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Continuous Low Level Feed Administration of Pyrantel Tartrate in Lambs
BT. vet. J. ( 1969), Ill5, 235
CONTINUOUS LOW LEVEL FEED ADMINISTRATION OF PYRANTEL TARTRATE IN LAMBS I. Prophylaxis of Experimental T. colubriformis infections By R. L.
CORNWELL AND
R. M.
JONES
Department of Parasitology Research, Pfizer Ltd, Sandwich, Kent
SUMMARY
In two experiments, worm-free lambs were given 2000 or 3000 T. colubriformis larvae daily for 20 days and medicated in the food for 7 weeks, with daily doses of pyrantel tartrate varying from 2·5 to 10 mg./kg. Faecal egg counts during the experiments and worm burdens at post-mortem examination were reduced by 97- 100 per cent compared with controls in groups receiving 3 mg. /kg. and higher. INTRODUCTION
Pyrantel tartrate is one of a series of highly active broad spectrum anthelmintics described by Austin et al. (1966). Laboratory trials in sheep (Cornwell, 1966) revealed high activity of single doses of 25 mg. /kg. against mature and immature worms of important species. Further experiments, including those reported by Gibson & Parfitt (1968), have since shown that activity against parasitic third-stage larvae is particularly high especially in T. colubriformis infections. It was therefore argued that continuous low-level feeding may be a feasible method of preventing the development of infection by destroying the third-stage larvae as they are acquired. The present experiments were carried out to define the dosage of pyrantel which would accomplish satisfactory prophylaxis under experimental conditions. METHODS
Experiment 1. Eight-month-old worm-free Masham crossbred lambs were divided into five equal groups offour on a bodyweight basis, and fed hay and a concentrate ration of I lb. per head per day of a proprietary lamb meal. Each morning for 20 days 3000 infective T. colubriformis larvae were administered to each animal. Each evening for 50 days four of the groups received 2·5, 5, 7·S and 10 mg. /kg. pyrantel respectively as a 0·2 per cent mixture in the lamb meal. The amount of medicated feed was adjusted according to bodyweight twice weekly. The remaining group served as unmedicated controls until all animals were killed on day 51 and the worms in the small intestine recovered and counted.
BRITISH VETERINARY JOURNAL, 12 5, 5
During the experiment, faeces samples for M cMaster egg counts were taken on d ay 18 and thrice weekly thereafter. Experiment 2. This experiment was conducted in the same way except that the lambs were Dorset Horns, 3 months old at the commencement and received 2000 larvae per day. The ration consisted of ! lb. lamb meal per head per d ay and the four medicated groups received 3, 3'5, 4'0 and 4'5 mg. /kg. pyrantel respectively. All animals were killed on day 49. Faeces samples were collected on day 16 and twice weekly thereafter. RESULTS
Experiment I The mean faecal egg counts of each group, apart from the IO mg. /kg. group which remained negative throughout, are shown in Fig. I. Worm counts at post-mortem examination are shown in T able I. TABLE I FAECAL EGG COUNTS AND WO RM TREATMENT OF EXPERIME NTAL
Experimental details
EXPERIMENT I 3000 T. colubriformis
for 20 days; killed day 51 EXPERIMENT 2 2000 T. colubriformis
for 20 days; killed day 49
No. of
BURDENS
AT
T . colubriformis
POST-MORTEM EXAM I NAT IO N AFTE R DAILY INFECTION WITH PYRANTEL TA RTR ATE
Egg counts at slaughter·
Worms
lambs
Treatment (mg./kg. /day )
4 4 4 4 4
2'5 5 7'5 10 Controls
3660 (600-7880) 230 (40-320) 270 (0-1080) 70 (0-160) o 1675 (800-21 50) 35480 (29480-4404 0)
89'7 99'4 99'3 99'9
4 4
3 3'5 4 4'5 Controls
250 (50-800) 780 (40- 19 60 ) 830 (280-2440) 238 (0-750) 88 (0-200) 420 (160-760) 240 (8o-Q40) 25 (0-50) 5 200 (350o-Q95 0) 26470 (22480-3 04 80 )
97'1 96 '9 98 '4 99'1
4 4 4
at p.m.·
462 (50-1200) 12 (0-50) 25 (0-100)
E.fficacy (%)
• Mean, and range in parentheses.
