L'ererinory Dennurolo~y, Vol. 3, No 6 . pp 215 219. 1992 Printed in Grcat Britain.

0959 4491/92 $5 00 + 0 00 1991 I FSVD m d ACVD

Randomized Single-blind Comparison of an Evening Primrose Oil and Fish Oil Combination and

Concentrates of these Oils in the Management of Canine Atopy

ROSS BOND & DAVID H. LLOYD

Dermatology Unit, Department of Small Animal Medicine and Surgery, The Royal Veterinary College, University of London, Hawkshead Lane, North Mymms, Hatfield, Herts AL9 7TA, U.K.

Veterinary Dermatology 1992; 3: 215-219

Abstract- A randomized single-blind parallel study was devised to compare the efficacy of a commercially available evening primrose oil and fish oil supplement (EfaVet Regular, Efamol Vet, Guildford, U.K.) with a concentrated preparation (HGF capsules; Efamol Vet) containing gammalinolenic acid and eicosapen- taenoic acid (EPA). Thirty-seven perennially affected atopic dogs whose clinical signs were well-controlled by EfaVet Regular either continued to receive EfaVet Regular at the previous dose, or were switched to HGF capsules. Twenty-eight dogs completed the 16 week study and nine were withdrawn. Nine dogs continuing to receive EfaVet Regular were unchanged, and five deteriorated. Three dogs switched to HGF improved, six were unchanged, and five deteriorated. Differences in clinical scores within or between the two treatment groups were not significant. There was a significant (P < 0.05) reduction in the mean plasma phospholipid EPA concentration in both treatment groups at week 16. It was concluded that EfaVet Regular and HGF capsules were of comparable efficacy in controlling the clinical signs in this group of atopic dogs.

Key Wordy: Dog; Atopy; Essential fatty acids; Gammalinolenic acid; Eicosapentaenoic acid

INTRODUCTION

The beneficial effects of dietary essential fatty acid (EFA) supplementation in the management of ca- nine atopy are now well recognized, and are believed to be associated with the actions of gammalinolenic acid (GLA) and eicosapentaenoic acid (EPA) (1 -9).

Natural sources of the n6 and n3 EFAs are lim- ited. Evening primrose oil (EPO) is a potent source of the n6 EFAs but typically contains only 8-9%~ GLA (8). Cold water marine fish oil (FO), a potent source of n3 EFAs, contains approximately 18% EPA (10). Therefore, the EFAs believed to be most beneficial in skin disease are a small fraction of the total fatty acid content of the source oils. Conse- quently, large doses may be required to provide sufficient EFA for satisfactory therapeutic effects. In one previous study at the Royal Veterinary College, the dose of a 500mg capsule containing 80%0 EPO and 20% F O (EfaVet Regular; Efamol Vet) required for satisfactory control of the clinical signs in a group of 25 atopic dogs ranged from 1.5 to 10.6 capsules per 10 kg, with a mean of 4.1 ( 1 1).

Although dietary supplementation with EFAs is usually well-tolerated, certain individuals may de-

Correspondence to Mr R . Bond at the above address. Copyright European Society of Veterinary Dermatology and the American College of Veterinary Dermatology.

velop loose stools when given large doses of oil, and the administration of numerous capsules may present practical difficulties in some cases. In order to avoid these difficulties, a capsule containing con- centrates of EPO and FO has been produced ( H G F capsules; Efamol Vet). HGF 500mg capsules con- tain 280 mg of GLA and 50 mg EPA, in contrast to EfaVet Regular capsules which provide 34.4 mg of GLA and 17.3 mg EPA.

A randomized single-blind parallel study was per- formed to determine whether HGF capsules could control the clinical signs in a group of atopic dogs successfully managed by dietary supplementation with EfaVet Regular.

MATERIALS AND METHODS

The study was performed on a group of 37 perenni- ally affected atopic dogs which fulfilled the diagnos- tic criteria proposed by Willemse (12). Each dog had positive intradermal skin test reactivity to various allergens, including commonly housedust, Derma- tophagoides pteronyssinus and D. farinae (housedust mites), human dander and in some cases, pollens and moulds. One dog reacted positively to the flea allergen. Two dogs were known to have concurrent dietary sensitivities, which were controlled by dietary restriction.

