efficacy of ivermectin on natural heartworm infections

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efficacy of ivermectin on natural heartworm infections

Postby malernee » Sun Oct 17, 2004 8:44 pm

Vet Parasitol. 2004 Oct 5;124(3-4):259-68.

Efficacy of long-term monthly administration of ivermectin on the progress of naturally acquired heartworm infections in dogs.

Venco L, McCall JW, Guerrero J, Genchi C.

Clinica Veterinaria Citta di Pavia, Viale Cremona, Pavia, Italy.

This study was designed to evaluate the efficacy of prolonged monthly ivermectin treatment against Dirofilaria immitis in client-owned dogs with naturally acquired infections and to clinically monitor the animal's response to the slow killing of heartworms, with death of the worms distributed over a period of up to 2 years. A total of 17 male and female dogs of different breeds and ages were used. Prior to treatment, all of the dogs tested positive for heartworm antigen (Ag) and all but two had microfilariae (mf). The dogs were randomly allocated to one group of seven dogs which received a commercial formulation of ivermectin (minimum, 6mcg IVM/kg) plus pyrantel (minimum, 5mg PP/kg) (Heartgard Plus trade mark Chewables, Merial, Ltd.), another group of seven dogs which received a commercial formulation of IVM (min, 6mcg/kg) (Heartgard((R)) Chewables, Merial Ltd.), and a group of three dogs which served as an untreated controls. All dogs were evaluated prior to initiation of treatment and thereafter at 3- to 5-month-intervals for mf, Ag, and radiographic and echocardiographic findings. All of the 17 dogs, with the exception of two dogs in the IVM group, had circulating mf of D. immitis prior to the 1st monthly dose, and a few also had mf of Dirofilaria repens. After 4 monthly doses, only one dog in the IVM/PP group and two dogs in the IVM group had a patent heartworm infection, and no heartworm mf were seen in the 14 treated dogs thereafter. After 10 monthly doses, the number of Ag-positive dogs in both of the treated groups decreased gradually. Efficacy, based on the reduction in number of Ag-positive dogs, was similar for the IVM/PP and IVM groups, with overall efficacy scores for the 14 dogs of 21, 21, 43, and 71% after 10, 14, 19, and 24 monthly doses, respectively. Two of the seven dogs treated with IVM/PP, one of the seven treated with IVM, and two of the three untreated controls showed echocardiographic evidence of a parasitic burden prior to treatment, and all of these scores had decreased by the end of the study. Only one dog (IVM/PP group) had a cardiovascular pattern of heartworm disease by echocardiography prior to treatment, but this dog's score increased to two and the scores of two additional dogs increased from zero to two (IVM group) or three (IVM/PP group) by the end of the study. Only 1 (IVM/PP group) of the 17 dogs showed a pulmonary pattern of heartworm disease by radiography prior to treatment, but this dog's score increased to three by the end of the study. The radiographic scores of two additional dogs in the treated groups increased from zero to three (IVM/PP) or two (IVM) by the end of the study. Thus, monthly administration of IVM to dogs with clinical, radiographic or echocardiographic evidence of heartworm disease is ill-advised and such treatment of even the asymptomatic dog should be done only with much caution and frequent monitoring by the veterinarian
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Effect of Monthly Heartworm Preventatives on Dogs

Postby malernee » Thu Oct 21, 2004 1:52 pm

Articles by Rawlings, C. A.
Journal of the American Animal Hospital Association 38:311-314 (2002)
© 2002 American Animal Hospital Association Pearls of Veterinary
Effect of Monthly Heartworm Preventatives on Dogs With Young Heartworm
Clarence A. Rawlings, DVM, PhD, Diplomate ACVS From the Department of
Small Animal Medicine, College of Veterinary Medicine, University of
Georgia, Athens, Georgia 30602-7390.