Egg counts. The development of an untreated infection may be judged from the mean egg count of the control group which rose to a peak at day 42 when most of the administered larvae would be expected to have matured. A slight fall continuing to the end of the experiment was then apparent. In the groups receiving daily treatment no egg output was recorded from the IO mg. /kg. group and the counts in the 7'5 and 5 mg. /kg. groups were negligible. The lowest level treatment group-2'5 mg. /kg.- showed a fairly even output of eggs reaching 28 per cent of that in the controls. Worm counts. The mean worm count in the controls at slaughter showed that 59 per cent of the administered larvae had developed to maturity, there being less than I per cent of immature worms present. The treated groups receiving 5 mg. /kg. and upwards showed a reduction in worm burden greater than 99 per cent compared with controls and the 2'5 mg. /kg. group showed 89'7 per cent reduction.
PYRANTEL TARTRATE AGAINST T . COLUBRIFORMIS IN LAMBS 8
237
Experiment 2
Experiment I
7
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15 . Days of experiment
Fig.
l.
25
30
35
40
45
Mean faecal egg output per gram (e.p.g.), in trea ted and control groups throughout experiments I and 2. Numerals 2·5- 7"5 indicate treatments in mg./kg./day.
Experiment
2
The data relating to this experiment are shown in Fig. I and Table 1. Egg counts. The development of the untreated infection was accompanied by faecal egg output commencing on day 19 and reaching a peak at day 40, followed by some fluctuation to the end of the experiment at day 49. The egg counts of the medicated groups remained low throughout and were related to the dose of pyrantel received. The egg count of the group receiving the lowest dose-3 mg. /kg.-was 7 per cent of the controls at the peak of excretion. Worm counts. Counts at post-mortem examination showed that 66 per cent of the administered larvae had developed and there were no immature worms present. Worm burdens of the feed-medicated groups were reduced by 97-99 per cent compared with controls. DISCUSSION
The development of the untreated infection consisting of daily doses of larvae produced similar worm burdens, with a 59- 66 per cent "take", as a single infection of a similar total number of larvae (unpublished observations). There were no inhibited larvae present at slaughter indicating that this type of immune mechanism was not operating on the later doses of larvae. However, the egg output did show signs of declining after the peak at day 41 in both experiments when all larvae given would be expected to have reached adult
BRITISH VETERINARY JOURNAL, 12 5, 5
egg-laying status. There is therefore the possibility of some immune mechanism coming into play. The egg output in the second experiment was twice that of the first despite fewer worms present. It may be that the use of younger lambs resulted in this phenomenon, or the acquisition of 2000 larvae per day is nearer the optimum than 3000 for resulting egg output. No clinical signs or weight loss appeared in the control lambs containing 24,000-36,000 worms which is surprising in view of work reported by Andrews ( I 939) and Gordon (I 950) indicating a high degree of pathogenicity at similar dosage levels. Kates & Turner ( I 953), however, found only minor effects in lambs given 50,000 larvae. Possibly a single infection is more pathogenic than daily doses even though the final worm burden is the same, or strain differences of parasite and host, as suggested by the latter authors, may explain these differences. The daily treatment with pyrantel tartrate was highly effective in preventing the development of the infection. The dose-related response over the two experiments showed a reduction of 90 per cent at 2·5 mg. /kg. and IOO per cent at IO mg. /kg., although dosages of 4·5 mg. /kg. and above were 99 per cent effective. Further experiments are necessary to establish the feasibility and economics of preventing parasitic gastro-enteritis by continuous low level anthelmintic medication in the field. ACKNOWLEDGMENTS
The authors acknowledge the able technical assistance of Misses Marcia Blore, Jean Berry and Susan Rees and Messrs K. E. R. Tyrrell and C. P. Wilkins. The Directors of the Pfizer Group are thanked for permission to publish this paper. REFERE NCES
s.
ANDREWS,J. (1939).J. agric. Res., 58, 761. AUSTIN, W. C., COURTNEY, W., DANILEWICZ, J . C., MORGAN, D . H., CONOVER , L. H ., HOWES, H. L. JR ., LYNCH, J . E., McFARLAND, W., CORNWELL, R. L. & THEODORJDES, V .
J.
J.
( 1966). Nature, Lond., 212, 1273. CORNWELL, R. L. (1966). Vet. Rec. , 79, 590. GIBSON, T . E. & PARFITT, J. W. (1968). BT. vet. ]., 124,63. GORDON, H. MeL. (1950). Aust. vet.]., 26, 14,46, 93. KATES, K. C. & TURNER, J. H . (1953) · Am. J. vet. Res., 14, 72. (Accepted for publication 13 December 1968 ) Adtninistration continue, a faible dose, de tartrate de pyrantel a des agoeaWit (dans leur nourriture). I. Prophylaxie des infections experilnentales de T. colubriformis (Cornwell etJones) ResUIDe. Dans deux experiences, on donna quotidiennement, pendant 20 jours, 2000 OU 3000 larves de T. colubriformis a des agneaux sans vers et on les traita, pendant 7 semaines, en ajoutant a leur nourriture des doses journalieres de tartrate d e pyrantel, variant de 2,5 a JO mg./kg. Le nombre d'oeufs fecaux au cours des experiences et les charges de vers a l'examen post-mortem etaient reduits de 97-100 pour cent, en comparaison avec les cas temoin des groupes recevant 3 mg./ kg. et plus.