215

216 Ross Bond & David H. Lloyd

The dose of EfaVet Regular had been adjusted to give satisfactory control of the clinical signs in each dog, so that clinical signs were absent or mild, and that the owners considered that no additional anti- inflammatory therapy was necessary. The mean cap- sule dosage in this group was 4.5 per 10 kg, with a range of 1.5 to 10.0. Adjunctive therapy with a range of shampoos was used in certain cases, mostly on a weekly basis. The preparations included antibacterial shampoos containing benzoyl peroxide (OxyDex, C- Vet, Bury St Edmunds, U.K.) and ethyl lactage (Etiderm, Virbac, Tonbridge, U.K.), an emollient shampoo (Sebocalm; Virbac), and a tar-sulphur- salicylic acid-containing shampoo (Sebolytic; Vir- bac). The owners were instructed to use an insecticidal spray containing fenitrothion and dichlorvos (Nuvan Top; Ciba-Geigy Agrochemicals, Cambridge, U.K.) on a weekly or fortnightly basis. Any dogs requiring topical and systemic glucocorti- coids, antihistamines and other non-steroidal anti- inflammatory drugs were not included. Antibacterial therapy was limited to those dogs which developed clinically significant bacterial skin disease during the study period.

All dogs entered the study between March and July 1991. The dogs either continued to receive the same dose of EfaVet Regular or were switched to the HGF capsules; a computer-generated schedule was used to determine, at random, which supplement each dog received. The dosage of HGF capsules was calculated to provide the same mean daily amount of GLA and gave an 8-fold reduction in the total number of capsules given daily. This also resulted in a 64% decrease in the daily dosage of EPA in the HGF treated group. The capsules were dispensed by an attendant in identical sealed pots. Although the owners knew if the supplement had been changed, the investigator was unaware which oils the dogs were receiving. The owners were instructed to main- tain the dogs on their usual commercial or home- prepared diets throughout the study period.

The dogs were examined by the same veterinary surgeon (RB) at 4 week intervals throughout the 16 week study period, and the clinical findings and owners’ observations were recorded. The veterinary surgeon’s assessment of pruritus, scaling, erythema, infiltration and oedema, coat condition and overall severity was scored on a digital scale with a range of 0 (absent) to 9 (severe). The owners’ opinions of the clinical condition of the dogs were incorporated into the scores for pruritus and overall severity. Dogs whose clinical condition deteriorated such that addi- tional anti-inflammatory therapy was deemed neces- sary were withdrawn from the blinded study.

Blood samples were collected into heparin at the beginning, middle and end of the study period, cen- trifuged within 30min, and the separated plasma stored at -20°C. Analysis of linoleic acid (LA), dihomogammalinolenic acid (DGLA), arachidonic acid (AA) and EPA in the plasma phospholipid was

performed as described by Manku et al. (13); all samples were processed as a batch on the same day. Clinical responses and blood results were assessed by a repeated measures factorial analysis of variance using the Genstat statistical software package (Gen- stat, Numerical Algorithms Group, Oxford, U.K.).

RESULTS

Nineteen dogs continued to receive EfaVet Regular, and eighteen dogs had their supplement changed to HGF. Fourteen dogs in each treatment group com- pleted the 16 week study period. Of the remaining nine dogs, six were withdrawn due to deterioration in their dermatological condition, and three for rea- sons unrelated to skin disease (Table l). Of the fourteen dogs in the EfaVet Regular treated group, nine were considered unchanged at the end of the study period, and five had deteriorated. Four of these dogs displayed mild increases in pruritus and no changes in the treatment regime were considered necessary, and one dog received a 3 week course of lincomycin for a ventral superficial pyoderma at the week 4 assessment.

Three of the dogs switched to the HGF capsules were considered to have improved over the period of the study, six were unchanged and five deteriorated (Table 1). Reduced pruritus was reported in two cases, and a marked reduction in scaling was noted in one dog. Of the five dogs which deteriorated, two dogs received a 3 week course of potentiated- sulphonamides for superficial pyoderma, whereas no treatment alterations were necessary in the remaining three dogs.

Although there was some variation in the mean scores for the criteria assessed during the period of the study (Table 2), the changes for each parameter were not significant either within or between the two treatment groups ( P > 0.1).

There was a significant ( P < 0.05) reduction in the mean plasma phospholipid EPA concentration in both treatment groups at week 16 (Table 3). The differences in the other EFA concentrations mea- sured were not significant either within or between the two treatment groups.

