenil antagonises the actions of benzodiazepines. There has been no prior research specifically investigating this anaesthetic reversal agent for horses. Objective: To determine the effects of flumazenil administration in horses on (a) ventilatory parameters after midazolam-ketamine induction and maintenance with isoflurane in oxygen and on (b) the characteristics of recovery from general anaesthesia. Methods: Blinded, randomised, crossover experiment. Methods: Six horses were randomly assigned to receive high-dose flumazenil (F , 20 µg/kg), low-dose flumazenil (F , 10 µg/kg) and sali...
Metabolic study of GW1516 in equine urine using liquid chromatography/electrospray ionization Q-Exactive high-resolution mass spectrometry for doping control.
Rapid communications in mass spectrometry : RCM    December 16, 2020   Volume 35, Issue 5 e9028 doi: 10.1002/rcm.9028
Ishii H, Shibuya M, Leung GN, Yamashita S, Yamada M, Kushiro A, Kasashima Y, Okada J, Kawasaki K, Kijima-Suda I.The use of GW1516, a peroxisome proliferator-activated receptor δ (PPAR δ) agonist, is strictly prohibited in both horseracing and equestrian competitions. However, little is known about its metabolic fate in horses. To the best of our knowledge, this is the first reported metabolic study of GW1516 in equine urine. Methods: Urine samples obtained from a thoroughbred after nasoesophageal administration with GW1516 were protein-precipitated and the supernatants were subsequently analyzed by liquid chromatography/electrospray ionization high-resolution mass spectrometry (LC/ESI-HRMS) with a Q-E...
Imidocarb Dipropionate Lacks Efficacy against Theileria haneyi and Fails to Consistently Clear Theileria equi in Horses Co-Infected with T. haneyi.
Pathogens (Basel, Switzerland)    December 10, 2020   Volume 9, Issue 12 1035 doi: 10.3390/pathogens9121035
Sears K, Knowles D, Dinkel K, Mshelia PW, Onzere C, Silva M, Fry L.Control of , the primary cause of equine theileriosis, is largely reliant on acaracide use and chemosterilization with imidocarb dipropionate (ID). However, it is currently unknown if ID is effective against , the recently identified second causative agent of equine theileriosis, or if the drug maintains effectiveness against in the presence of co-infection. The purpose of this study was to address these questions using ID treatment of the following three groups of horses: (1) five infected horses; (2) three - infected horses; and (3) three - infected horses. Clearance was first evaluated u...
Towards compound identification of synthetic opioids in nontargeted screening using machine learning techniques.
Drug testing and analysis    December 9, 2020   Volume 13, Issue 5 990-1000 doi: 10.1002/dta.2976
Klingberg J, Cawley A, Shimmon R, Fu S.The constant evolution of the illicit drug market makes the identification of unknown compounds problematic. Obtaining certified reference materials for a broad array of new analogues can be difficult and cost prohibitive. Machine learning provides a promising avenue to putatively identify a compound before confirmation against a standard. In this study, machine learning approaches were used to develop class prediction and retention time prediction models. The developed class prediction model used a naïve Bayes architecture to classify opioids as belonging to either the fentanyl analogues, AH...
Endochin-like quinolone-300 and ELQ-316 inhibit Babesia bovis, B. bigemina, B. caballi and Theileria equi.
Parasites & vectors    December 3, 2020   Volume 13, Issue 1 606 doi: 10.1186/s13071-020-04487-3
Silva MG, Bastos RG, Stone Doggett J, Riscoe MK, Pou S, Winter R, Dodean RA, Nilsen A, Suarez CE.The most common apicomplexan parasites causing bovine babesiosis are Babesia bovis and B. bigemina, while B. caballi and Theileria equi are responsible for equine piroplasmosis. Treatment and control of these diseases are usually achieved using potentially toxic chemotherapeutics, such as imidocarb diproprionate, but drug-resistant parasites are emerging, and alternative effective and safer drugs are needed. The endochin-like quinolones (ELQ)-300 and ELQ-316 have been proven to be safe and efficacious against related apicomplexans, such as Plasmodium spp., with ELQ-316 also being effective aga...
Characterization of semen collected by pharmacologically induced ejaculation from a stallion with seminal vesiculitis.