PYRANTEL TARTRATE AGAINST T. COLUBRIFORMIS IN LAMBS
239
Kontinuierliche Verabreichung Geringer Dosen von Pyranteltartrat an Lanuner I. Propbylaxe bei experilnentellen T. colubriformis Infektionen (Cornwell und Jones) ZusaDlDlenfassung. In zwei Versuchsreihen wurden wurmfreie Lammer taglich tiber einen Zeitraum von 20 Tagen mit 2000 oder 3000 T. colubriformis Larven infiziert. Die Behandlung erfolgte tiber einen Zeitraum von 7 Wochen, indem dem Futter taglich eine Dosis von 2,5 bis 10 mg. /kg. Pyranteltartrat beigegeben wurde. Eine Zahlung der Eier in dem Auswurf wah rend der Versuche und die Wurmermittlung der Post-Mortem Untersuchung ergab, daB die Verringerung im Vergleich zu Versuchstieren, die eine Dosis von 3 mg./ kg. und mehr erhalten hatten 97- 100 Prozent niedriger lag. Acbninistracion continua de tartrato de pyrantel a bajo mvel en los piensos de los corderos. I. Profilaxis de las infecciones experiDlentales de T. colubriformis (Cornwell y Jones) ReSUDlen. En dos experimentos, se administraron 2000 0 3000 larvas de T. colubriformis a unos cord eros sin lombrices diariamente durante 20 dias, medicandose en la comida durante 7 semanas, con dosis diarias de tartrato de pyrantel que variaban de 2,5 a 10 mg./ kg. Los cuentos de huevos fecales durante los experimentos y las cargas de lombrices en los examenes despues de la muerte presentaron una reducci6n de 97- 100 por cien en comparaci6n con los animales de referencia en grupos que recibieron 3 mg./kg. 0 mas.
CONTINUOUS LOW LEVEL FEED ADMINISTRATION OF PYRANTEL TARTRATE IN LAMBS I. Prophylaxis of Experimental T. colubriformis infections By R. L.
CORNWELL AND
R. M.
JONES
Department of Parasitology Research, Pfizer Ltd, Sandwich, Kent
SUMMARY
In two experiments, worm-free lambs were given 2000 or 3000 T. colubriformis larvae daily for 20 days and medicated in the food for 7 weeks, with daily doses of pyrantel tartrate varying from 2·5 to 10 mg./kg. Faecal egg counts during the experiments and worm burdens at post-mortem examination were reduced by 97- 100 per cent compared with controls in groups receiving 3 mg. /kg. and higher. INTRODUCTION
Pyrantel tartrate is one of a series of highly active broad spectrum anthelmintics described by Austin et al. (1966). Laboratory trials in sheep (Cornwell, 1966) revealed high activity of single doses of 25 mg. /kg. against mature and immature worms of important species. Further experiments, including those reported by Gibson & Parfitt (1968), have since shown that activity against parasitic third-stage larvae is particularly high especially in T. colubriformis infections. It was therefore argued that continuous low-level feeding may be a feasible method of preventing the development of infection by destroying the third-stage larvae as they are acquired. The present experiments were carried out to define the dosage of pyrantel which would accomplish satisfactory prophylaxis under experimental conditions. METHODS
Experiment 1. Eight-month-old worm-free Masham crossbred lambs were divided into five equal groups offour on a bodyweight basis, and fed hay and a concentrate ration of I lb. per head per day of a proprietary lamb meal. Each morning for 20 days 3000 infective T. colubriformis larvae were administered to each animal. Each evening for 50 days four of the groups received 2·5, 5, 7·S and 10 mg. /kg. pyrantel respectively as a 0·2 per cent mixture in the lamb meal. The amount of medicated feed was adjusted according to bodyweight twice weekly. The remaining group served as unmedicated controls until all animals were killed on day 51 and the worms in the small intestine recovered and counted.
