A Review of Three Clinically Impactful Journal Articles

By Doug Brum, DVM
internalmedicine@angell.org
angell.org/internalmedicine
617-541-5186

With so many new articles coming out of veterinary literature each year, it can be hard to keep current and gain clinically relevant information that one can put into practice. This review focuses on a few recent journal articles with clinically relevant information that can have an immediate impact on one’s practice.

Use of Sildenafil in Congenital Idiopathic Megaesophagus

The first article examined the use of sildenafil in congenital idiopathic megaesophagus.¹  The study included 21 puppies that were diagnosed with congenital idiopathic megaesophagus on the basis of clinical signs, plain radiographs, and esophagrams.  Treatment of these dogs typically involves the use of prokinetic drugs that have varying results. Recent studies with high-resolution manometry showed that cisapride significantly increased the lower esophageal sphincter pressure in healthy dogs, and this could represent a serious concern in dogs with megaesophagus.

Swallowing and esophageal motility are complex processes between excitatory innervation, mostly vagal cholinergic fibers, and inhibitory innervation, which release nitric oxide (NO) as the main neurotransmitter.  Endogenous NO induces smooth muscle relaxation through the synthesis of the second messenger, cyclic guanosine monophosphate (cGMP).  Sildenafil is a selective phosphodiesterase-type 5 (PDE-5) inhibitor that indirectly potentiates the action of endogenous NO by reducing cGMP degradation due to PDE-5. Because of this, Sildenafil is an effective vasodilator and smooth muscle relaxant.  In humans and cats sildenafil has also been shown to induce the relaxation of the lower esophageal sphincter.  A decreased lower esophageal sphincter tone would facilitate the entry of the ingesta into the stomach, thus reducing the pressure inside the esophageal lumen.

The study was a randomized controlled trial; treatment and control (placebo). The dose of sildenafil was 1mg/KG BID.  The dogs were monitored for 2 weeks. Additionally, a set of in vitro experiments on muscle samples of canine lower esophageal sphincter was also performed, and the effects of increasing concentrations of sildenafil on basal tone and electrically-stimulated motility were assessed.

The results showed that puppies in the control group had more than two-times total regurgitation episodes throughout the study period, compared to the treatment group. Additionally, Sildenafil-treated dogs gained significantly more weight, and radiographically, the relative esophageal diameter was significantly lower compared to the controls. The in vivo findings showed that sildenafil dose-dependently reduced basal muscle tone and increased electrically-induced relaxation of dog lower esophageal sphincter samples.

In dogs, the esophagus possesses a striated muscle layer throughout its entire length, excluding the lower esophageal sphincter; therefore, prokinetic agents which act on smooth muscle, such as metoclopramide and cisapride (selective serotonin agonist in the 5-HT₄ receptor subtype) should not be affective, and could actually be contraindicated.  In accordance with this, 5-HT4 serotonin receptors were not detected in the esophageal muscle of dogs. Moreover, metoclopramide and cisapride tend to increase lower esophageal sphincter tone, further hindering the emptying of esophageal content, and thus potentially worsening the clinical signs.

The paper suggested a novel therapeutic approach using Sildenafil to relax the lower esophageal sphincter smooth muscle and promote the emptying of the esophagus.  The ability of sildenafil to relax smooth muscle and thus decrease esophageal peristalsis is not a concern in dogs, as the esophageal muscle is almost entirely striated (unlike in cats and humans). Since peristalsis of the esophagus is unchanged, the dogs affected by congenital idiopathic megaesophagus treated with sildenafil would still require to be fed from an elevated position; however, they could benefit greatly from the easier esophageal emptying and the decrease in esophageal dilatation, resulting in an improvement in clinical signs and general health status.

We have been using sildenafil for various other kinds of esophageal motility issues and have been seeing good results.

Comparison of Initial Treatment With and Without Corticosteroids for Suspected Acute Pancreatitis in Dogs

Another article clinically relevant and perhaps a bit contrary to our past clinical belief is: “Comparison of initial treatment with and without corticosteroids for suspected acute pancreatitis in dogs.”²  This article investigated the potential benefit of corticosteroids in acute pancreatitis.²  Historically, the use of glucocorticoids has been avoided in dogs with acute pancreatitis because they were considered a risk factor for the condition; however, recent studies have shown this not to be the case. Glucocorticoids are known to counteract nearly all pathways of inflammation. They enhance apoptosis and increase the production of pancreatitis-associated proteins, which confer a protective effect against pancreatic inflammation. They have been shown to reduce the severity of lesions in pancreatic acinar cells possibly by increasing in pancreatic arterial blood flow and suppressing the production of pro-inflammatory cytokine interleukins (IL-1β, IL-6, IL-10) and phospholipase A2.