Dogs develop heartworm disease in response to live and dead heartworms.
Disease control should emphasize infection prevention by regular
administration of preventatives and surveillance testing. Two excellent
heartworm preventatives, ivermectin and milbemycin oxime, have been the
mainstays of infection prevention for approximately 20 years.1 Recent
research has established that these macrolide drugs, especially
ivermectin, have some adulticidal effect when given at 3 to 7 months
following infection with third-stage larvae of Dirofilaria immitis.2–6
This "pearl of veterinary practice" will summarize our recently
published research on how the macrolide-induced killing of young
heartworms affects the host dog, possibly your canine patient.7

Review of Heartworm Infection and Disease

Heartworm disease starts 3 months after infective larvae are
deposited at the feeding puncture wound by a carrier mosquito [Figure
1]. At 70 to 90 days, young adult worms arrive in the smaller pulmonary
arteries, especially in the caudal lung lobes.8,9 Within 3 months of
arrival in the pulmonary arteries (6 months after the mosquito bite),
the heartworms have matured and begin producing circulating microfilaria
and positive adult antigen test results.2 Even a few live worms rapidly
produce disease within the pulmonary arteries and lungs. The initial
response includes endothelial swelling, widened intercellular junctions,
sloughing of longitudinal endothelial strips, and adhesion of activated
leukocytes and platelets to the injured arterial sites. These arterial
changes produce the classical myointimal proliferative villi, and the
increased vascular permeability produces perivascular edema and
inflammation, the classical interstitial signs seen on thoracic
radiography.10,11 Arteries dilate sufficiently that the right and left
caudal lobar arteries can be seen with survey radiographs taken within a
few weeks of worms residing here.12 The disease response to live worms
is further magnified once worms begin to die, generally as a consequence
to heartworm treatment; as dying and dead worms are swept distally into
the arteries, the endothelial injury, thromboembolism, and inflammation
are accelerated. In addition to worsening of arterial disease, the
increased inflammation and permeability produces alveolar disease
adjacent to the diseased arteries,13,14 which is easily recognized on
thoracic radiography and may progress to clinical signs of severe
coughing, dyspnea, and even hemoptysis. To anticipate the changes
associated with heartworm death in the client-owned dog, it is important
that the timing of drug treatment be known and that the patient be
closely monitored. Exercise must be restricted and other treatments may
be indicated following adulticide treatment. A few months after
arsenical adulticide treatment, heartworm disease markedly resolves as
characterized by histopathology, pulmonary arteriograms, radiographs,
and cardiopulmonary function.12,15–17
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Figure 1— The life cycle of Dirofilaria immitis.