BRITISH VETERINARY JOURNAL, 12 5, 5
During the experiment, faeces samples for M cMaster egg counts were taken on d ay 18 and thrice weekly thereafter. Experiment 2. This experiment was conducted in the same way except that the lambs were Dorset Horns, 3 months old at the commencement and received 2000 larvae per day. The ration consisted of ! lb. lamb meal per head per d ay and the four medicated groups received 3, 3'5, 4'0 and 4'5 mg. /kg. pyrantel respectively. All animals were killed on day 49. Faeces samples were collected on day 16 and twice weekly thereafter. RESULTS
Experiment I The mean faecal egg counts of each group, apart from the IO mg. /kg. group which remained negative throughout, are shown in Fig. I. Worm counts at post-mortem examination are shown in T able I. TABLE I FAECAL EGG COUNTS AND WO RM TREATMENT OF EXPERIME NTAL
Experimental details
EXPERIMENT I 3000 T. colubriformis
for 20 days; killed day 51 EXPERIMENT 2 2000 T. colubriformis
for 20 days; killed day 49
No. of
BURDENS
AT
T . colubriformis
POST-MORTEM EXAM I NAT IO N AFTE R DAILY INFECTION WITH PYRANTEL TA RTR ATE
Egg counts at slaughter·
Worms
lambs
Treatment (mg./kg. /day )
4 4 4 4 4
2'5 5 7'5 10 Controls
3660 (600-7880) 230 (40-320) 270 (0-1080) 70 (0-160) o 1675 (800-21 50) 35480 (29480-4404 0)
89'7 99'4 99'3 99'9
4 4
3 3'5 4 4'5 Controls
250 (50-800) 780 (40- 19 60 ) 830 (280-2440) 238 (0-750) 88 (0-200) 420 (160-760) 240 (8o-Q40) 25 (0-50) 5 200 (350o-Q95 0) 26470 (22480-3 04 80 )
97'1 96 '9 98 '4 99'1
4 4 4
at p.m.·
462 (50-1200) 12 (0-50) 25 (0-100)
E.fficacy (%)
• Mean, and range in parentheses.
Egg counts. The development of an untreated infection may be judged from the mean egg count of the control group which rose to a peak at day 42 when most of the administered larvae would be expected to have matured. A slight fall continuing to the end of the experiment was then apparent. In the groups receiving daily treatment no egg output was recorded from the IO mg. /kg. group and the counts in the 7'5 and 5 mg. /kg. groups were negligible. The lowest level treatment group-2'5 mg. /kg.- showed a fairly even output of eggs reaching 28 per cent of that in the controls. Worm counts. The mean worm count in the controls at slaughter showed that 59 per cent of the administered larvae had developed to maturity, there being less than I per cent of immature worms present. The treated groups receiving 5 mg. /kg. and upwards showed a reduction in worm burden greater than 99 per cent compared with controls and the 2'5 mg. /kg. group showed 89'7 per cent reduction.
PYRANTEL TARTRATE AGAINST T . COLUBRIFORMIS IN LAMBS 8
237
Experiment 2
Experiment I
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C
4
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3
& 2
15 . Days of experiment
Fig.
l.
25
30
35
40
45
Mean faecal egg output per gram (e.p.g.), in trea ted and control groups throughout experiments I and 2. Numerals 2·5- 7"5 indicate treatments in mg./kg./day.
Experiment
2
The data relating to this experiment are shown in Fig. I and Table 1. Egg counts. The development of the untreated infection was accompanied by faecal egg output commencing on day 19 and reaching a peak at day 40, followed by some fluctuation to the end of the experiment at day 49. The egg counts of the medicated groups remained low throughout and were related to the dose of pyrantel received. The egg count of the group receiving the lowest dose-3 mg. /kg.-was 7 per cent of the controls at the peak of excretion. Worm counts. Counts at post-mortem examination showed that 66 per cent of the administered larvae had developed and there were no immature worms present. Worm burdens of the feed-medicated groups were reduced by 97-99 per cent compared with controls. DISCUSSION
The development of the untreated infection consisting of daily doses of larvae produced similar worm burdens, with a 59- 66 per cent "take", as a single infection of a similar total number of larvae (unpublished observations). There were no inhibited larvae present at slaughter indicating that this type of immune mechanism was not operating on the later doses of larvae. However, the egg output did show signs of declining after the peak at day 41 in both experiments when all larvae given would be expected to have reached adult
BRITISH VETERINARY JOURNAL, 12 5, 5
egg-laying status. There is therefore the possibility of some immune mechanism coming into play. The egg output in the second experiment was twice that of the first despite fewer worms present. It may be that the use of younger lambs resulted in this phenomenon, or the acquisition of 2000 larvae per day is nearer the optimum than 3000 for resulting egg output. No clinical signs or weight loss appeared in the control lambs containing 24,000-36,000 worms which is surprising in view of work reported by Andrews ( I 939) and Gordon (I 950) indicating a high degree of pathogenicity at similar dosage levels. Kates & Turner ( I 953), however, found only minor effects in lambs given 50,000 larvae. Possibly a single infection is more pathogenic than daily doses even though the final worm burden is the same, or strain differences of parasite and host, as suggested by the latter authors, may explain these differences. The daily treatment with pyrantel tartrate was highly effective in preventing the development of the infection. The dose-related response over the two experiments showed a reduction of 90 per cent at 2·5 mg. /kg. and IOO per cent at IO mg. /kg., although dosages of 4·5 mg. /kg. and above were 99 per cent effective. Further experiments are necessary to establish the feasibility and economics of preventing parasitic gastro-enteritis by continuous low level anthelmintic medication in the field. ACKNOWLEDGMENTS
The authors acknowledge the able technical assistance of Misses Marcia Blore, Jean Berry and Susan Rees and Messrs K. E. R. Tyrrell and C. P. Wilkins. The Directors of the Pfizer Group are thanked for permission to publish this paper. REFERE NCES
s.