Glucocorticoids also benefit in the treatment of septic shock and systemic inflammatory response syndrome (SIRS). They are used for treatment of critical illness-related corticosteroid insufficiency—(CIRCI-adrenal insufficiency due to a severe pro-inflammatory state, resulting in hypotension and a poor response to fluids or vasopressor therapy).  Low-dose corticosteroids are recommended as a therapy for humans with CIRCI, and its use in veterinary medicine is beginning to be recognized.

This study investigated the efficacy of prednisolone, for the initial treatment of acute pancreatitis. Dogs diagnosed with pancreatitis (45 dogs) were treated either with prednisone (1 mg/kg/day SQ during the hospitalization period) or without prednisone (20 dogs).  Aside from the prednisone, both groups received similar supportive care. The study showed that dogs treated with prednisone had improved clinical score, a more rapid decrease in C – reactive protein, and a shorter duration of hospitalization.  Although there was no difference in mortality while hospitalized, 1 month after hospitalization the prednisone-treated group had a significant decreased mortality rate.  These results suggest that the use of prednisone in cases of acute pancreatitis lead to a more rapid recovery and improved long term prognosis.

A Pivotal Field Study to Support the Registration of Levothyroxine Sodium Tablets for Canine Hypothyroidism

The final article is: “A Pivotal Field Study to Support the Registration of Levothyroxine Sodium Tablets for Canine Hypothyroidism.”  The main objective of the study was to investigate whether a lower dose of Levothyroxine would be sufficient to treat hypothyroidism. Levothyroxine sodium was administered to dogs as the whole dose q 24 hr or as half the dose q 12 hr.  Dosing started at 0.1 mg/10 lb (0.022 mg/kg) and continued for approximately 6 months.  It should be noted that the dose used for both groups is half of the generally accepted dose of 0.1mg/10lb BID. There were 92 dogs enrolled in the study.

In humans, small variations in Levothyroxine potency or bioavailability can lead to underdosing or overdosing and historically this has been a significant issue.  In dogs there is a much wider margin of safety but compliance in medicating is more of a concern.  Giving a drug SID (once daily) instead of BID (twice daily) is far more acceptable.  Additionally, there is a lot of information in the literature about the bio-availability differences between different brands of levothyroxine sodium tablets and the problems associated with interchanging different products.  However, not much exists on the same subject for dogs. This study used one brand (Thyro-tabs 4) to assess efficacy.

The study showed that there was no difference in the resolution of clinical and pathologic signs of hypothyroidism in either group.  There was no significant difference in how quickly the dogs responded or in adverse effects.  The results of this study supported a daily starting dose of 0.1 mg per 10 lb (0.022 mg per kg) body weight and showed that the treatment regimen has no effect on clinical outcome. Giving the full dose SID instead of BID should also increase owner compliance.

Footnotes

1. Sildenafil improves clinical signs and radiographic features in dogs with congenital idiopathic megaoesophagus: a randomised controlled trial F. Quintavalla, A. Menozzi, C. Pozzoli, E. Poli, P. Donati, D. K. Wyler, P. Serventi, S. Bertini ‘ veterinary record, may 2017
2. Comparison of initial treatment with and without corticosteroids for suspected acute pancreatitis in dogs H. Okanishi*,†, T. Nagata†, S. Nakane† and T. Watari1,* *Laboratory of Veterinary Internal Medicine, Department of Veterinary Medicine, Faculty of Bioresource Sciences, Nihon University, Fujisawa, 252-0880, Japan: Journal of Small Animal Practice (2019) 60, 298–304 DOI: 10.1111/jsap.12994 Accepted: 25 January 2019; Published online: 13 March 2019
3. A Pivotal Field Study to Support the Registration of Levothyroxine Sodium Tablets for Canine Hypothyroidism–Victoria A. Lewis, DVM, RPh*, Carla M.K. Morrow, DVM, PhD, DABVT, Johnny A. Jacobsen, DVM, MSc, W. Eugene Lloyd, DVM, PhD, DABVTy (J Am Anim Hosp Assoc 2018; 54:201–208. DOI 10.5326/ JAAHA-MS-6649)
4. Thyro-Tabs Canine (levothyroxine sodium tablets) USP, LLOYD, Inc., Shenandoah, Iowa