Dogs withdrawn from the study Two EfaVet Regular treated dogs were eliminated

as glucocorticoid therapy was deemed necessary to control exacerbation of pruritus, and one dog known to have a concurrent dietary sensitivity developed severe facial pruritus associated with an unautho- rized dietary alteration at week 8. Three dogs switched to HGF developed marked pruritus within 2 weeks of entering the study and were returned to their original supplement; however, two of the dogs were not controlled by this measure and required additional therapy with oral prednisolone.

Essential fatty acids in canine atopy 217

TABLE 1. Clinician’s assessment at the end of the study (overall severity, comparison with week 0)

Clinical response Total number

Supplement Improved Unchanged Deteriorated* Withdrawn? of dogs

EfaVet Regular 0 9 5( + 3) 2 19 HGF capsules 3 6 5( +3) 1 18

*Figures in parentheses indicate dogs withdrawn due to deteriorations in skin condition ?Dogs withdrawn for reasons unrelated to skin disease.

TABLE 2. Clinical scores of the dogs which completed the study, on a scale of 0 (absent) to 9 (severe) ~ ~ ~ ~ ~

Week 16 Week 8 Week 0 Clinical criteria Supplement Mean SEM Mean SEM Mean SEM

Pruritus EfaVet Regular

Scaling EfaVet Regular

Erythema EfaVet Regular

HGF

HGF

HGF

Infiltration/oedema EfaVet Regular HGF

Coat condition EfaVet Regular HGF

Overall impression EfaVet Regular HGF

2.93 0.27 3.21 0.30 2.86 0.34 2.64 0.17 2.93 0.34 2.93 0.32

1.00 0.43 0.93 0.40 0.86 0.40 1.50 0.54 1.36 0.40 1.14 0.29

1.86 0.27 1.64 0.31 1.71 0.30 2.00 0.30 2.14 0.31 2.21 0.30

0.43 0.23 0.93 0.29 0.86 0.38 0.64 0.27 0.79 0.30 0.93 0.34

1.00 0.26 1.00 0.30 0.93 0.27 1.36 0.32 1.36 0.29 1.14 0.25

2.43 0.26 2.86 0.20 2.79 0.40 2.43 0.23 2.64 0.25 2.64 0.30

SEM, Standard error of the mean.

TABLE 3. EFA levels in the plasma phospholipids of the dogs which completed the study ~~

Supplement Week 0 Week 8 Week 16 Fatty acid Mean SEM Mean SEM Mean SEM

EfaVet Regular? Linoleic acid Dihomogammalinolenic acid Arachidonic acid Eicosapentaenoic acid

HGF capsulesf Linoleic acid Dihomogammalinolenic acid Arachidonic acid Eicosapentaenoic acid

23.58 0.60 2.23 0.21

18.81 1.35 3.47 0.60

23.24 1.02 2.28 0.19

20.35 0.97 3.40 0.47

22.64 2.16

19.23 3.93

20.02 2.42

19.14 3.44

0.71 21.91 0.80 0.19 2.1 1 0.19 1.30 21.83 1.06 0.56 I.@* 0.21

1.43 21.31 1.04 0.23 2.64 0.23 1.02 20.93 0.92 0.72 2.73* 0.37

Units are expressed as mg per 100 mg of total plasma phospholipid. SEM Standard error of the mean. Comparison between weeks, *P < 0.05 (Analysis of variance). ?Two week 16 samples not available for analysis; l o n e week 16 sample not available for analysis.

DISCUSSION

The results of clinical trials with atopic dogs may be difficult to interpret as the clinical signs often fluctu- ate in response to seasonal and other factors influ- encing allergen challenge and host reactivity, and as a result of secondary pyoderma or ectoparasitic in- festations (16, 17). As most of the dogs entered the study during the spring and early summer months, it

was not surprising that certain individuals deterio- rated during the trial period. A previous study has shown that higher doses of EfaVet Regular were required to successfully manage a group of atopic dogs during the summer months (18); however, the protocol of the current trial did not allow modifica- tion of the capsule dose during the assessment pe- riod. The variations in clinical condition observed in certain individuals of both the control and test

218 Ross Bond & David H. Lloyd

groups emphasize the need for well-designed and controlled long-term trials when critically evaluating treatments for this disease.