Reproduction in domestic animals = Zuchthygiene    November 27, 2020   Volume 55, Issue 12 1808-1811 doi: 10.1111/rda.13860
Cavalero TMS, Segabinazzi LGTM, Scheeren VFDC, Freitas-Dell'Aqua CP, Papa FO.The present study compared the quality of sperm collected by artificial vagina or pharmacologically induced ejaculation from a 10-year-old thoroughbred stallion with seminal vesiculitis. The pharmacological protocol involved intravenous administration of detomidine (0.01 mg/kg) and oxytocin (20 IU) and successfully induced ejaculation in all attempts of semen collection. Sperm motility, plasma membrane and acrosome integrity (PMAI), reactive oxygen species (ROS) levels, polymorphonuclear neutrophil (PMN) percentage, and bacterial profiles of fresh and cooled semen (5°C for 24 hr) were eval...
Hastening Time to Ejaculation in Donkey Jacks Treated with the PGF2α Analog, Cloprostenol Sodium.
Animals : an open access journal from MDPI    November 27, 2020   Volume 10, Issue 12 doi: 10.3390/ani10122231
Panzani D, Quaresma M, Fanelli D, Camillo F, Moroni R, Rota A, Martins-Bessa A, Nóvoa M, Catalán J, Canisso IF, Conte G, Mirò J.Due to the long courtship needed to attain excitation and erection, donkey semen collection can take up to 90 min. ProstaglandinF2α (PGF2α) has been reported to hasten the onset of erection and ejaculation in domesticated mammals, presumably by inducing smooth muscle contractions in the internal genitalia. However, while it has been anecdotally used in donkeys, it has yet to be critically evaluated. This study aimed to compare behavioral and semen parameters in Catalan, Balearic, Amiata, and Miranda jacks treated with the PGF2α analogue cloprostenol sodium immediately prior to exposure to a...
Tackling antibiotic use in pets and horses.
The Veterinary record    November 25, 2020   Volume 187, Issue 12 e106 doi: 10.1136/vr.m4606
No abstract available
An assessment of the effectiveness of hyaluronic acid and polyacrylamide hydrogel in horses with osteoarthritis: Systematic review and network meta-analysis.
Research in veterinary science    November 20, 2020   Volume 134 42-50 doi: 10.1016/j.rvsc.2020.11.013
da Silva Xavier AA, da Rosa PP, de Brum Mackmill L, Roll VFB.For several years, hyaluronic acid (HyA) and, more recently, polyacrylamide hydrogel (PHyd) have been used to reduce lameness and pain caused by osteoarthritis. However, there is still a lack of scientific evidence of the efficacy of these substances to allow veterinary experts to make decisions about their use in horses. The objective of this study was to evaluate, through a systematic review and network meta-analysis (NMA), the efficacy of HyA, associated or not with other drugs, and PHyd in relieving lameness in horses with osteoarthritis. The searches for primary studies were conducted on ...
Transport processes in equine oocytes and ovarian tissue during loading with cryoprotective solutions.
Biochimica et biophysica acta. General subjects    November 17, 2020   Volume 1865, Issue 2 129797 doi: 10.1016/j.bbagen.2020.129797
Lotz J, Içli S, Liu D, Caliskan S, Sieme H, Wolkers WF, Oldenhof H.Rational design of cryopreservation strategies for oocytes and ovarian cortex tissue requires insights in the rate at which cryoprotective agents (CPA) permeate and concomitant water transport takes place. The aim of the current study was to investigate possible differences in permeation kinetics of different CPAs (i.e., glycerol/GLY, ethylene glycol/EG, dimethyl sulfoxide/DMSO, and propylene glycol/PG), in equine oocytes as well as ovarian tissue. Membrane permeability of oocytes to water (Lp) and to CPAs (Ps) was inferred from video microscopic imaging of oocyte volume responses during perfu...
Corrigendum to “Clinical comparison of dexmedetomidine and medetomidine for isoflurane balanced anaesthesia in horses” [Vet Anaesth Analg 44 (2017) 1128-1138].