Research Findings on the Effect of the Macrolides on Young Adult

The heartworm prevention efficacy of monthly oral treatments of both
ivermectin and milbemycin is well documented both in research dogs and
in clinical practice.1,18–24 Appropriate administration during the
transmission season consistently prevents heartworm infection. Early
studies indicated that these drugs were partially effective in
preventing the development of heartworm infection even when monthly
treatments were missed.23,24 These observations have resulted in two
clinical questions. The first question concerns whether an owner can be
less compliant (i.e., miss treatments) with the monthly administration
and still prevent infection. The second question is whether this effect
is long-lasting enough that the preventative-dosing protocol can be used
to kill heartworms when diagnosed by the presence of either heartworm
antigen or microfilaria. Dr. John McCall, et al., has investigated this
effect in research dogs administered preventatives at various intervals
after artificial infection with infective larvae.2–5 McCall's studies
are rigorous and involve a well-established model of subcutaneously
injecting 50 infective larvae into heartworm-negative dogs, usually
purpose-bred beagles. At 3, 4, 5, or 7 months after infection, the dogs
are started on a monthly macrolide. These studies have been repeated and
the protocol slightly modified. The macrolide effect is defined as the
reduction of adult heartworm burden as compared to the number of
heartworms developing in the nontreated, infected control dogs. When
preventatives were started 3 months after infection, the worm number
reduction after 13 months of treatment with an ivermectin/pyrantel
pamoate combination (ivermectin) was 98%, and with milbemycin oxime
(milbemycin) it was 97%. When started at 4 months, the worm number
reduction after 12 months of ivermectin was 95% and after milbemycin the
reduction was 41%.2,3 A different study determined the efficacy of
ivermectin against 5-month-old worms when treated for 34 months to be
99%, and efficacy against 7-month-old worms when treated for 32 months
was 95%.5 In a separate research model, 8-month-old worms, which had
been transplanted from their initial host, were treated for 16 months
with the macrolides; the percent reduction of the geometric mean of the
heartworm number was 56% in the five ivermectin-treated dogs, and there
was no reduction of worm number in the five milbemycin-treated dogs.4
This effect of the macrolide to kill some young adult worms has been
termed as "reachback."4 It has been proposed that ivermectin, when used
at preventative dosages, might be a novel, highly effective, adulticidal
treatment with minimal side effects.4 In an effort to duplicate these
studies, the author followed nine groups of beagles similarly injected
with 100 infective larvae and then started on monthly macrolides at
preventative dosages. Two groups received either ivermectina or
milbemycinb starting at 3.5 months after infection and continuing for 1
year. In additional pairs of experimental groups, monthly macrolide
treatment was initiated at 4.5, 5.5, and 6.5 months after infection and
continued for 1 year. The percentage of reduction of the mean worm
population in dogs treated with ivermectin started at 3.5 months was
98%, at 4.5 months the percentage of reduction was 87%, at 5.5 months it
was 56%, and at 6.5 months it was 35%. In contrast, the worm reduction
in milbemycin-treated dogs was 57% when started at 3.5 months, 12% when
started at 4.5 months, no reduction at 5.5 months, and 15% reduction at
6.5 months. All dogs had worms at necropsy, except for two that had
ivermectin started 3.5 months after infection with infective larvae.25 A
comparison of this data with that of McCall, et al., would suggest that
there might be a continued and slowly progressive adulticide effect of
ivermectin. This could be considered as a "trickle kill."
Host Response When Macrolides are Started After Heartworm

Since young heartworms were probably being killed, the author sought
to determine if a disease response could be identified following monthly
preventative.7 The dogs (mentioned in the previous paragraph) were
radiographed at regular intervals before and after the start of the
preventative programs, and necropsies were performed 1 year after the
preventatives were begun. Another group of dogs served as nontreated
heartworm-infected controls. All dogs developed antigenemia, all had
radiographic signs of heartworm disease, and all had heartworm-related
arterial changes at necropsy.7,25 This included the two dogs that had no
live worms at necropsy performed after 1 year of ivermectin treatment
that was started 3.5 months after heartworm infection. None of the dogs
developed microfilaremia when either macrolide was started 3.5 months
after infection, and most of the dogs had only brief periods of
microfilaremia when the preventatives were started 4.5 months following
infection.25 From days 210 to 330 after infection, interstitial lung
disease was less severe in dogs started with milbemycin at 3.5 months
after infection than in dogs given ivermectin at the same time [Figures
2, 3]. The increased caudal lobar arterial and interstitial disease in
the dogs treated with ivermectin, as compared with dogs treated with
milbemycin, was attributed to the death of young worms within the caudal
pulmonary arteries. In contrast, damage to arterial surfaces was more
severe at necropsy in the dogs started on milbemycin at 4.5 months than
in the dogs started on ivermectin at the same time. Disease severity
based on radiographic and necropsy evaluations was the same for
nontreated infected dogs as for infected dogs treated with either
milbemycin or ivermectin when started at 5.5 and 6.5 months after
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Figure 2— Thoracic radiographs from a heartworm-infected dog
started on ivermectin/pyrantel pamoate 4.5 months after infection.
Interstitial and arterial disease are present in the caudal lobes 269
days after infection, lateral and ventrodorsal views. The caudal
arterial to rib diameter ratio was 1.47 for the right caudal lobe and
1.04 for the left caudal lobe. The interstitial score was an "8" on a
10-point scale for both caudal lung lobes. These arterial measurements
and interstitial scores improved over time.
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Figure 3— Interstitial scores for the right caudal lung lobe in
heartworm-infected dogs started on monthly heartworm preventatives 3.5
months after infection.
*Mean score for dogs treated with milbemycin oxime is significantly less
severe (P0.05) than the mean score for non-treated controls and dogs
treated with ivermectin/pyrantel pamoate.