It is possible that EfaVet Regular may have had some residual therapeutic effect in the HGF treated dogs, particularly during the first few weeks of the study. In a previous double-blind parallel study last- ing 8 weeks ( 1 I ) , deterioration in the clinical condi- tion of eight out of 10 dogs switched from EfaVet Regular was evident within 2-4 weeks, and four of these dogs showed further deteriorations when as- sessed after 8 weeks. It seems unlikely, therefore, that the prior treatment with EfaVet Regular would have had a significant effect on the condition of the HGF treated dogs at the final assessment in this study.

The absence of statistically significant differences in the clinical responses between the two treatment groups indicated that the HGF capsules could re- place EfaVet Regular as an anti-inflammatory agent in this group of atopic dogs. Overall, the clinical condition of the test group was maintained by con- tinuing to provide the same mean daily amount of GLA, and despite a 64% reduction in the EPA dose. However, this study was not designed to assess the relative therapeutic importance of GLA and EPA; further studies are needed to clarify this issue and to determine whether combinations of the two fatty acids have synergistic effects. Supplementation with the concentrates makes EFA therapy a much more practicable approach in dogs when high doses are needed. However, as the dogs were selected for this study on the basis of a good response to one partic- ular supplement (EfaVet Regular), assessments of the effects of HGF capsules in a wider group of atopic dogs are now required.

The mean plasma phospholipid EPA concentra- tions did not reflect the different levels'of supplemen- tation with this fatty acid between the two treatment groups. The significant reduction in the EfaVet Reg- ular treated group was surprising as the dosage of EPA provided by the capsules was unaltered; the reason for this is unknown. As all samples were processed on the same day in an identical fashion, laboratory error does not seem likely. The EFA content of both EfaVet Regular and HGF capsules is routinely monitored on production to ensure concen- trations are as stated, and capsules were stored at room temperature as recommended by the manufac- turer. The reduction seen in the HGF-treated dogs may have reflected the reduced level of supplementa- tion in this group. However, in a previous study in which a group of atopic dogs was switched from EfaVet Regular to olive oil, which contains minimal n3 EFAs (15), the mean plasma phospholipid EPA concentration was not significantly reduced (1 1). It is clear that a greater understanding of the metabolism of EFAs in dogs and their status in the plasma phospholipid fraction is needed.

ACKNOWLEDGEMENTS

The authors are grateful to Mrs L. Steele VN for her skilled technical assistance. Plasma essential fatty acids were analysed by Efamol Research Institute, Nova Scotia, and Mr P. Morse BSc, Dip. Stat. (London), CStat., of Scotia Pharmaceuticals assisted with the statistical analyses.

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Essential fatty acids in canine atopy 219

and roles in clinical medicine. New York: Wiley-Liss, 1990: 187-201.

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17. Nesbitt, G. H., Kedan, G. S. Caciolo, P. Canine atopy. Part 11. Management. Compendium on Continu- ing Education 1984; 6: 264-78.

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RCsumC-Une etude parallele en double aveugle a kt6 conduite pour comparer l’efficacite d’une preparation commerciale i base d’huile d’onagre et d’huile de poisson (EfaVet, Efamol Vet, Guilford, U.K.) a une preparation concentree (HFG capsules, Efamol Vet) contenant de l’acide gammalinolenique et de l’acide Cicosapentaenoique (EPA). Trente sept chiens atopiques presentant des symptames perannuels controlks par de I’EfaVet Regular, ou continuait a recevoir de 1’EfaVet Regular a la m&me dose, ou prenaient des capsules d’HGF. Vingt huit chiens ont suivi le traitement de 16 semaines et 9 ont ete klimines de l’ttude. Pour trois des chiens ayant change pour I’HGF les signes cliniques ont etC ameliores, aucun changement n’a &tC observe pour six et une aggravation a ete notee pour cinq. Les differences entre les scores cliniques des groupes ne sont pas significatives. Une diminution significative ( P < 0.05) de la concentration plasmatique de phos- phalipides FPA dans les deux groupes a ete observee a la semaine 16. En conclusion, 1’EfaVet Regular et les capsules d’HGF ont une efficacite comparable dans le contrble des symptbmes dans ce groupe de chiens atopiques. [Band, R., Lloyd, D. Randomized single-blind comparison of an evening primrose oil and fish oil combination and concentrates of these oils in the management of canine atropy (Comparision en double aveugle de l’utilisation d’huile d’anagre et de d’huile de poisson a differentes concentrations dans le traitement de l’atropie canine). Veterinary Dermatology, 1992; 3: 21 5-2191.