Veterinary anaesthesia and analgesia    November 8, 2020   Volume 47, Issue 6 859 doi: 10.1016/j.vaa.2020.10.002
Sacks M, Ringer SK, Bischofberger AS, Berchtold SM, Bettschart-Wolfensberger R.No abstract available
The effect of serial administration of bicarbonate on plasma total CO2 concentrations in horses.
Drug testing and analysis    November 8, 2020   Volume 13, Issue 2 397-403 doi: 10.1002/dta.2937
Bailey SR, Forbes G, Selvadurai N, McLarney K, Jones S, Steel CM.The administration of alkalinising agents including bicarbonate is of concern to racing authorities because resultant alkalosis may enhance performance and interfere with the detection of drugs in post-race urine. A threshold for total carbon dioxide (TCO ) of 36.0 mmol/L in plasma (with action limit of 37.0 mmol/L) has been set. Serial dosing of sodium bicarbonate has gained popularity in human athletes but has not been studied in horses previously. Sodium bicarbonate (200 g per horse) and 60 g of an electrolyte-vitamin complex was administered in 2-L water via nasogastric intubation to five ...
In vitro assessment of triterpenoids NVX-207 and betulinyl-bis-sulfamate as a topical treatment for equine skin cancer.
PloS one    November 5, 2020   Volume 15, Issue 11 e0241448 doi: 10.1371/journal.pone.0241448
Weber LA, Funtan A, Paschke R, Delarocque J, Kalbitz J, Meißner J, Feige K, Kietzmann M, Cavalleri JV.Equine sarcoid (ES) is the most prevalent skin tumor in equids worldwide. Additionally, aging grey horses frequently suffer from equine malignant melanoma (EMM). Current local therapies targeting these skin tumors remain challenging. Therefore, more feasible topical treatment options should be considered. In order to develop a topical therapy against ES and EMM, betulinyl-bis-sulfamate and NVX-207, derivatives of the naturally occurring betulin and betulinic acid, respectively, were evaluated for their antiproliferative (crystal violet staining assay), cytotoxic (MTS assay) and apoptotic (Anne...
Efficacy of oral Cynara scolymus and Silybum marianum on toxicity of imidocarb dipropionate in horses.
Veterinary record open    November 5, 2020   Volume 7, Issue 1 e000416 doi: 10.1136/vetreco-2020-000416
Jaramillo FM, Piñeros DDV, Corrêa RR, Pogliani FC, Cogliati B, Baccarin RYA.Despite hepatotoxic effects, imidocarb dipropionate is the drug of choice for treatment of equine piroplasmosis. It is important, therefore, to identify adjuvant therapies that may improve the safety of imidocarb dipropionate by reducing the risk of liver damage during its use. The aim of the present study was to evaluate the hepatoprotective and hepatoregulatory effects of treatment with and during administration of imidocarb dipropionate. Methods: Ten healthy horses, seroconverted to by C-ELISA, were treated with 5 mg/kg/day of imidocarb dipropionate for three consecutive days. The study ...
Protective Effect of Silibinin on Lipopolysaccharide-Induced Inflammatory Responses in Equine Peripheral Blood Mononuclear Cells, an In Vitro Study.
Animals : an open access journal from MDPI    November 3, 2020   Volume 10, Issue 11 2022 doi: 10.3390/ani10112022
Gugliandolo E, Crupi R, Biondi V, Licata P, Cuzzocrea S, Passantino A.Although inflammation is an important physiological response, it plays a prominent role in several diseases across the mammalian species. In horses, in particular, inflammation secondary to bacterial infection or translocation is one of the most frequent causes of morbidity and mortality. Research in new molecules with anti-inflammatory and immunomodulatory proprieties and safe use profile is constantly an active field; natural compounds are an important source of molecules with peculiar properties such as antioxidants, anti-inflammatory and immune modulating. Silibinin, a natural polyphenolic...
Unravelling androgens in sport: Altrenogest shows strong activation of the androgen receptor in a mammalian cell bioassay.