Clinical Recommendations Based on "Reachback" or "Trickle Kill"

The macrolides, ivermectin and milbemycin, are approved by the Food
and Drug Administration and recommended by the American Heartworm
Society for the prevention of heartworm infection.1 When evaluated as an
adulticide, fewer worms are killed using ivermectin for 1 year as
compared to previous reports of melarsomine's efficacy.26–28 Live
worms were found at necropsy in four of the six dogs started on a 1-year
course of ivermectin preventative when the worms were 3.5 months old.
Three years of monthly treatment with ivermectin appears to be required
to approach the efficacy of the standard two injections of
melarsomine.5,26–28 This is compounded in geographic regions where
heartworm prophylaxis is only given for 6 months of the year; the effect
of intermittent monthly ivermectin treatment, as is commonly done in
these regions, is unknown. There is apparently a sufficient number of
dying worms that pulmonary and arterial disease is increased when
ivermectin is given starting at 3.5 and 4.5 months after infection.7
There is a strong rationale for knowing when an adulticide is killing
the worms so the clinician can then more fully evaluate the patient and
manage the response to the dying worms. In addition, the clinician using
melarsomine dihydrochloride knows that the drug is administered;
whereas, the monthly use of ivermectin by a client assumes client
compliance, which may not have been practiced when the dog was
developing heartworm infection.
This study reinforces the recommendation of the American Heartworm
Society that mature dogs be evaluated for infection prior to starting a
monthly preventative and that an antigen test be performed within 6 to
12 months of starting the preventative.1 The very high incidence of
occult infections during macrolide prophylaxis verifies the limited
value of microfilarial tests for surveillance testing.29,30 Any dog with
a positive antigen test should be thoroughly evaluated and, based on
clinical judgment, have the adults treated with either melarsomine or
surgical removal. If microfilaria are present after adulticide
treatment, a microfilaricide should be administered, and an antigen test
should then be performed approximately 3 months after the adulticide
treatment. After completion of treatment to eliminate adult heartworms,
dogs should be started on a preventative program.1

This project was initially reported in Veterinary Therapeutics
This research was sponsored by Novartis Animal Health US Inc.,
Greensboro, North Carolina.
a Heartgard-30; Merial Ltd, Duluth, GA
b Interceptor; Novartis Animal Health, Greensboro, NC

American Heartworm Society: 1999 guidelines for the diagnosis,
prevention, and management of heartworm (Dirofilaria immitis) infection
in dogs. In: Seward RL, ed. Recent advances in heartworm disease:
Symposium '98. Batavia, Illinois: American Heartworm Society,
McCall JW, McTier TL, Supakorndej N, et al. Clinical prophylactic
activity of macrolides on young heartworms. In: Soll MD, Knight DH, eds.
Recent advances in heartworm disease: Symposium '95. Batavia, Illinois:
American Heartworm Society, 1995:187–195. McCall JW, McTier TL, Ryan
WG, et al. Evaluation of ivermectin and milbemycin oxime efficacy
against Dirofilaria immitis infections of three and four months'
duration in dogs. Am J Vet Res 1996;57:1189–1192.[Medline]
McCall JW, Ryan WG, Roberts RE, et al. Heartworm adulticide activity of
prophylactic doses of ivermectin (6 µg/kg) plus pyrantel administered
monthly to dogs. In: Seward RL, Knight DH, eds. Recent advances in
heartworm disease: Symposium '98. Batavia, Illinois: American Heartworm
Society, 1998:209–215.
McCall JW, Roberts RE, Suakornjej MS, et al. Further evidence of
clinical prophylactic (reach-back) and adulticide activity of monthly
administration of ivermectin and pyrantel pamoate in dogs experimentally
infected with heartworms. 10th triennial Heartworm Symposium 2001, San
Antonio, Texas: 46.
Bowman DD, Neuman NR, Rawlings CA, et al. Effects of avermectins on
microfilariae in dogs with existing and developing heartworm infections.
10th triennial Heartworm Symposium 2001, San Antonio, Texas: 44.
Rawlings CA, Bowman DD, Howerth EW, Stansfield DG, Luempert LG. Response
of dogs treated with ivermectin and milbemycin started at various
intervals after Dirofilaria immitis infection. Vet Ther Res Appl Vet Med
Rawlings CA. Heartworm disease in dogs and cats. Philadelphia: WB
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Boreham PFL, Atwell RB. Dirofilariasis. Boca Raton, Florida: CRC Press,
Schaub RG, Rawlings CA, Keith JC Jr. Platelet adhesion and myointimal
proliferation in canine pulmonary arteries. Am J Pathol
Keith JC Jr, Schaub RG, Rawlings CA. Early arterial injury-induced
myointimal proliferation in canine pulmonary arteries. Am J Vet Res
Rawlings CA, Losonsky JM, Lewis RE, McCall JW. Development and
resolution of radiographic lesions in canine heartworm disease. J Am Vet
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JP, Lewis RE, Duncan JR. Pulmonary thromboembolism and hypertension
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reduce female heartworm mass with ivermectin