ANDREWS,J. (1939).J. agric. Res., 58, 761. AUSTIN, W. C., COURTNEY, W., DANILEWICZ, J . C., MORGAN, D . H., CONOVER , L. H ., HOWES, H. L. JR ., LYNCH, J . E., McFARLAND, W., CORNWELL, R. L. & THEODORJDES, V .
J.
J.
( 1966). Nature, Lond., 212, 1273. CORNWELL, R. L. (1966). Vet. Rec. , 79, 590. GIBSON, T . E. & PARFITT, J. W. (1968). BT. vet. ]., 124,63. GORDON, H. MeL. (1950). Aust. vet.]., 26, 14,46, 93. KATES, K. C. & TURNER, J. H . (1953) · Am. J. vet. Res., 14, 72. (Accepted for publication 13 December 1968 ) Adtninistration continue, a faible dose, de tartrate de pyrantel a des agoeaWit (dans leur nourriture). I. Prophylaxie des infections experilnentales de T. colubriformis (Cornwell etJones) ResUIDe. Dans deux experiences, on donna quotidiennement, pendant 20 jours, 2000 OU 3000 larves de T. colubriformis a des agneaux sans vers et on les traita, pendant 7 semaines, en ajoutant a leur nourriture des doses journalieres de tartrate d e pyrantel, variant de 2,5 a JO mg./kg. Le nombre d'oeufs fecaux au cours des experiences et les charges de vers a l'examen post-mortem etaient reduits de 97-100 pour cent, en comparaison avec les cas temoin des groupes recevant 3 mg./ kg. et plus.
PYRANTEL TARTRATE AGAINST T. COLUBRIFORMIS IN LAMBS
239
Kontinuierliche Verabreichung Geringer Dosen von Pyranteltartrat an Lanuner I. Propbylaxe bei experilnentellen T. colubriformis Infektionen (Cornwell und Jones) ZusaDlDlenfassung. In zwei Versuchsreihen wurden wurmfreie Lammer taglich tiber einen Zeitraum von 20 Tagen mit 2000 oder 3000 T. colubriformis Larven infiziert. Die Behandlung erfolgte tiber einen Zeitraum von 7 Wochen, indem dem Futter taglich eine Dosis von 2,5 bis 10 mg. /kg. Pyranteltartrat beigegeben wurde. Eine Zahlung der Eier in dem Auswurf wah rend der Versuche und die Wurmermittlung der Post-Mortem Untersuchung ergab, daB die Verringerung im Vergleich zu Versuchstieren, die eine Dosis von 3 mg./ kg. und mehr erhalten hatten 97- 100 Prozent niedriger lag. Acbninistracion continua de tartrato de pyrantel a bajo mvel en los piensos de los corderos. I. Profilaxis de las infecciones experiDlentales de T. colubriformis (Cornwell y Jones) ReSUDlen. En dos experimentos, se administraron 2000 0 3000 larvas de T. colubriformis a unos cord eros sin lombrices diariamente durante 20 dias, medicandose en la comida durante 7 semanas, con dosis diarias de tartrato de pyrantel que variaban de 2,5 a 10 mg./ kg. Los cuentos de huevos fecales durante los experimentos y las cargas de lombrices en los examenes despues de la muerte presentaron una reducci6n de 97- 100 por cien en comparaci6n con los animales de referencia en grupos que recibieron 3 mg./kg. 0 mas.