Drug testing and analysis    October 26, 2020   Volume 13, Issue 3 523-528 doi: 10.1002/dta.2941
Gillon A, Ho ENM, Chan GHM, Kauff A, Hughes G, Lund RA, Ashley Z, Wan TSM, Heather AK.Altrenogest is a commonly used progestogen for the suppression of oestrus and associated distracting behaviours that interfere with training and performance of female racehorses. The steroid is derived from 19-nor testosterone and is structurally similar to the anabolic androgenic steroid, trenbolone. In this study, the relative androgen potency of altrenogest was determined by a kidney (HEK293) cell androgen bioassay. The HEK293 bioassay shows that in its pure form, altrenogest has a high relative potency compared with testosterone but is not as strong as β-trenbolone. Our results also show ...
Bisphosphonates in veterinary medicine: The new horizon for use.
Bone    October 24, 2020   Volume 142 115711 doi: 10.1016/j.bone.2020.115711
Suva LJ, Cooper A, Watts AE, Ebetino FH, Price J, Gaddy D.Bisphosphonates (BPs) are characterized by their ability to bind strongly to bone mineral and inhibit bone resorption. However, BPs exert a wide range of pharmacological activities beyond the inhibition of bone resorption, including the inhibition of cancer cell metastases and angiogenesis and the inhibition of proliferation and apoptosis in vitro. Additionally, the inhibition of matrix metalloproteinase activity, altered cytokine and growth factor expression, as well as reductions in parameters of pain have also been reported. In humans, clinical BP use has transformed the treatment of post-m...
Plasma histamine concentrations in horses administered sodium penicillin, guaifenesin-xylazine-ketamine and isoflurane with morphine or butorphanol.
Veterinary anaesthesia and analgesia    October 24, 2020   Volume 48, Issue 1 17-25 doi: 10.1016/j.vaa.2020.10.003
Duke-Novakovski T, Jimenez CP, Fujiyama M, Beazley SG.Various drugs administered to horses undergoing surgical procedures can release histamine. Histamine concentrations were evaluated in horses prepared for surgery and administered butorphanol or morphine intraoperative infusions. Methods: Prospective studies with one randomized. Methods: A total of 44 client-owned horses. Methods: In one study, anesthesia was induced with xylazine followed by ketamine-diazepam. Anesthesia was maintained with guaifenesin-xylazine-ketamine (GXK) during surgical preparation. For surgery, isoflurane was administered with intravenous (IV) morphine (group M: 0.15 mg ...
Severe asthma is associated with a remodeling of the pulmonary arteries in horses.
PloS one    October 22, 2020   Volume 15, Issue 10 e0239561 doi: 10.1371/journal.pone.0239561
Ceriotti S, Bullone M, Leclere M, Ferrucci F, Lavoie JP.Pulmonary hypertension and cor pulmonale are complications of severe equine asthma, as a consequence of pulmonary hypoxic vasoconstriction. However, as pulmonary hypertension is only partially reversible by oxygen administration, other etiological factors are likely involved. In human chronic obstructive pulmonary disease, pulmonary artery remodeling contributes to the development of pulmonary hypertension. In rodent models, pulmonary vascular remodeling is present as a consequence of allergic airway inflammation. The present study investigated the presence of remodeling of the pulmonary arter...
Use of Detomidine Oromucosal Gel for Alleviation of Acute Anxiety and Fear in Horses: A Pilot Study.
Frontiers in veterinary science    October 20, 2020   Volume 7 573309 doi: 10.3389/fvets.2020.573309
Dai F, Rausk J, Aspegren J, Huhtinen M, Cannas S, Minero M.The aim of this randomized, double-blind, placebo-controlled, parallel group clinical field study was to evaluate the effect of detomidine oromucosal gel in alleviating anxiety and fear in horses. Sixteen horses with a history of acute anxiety and fear associated with firework-related noise entered the study. On New Year's Eve, eight horses were treated with 30 μg/kg detomidine gel and eight horses with placebo gel. When fireworks were present, 75% (6/8) of the detomidine-treated horses were scored by their owners as having a good or excellent treatment effect on anxiety and fear, while 50% (...
Oral misoprostol does not hasten oviductal transport of day-5 horse embryos.