Postby malernee » Sun Nov 28, 2004 4:26 pm

Efficacy Of Long-Term Monthly Administration Of Ivermectin On The Progress Of Naturally Acquired Heartworm Infections In Dogs
Symposium Of The American Heartworm Society 2004

"AHS 2003 canine guidelines now state, 'it is also beneficial to administer a prophylactic dose(s) of ivermectin for one to six months prior to administration of melarsomine, when the presentation does not demand immediate intervention. The reasoning for this approach is to greatly reduce or eliminate circulating microfilariae and migrating larvae, stunt immature D. immitis and reduce female worm mass by destroying the reproductive system. This results in reduced antigenic mass, which in turn reduces the risk of thromboembolism.'"
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Wolbachia filaria chemotaxis of neutrophils

Postby malernee » Mon Nov 29, 2004 4:05 pm

1: Microbes Infect. 2001 May;3(6):439-46. Related Articles, Links

Neutrophil accumulation around Onchocerca worms and chemotaxis of neutrophils are dependent on Wolbachia endobacteria.

Brattig NW, Buttner DW, Hoerauf A.

Department of Clinical Chemistry, Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Strasse 74, D-20359 Hamburg, Germany. nbrattig@bni.uni-hamburg.de

Unlike in many other helminth infections, neutrophilic granulocytes are major cellular components in the hosts immune response against filarial worms. The pathways that drive the immune response involving neutrophils are unclear. This study shows that Wolbachia endobacteria (detectable by polyclonal antibodies against endobacterial heat shock protein 60 and catalase and by polymerase chain reaction being sensitive to doxycycline treatment) are direct and indirect sources of signals accounting for neutrophil accumulation around adult Onchocerca volvulus filariae. Worm nodules from untreated onchocerciasis patients displayed a strong neutrophil infiltrate adjacent to the live adult worms. In contrast, in patients treated with doxycycline to eliminate the endobacteria from O. volvulus and to render the worms sterile, the neutrophil accumulation around live adult filariae was drastically reduced. Neutrophils were absent in worm nodules from the deer filaria Onchocerca flexuosa, a species which does not contain endobacteria. Extracts of O. volvulus extirpated from untreated patients showed neutrophil chemotactic activity and in addition, induced strong TNF-alpha and IL-8 production in human monocytes, in contrast to filarial extracts obtained after doxycycline treatment. Thus, neutrophil chemotaxis and activation are induced directly by endobacterial products and also indirectly via chemokine induction by monocytes. These results show that the neutrophil response is a characteristic of endobacteria-containing filariae.

PMID: 11377205 [PubMed - indexed for MEDLINE]
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