Zusammenfassung-Eine randomisierte Einfach-Blind-Parallelstudie wurde durchgefuhrt um die Wirk- samkeit eines kommerziell erhlltlichen Nachtkerzen-und Fischolerganzungspriparates (Efa Vet Regular, Efamol Vet, Guildford, U.K.) mit einer konzentrierten Praparation aus Gamma-Linolensaure und Eicosa- pentaensaure (EPA) (HGF Kapseln, Efamol Vet) zu vergleichen. 37 Patienten mit einer nichtsaisonalen Atopie, deren klinische Symptome mit Efa Vet Regular gut kontrolliert werden konnten, wurden entweder auf dieser Therapie belassen oder umgestellt auf HGF- Kapsseln 29 Patienten fuhrten die therapie iiber die die 16 Wochen der Studie bis zum SchluB durch, bei 9 Patienten wurde sie abgebrochen 9 Patienten die weiterhin Efa Vet Regular erhielten, blieben unverandert, 5 verschlechterten sich 3 Hunde, die auf HGF umgestellt wurden, zeigten eine Besserung, 6 blieben gleich, und 5 verschlechterten sich Die Unterschiede in den klimischen Ergebnissen innerhalb oder zwischen den beiden Behandlungsgruppen waren nicht signifikant. Es gab eine signifikante Reduktion ( P < 0,05) im Mittelwert der Plasma-Phospho- lipid-EPA-Konzentration zwischen den beiden Gruppen in der Woche 16. Efa Vet Regular und HGF Kapseln scheinen demnach eine vergleichbare Wirksamkeit in der Kontrolle der klinischen Symptome bei dieser Gruppe atopischer Hunde zu haben. [Bond, R., Lloyd, D.H. Randomized single-blind comparison of an evening primrose oil and fish oil combination and concentrates of these oils in the management of canine atopy (Eine randomisierte Einfach-Blind-Vergleichsstudie zwischen einer Kombination aus Nachtkerzenol und Fischol und Konzentraten dieser Ole in der Behandlung der kaninen Atopie). Veterinary Dermatology 1992; 3: 215-2191,

Resumen-Con el objetivo de comparar la eficacia de una marca comercial que contenia una combinacion de aceite primrosa y pescado, (Efa Vet Regular, Efamol Vet, Guilford, U.K.), con un preparacion de tipo concentrado, (HFG capsules; Efamol Vet), que contenia acido gammalinoleico y eicosapentanoico (EPA), se llevo a cab0 un estudio paralelo al azar de tipo ciego-sencillo. Treinta y siete perros que padecian atopia con sintomas de tipo estacional, cuyo coadro clinico fue controlado con Efa Vet Regular, continuaron recibiendo la misma medicacion a la misma dose, o comenzaron a recibir capsulas HFG. Veintiocho de 10s perros completaron las dieciseis semanas de estudio y neuve se retiraron del mismo. Neuve perros que continuaron recibiendo EfaVet permaneiceron sin cambios y cinco sufrieron una deterioracion. Tres de 10s que comenzaron a recibir HGF experimentaron una mejoria, en seis no vio cambio alguno y cinco empeoraron. Las diferencias entre las evaluaciones clinicas entre 10s dos grupos de tratamientos no fueron significativas. Se encontro una diferencia significativa en la reduccion del valor medio de la concentracion de fosfolipidos EPA en el plasma ( P < 0.05) entre 10s dos tipos de tratamientos, an la semans dkcimosexta. Finalmente, se consluyo que EfaVet Regular y las capsulas HGF fueron ambas de eficacia comparable en el prsente grupo de perros atopicos. [Bond, R., Lloyd, D. H. Randomized single blind comparison of an evening primrose oil and fish oil combination and concentrates of these oils in the management of canine atropy (Comparacion a1 azar de tipo sencilllo-ciego de aceite de primrosa y pescado con un concentrado de kstos aceites en el tratamiento de perros atopicos). Veterinary Dermatology, 1992; 3: 21 5-2191.