Animal reproduction science    October 14, 2020   Volume 223 106626 doi: 10.1016/j.anireprosci.2020.106626
Checura CM, Momont HW, Castañeira C, Flores-Bragulat A, Losinno L.In horses, prostaglandin E (PGE) is produced by embryos around Day 5 post-ovulation; PGE functions directly at the oviduct promoting embryo transport into the uterus. Non-surgical collection of horse embryos for cryopreservation is recommended at Day 6.5-7 post-ovulation. It was proposed that misoprostol administered orally will hasten oviductal transport of horse embryos. In Experiment 1 (n = 15) there was comparison of time of embryo recovery (Day 6 and 6.5 post-ovulation) from mares administered misoprostol (Day 5 and 5.5) orally to that of untreated mares. On Day 6, embryo collections were...
Interpretations on Preconditioning with Lidocaine and Xylazine in Experimental Equine Jejunal Ischaemia.
Medical archives (Sarajevo, Bosnia and Herzegovina)    October 13, 2020   Volume 74, Issue 4 323-324 doi: 10.5455/medarh.2020.74.323-324
Sengul I, Sengul D, Pelikán A.No abstract available
Ceftiofur Side Effect in a Mare-Case Report.
Journal of equine veterinary science    October 12, 2020   Volume 95 103295 doi: 10.1016/j.jevs.2020.103295
Pradella GD, Taschetto PM, Duarte CA, da Silva Azevedo M, Góss GC.Adverse drug reactions in horses are rare. The antimicrobials are in the list of the most common drugs associated with reaction in horses. The aim of this report is to describe the clinical presentation of an adverse drug reaction after the intramuscular administration of ceftiofur hydrochloride. A 5-year-old crioulo broodmare at one day postpartum presented signs of difficulty to walk, positive pulse in the four limbs, and heart rate of 80 beats per minute (bpm), with a history of fighting with another mare. The clinical suspicions were rhabdomyolysis and laminitis. Initially a dose of flunix...
Efficacy of pergolide for the management of equine pituitary pars intermedia dysfunction: A systematic review.
Veterinary journal (London, England : 1997)    October 8, 2020   Volume 266 105562 doi: 10.1016/j.tvjl.2020.105562
Tatum RC, McGowan CM, Ireland JL.Pergolide, a dopamine agonist, is commonly administered to manage pituitary pars intermedia dysfunction (PPID), a progressive neurodegenerative disease prevalent in aged horses. However, available evidence regarding pergolide's efficacy in improving clinical and endocrine parameters is limited. The aim of this systematic review was to assess published literature and evaluate evidence regarding whether pergolide treatment results in improvement of clinical signs and/or adrenocorticotrophic hormone (ACTH) concentration compared to no treatment or other unlicensed treatments. Systematic searches ...
Effects of administration of ascorbic acid and low-dose hydrocortisone after infusion of sublethal doses of lipopolysaccharide to horses.
Journal of veterinary internal medicine    October 7, 2020   Volume 34, Issue 6 2710-2718 doi: 10.1111/jvim.15896
Anderson MJ, Ibrahim AS, Cooper BR, Woolcock AD, Moore GE, Taylor SD.Sepsis is associated with ascorbic acid (AA) depletion and critical illness-related corticosteroid insufficiency (CIRCI) in humans. Objective: Intravenous infusion of lipopolysaccharide (LPS) would (a) decrease endogneous AA concentrations, (b) induce CIRCI and (c) administration of a combination of AA and hydrocortisone (HC) would have decreased indices of inflammation compared to either drug alone. Methods: Thirty-two healthy horses. Methods: Randomized placebo-controlled experimental trial. Horses were assigned to 1 of 4 groups (saline, AA and HC, AA only, or HC only). Treatments were admin...
A Systematic Review and Meta-analysis on Sodium Bicarbonate Administration and Equine Running Performance: Is it Time to Stop Horsing Around With Baking Soda?
Journal of equine veterinary science    October 6, 2020   Volume 95 103281 doi: 10.1016/j.jevs.2020.103281
Denham J, Hulme A.Sodium bicarbonate administration in the hours prior to exercise has been used as a performance-enhancing substance in horses since the late 1980s. Although sodium bicarbonate administration to racehorses 24 hours before racing is a banned practice in most racing industries, whether or not it improves running performance in racehorses is currently unclear. The aim of this systematic review and meta-analysis was to establish whether or not acute sodium bicarbonate administration improves running performance in trained Standardbred and Thoroughbred horses. Seven randomized controlled trials, in...
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