• 1

    Genta RM, 1989. Global prevalence of strongyloidiasis: critical review with epidemiologic insights into the prevention of disseminated disease. Rev Infect Dis 11 :755–767.

    • Search Google Scholar
    • Export Citation
  • 2

    Mahmoud AAF, 2000. Intestinal nematodes (roundworms). Mandell G, Douglas R, Bennett J, eds. Principles and Practice of Infectious Diseases. Volume 2. Philadelphia: Churchill Livingstone, 2938–2943.

  • 3

    Tarr P, Miele P, Peregoy K, Smith M, Neva F, Lucey D, 2003. Case report: rectal administration of ivermectin to a patient with Strongyloides hyperinfection syndrome. Am J Trop Med Hyg 68 :453–455.

    • Search Google Scholar
    • Export Citation
  • 4

    Boken D, Leoni P, Preheim L, 1993. Treatment of Strongyloides stercoralis hyperinfection syndrome with thiabendazole administered per rectum. Clin Infect Dis 16 :123–126.

    • Search Google Scholar
    • Export Citation
  • 5

    Chiodini P, Reid A, Wiselka M, Firmin R, Foweraker J, 2000. Parenteral ivermectin in Strongyloides hyperinfection. Lancet 355 :43–44.

  • 6

    Guzzo CA, Furtek CI, Porras AG, Chen C, Tipping R, Clineschmidt CM, Sciberras DG, Hsieh JY, Lasseter KC, 2002. Satety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. J Clin Pharmacol 42 :1122–1133.

    • Search Google Scholar
    • Export Citation
  • 7

    Fink D, Porras A, Pharmacokinetics of ivermectin in animals and humans. Campbell W, ed. Ivermectin and Abamectin. New York: Springer-Verlag, 1989:113–130.

  • 8

    Chen Y, Fleckenstein L, 2002. Liquid choromatographic assay of moxidectin in human plasma for application to pharmacokinetic studies. J Pharmaceut Biomed Anal 29 :917–926.

    • Search Google Scholar
    • Export Citation
  • 9

    Echeverria J, Mestorino N, Errecalade J, 2002. Comparative pharmacokinetics of ivermectin after its subcutaneous administration in healthy sheep and sheep infected with mange. J Vet Pharmacol Ther 25 :159–160.

    • Search Google Scholar
    • Export Citation
  • 10

    Lanusse C, Lifschitz A, Virkel G, Alvarez L, Sanchez S, Sutra JF, Galtier P, Alvinerie M, 1997. Comparative plasma disposition kinetics of ivermectin, moxidectin and doramectin in cattle. J Vet Pharmacol Ther 20 :91–99.

    • Search Google Scholar
    • Export Citation
  • 11

    Toutain P, Upson D, Terhune T, McKenzie M, 1997. Comparative pharmacokinetics of doramectin and ivermectin in cattle. Vet Parasitol 72 :3–8.

    • Search Google Scholar
    • Export Citation
  • 12

    Alvinerie M, Sutra J, Galtier P, 1993. Ivermectin in goat plasma and milk after subcutaneous injection. Vet Res 24 :417–421.

  • 13

    Barber S, Bowles V, Lespine A, Alvinerie M, 2003. The comparative serum disposition kinetics of subcuataneous administration of doramectin, ivermectin and moxidecin in the Australian Merino sheep. J Vet Pharmacol Ther 26 :343–348.

    • Search Google Scholar
    • Export Citation
  • 14

    Marriner S, McKinnon I, Bogan J, 1987. The pharmacokinetics of ivermectin after oral and subcuataneous administration to sheep and horses. J Vet Pharmacol Ther 10 :175–179.

    • Search Google Scholar
    • Export Citation
  • 15

    Baraka O, Mahmoud B, Marschke C, Gerary T, Homeida M, Williams J, 1996. Ivermectin distribution in the plasma and tissues of patients infected with Onchocerca volvulus. Eur J Clin Pharmacol 50 :407–410.

    • Search Google Scholar
    • Export Citation
  • 16

    Edwards G, Dingsdale A, Helsby N, Orme M, Breckenridge A, 1988. The relative systemic availability of ivermectin after administration as capsule, tablet, and oral solution. Eur J Clin Pharmacol 35 :681–684.

    • Search Google Scholar
    • Export Citation
  • 17

    Njoo FL, Beek WM, Keukens HJ, van Wilgenburg H, Oosting J, Stilma JS, Kijlstra A, 1995. Ivermectin detection in serum of onchocerciasis patients: relationship to adverse reactions. Am J Trop Med Hyg 52 :94–97.

    • Search Google Scholar
    • Export Citation
  • 18

    Marti H, Haji HJ, Savioli L, Chwaya HM, Mgeni AF, Ameir JS, Hatz C, 1996. A comparative trial of a single-dose ivermectin versus three days of albendazole for treatment of Strongyloides stercoralis and other soil-transmitted helminth infections in children. Am J Trop Med Hyg 55 :477–481.

    • Search Google Scholar
    • Export Citation
  • 19

    Datry A, Hilmarsdottir I, Mayorga-Sagastume R, Lyagoubi M, Gaxotte P, Biligui S, Chodakewitz J, Neu D, Danis M, Gentilini M, 1994. Treatment of Strongyloides stercoralis infection with ivermectin compared with albendazole: results of an open stud of 60 cases. Trans R Soc Trop Med Hyg 88 :344–345.

    • Search Google Scholar
    • Export Citation
  • 20

    Toma H, Sato Y, Shiroma Y, Kobayashi J, Shimabukuro I, Takara M, 2000. Comparative studies on the efficacy of three antihelminthics on treatment of human strongyloidaisis in Okinawa, Japan. Southeast Asian J Trop Med Public Health 31 :147–151.

    • Search Google Scholar
    • Export Citation
  • 21

    Adedayo O, Grell G, Bellot P, 2002. Hyperinfective strongyloidiasis in the medical ward: review of 27 Cases in 5 years. South Med J 97 :711–716.

    • Search Google Scholar
    • Export Citation
  • 22

    Klotz U, Ogbuokir J, Okonkwo P, 1990. Ivermectin bindings avidly to plasma proteins. Eur J Clin Pharmacol 39 :607–608.

  • 23

    Okonkwo P, Ogbuokiri J, Ofoegbu E, Klotz U, 1993. Protein binding and ivermectin estimations in patients with onchocerciasis. Clin Pharmacol Ther 53 :426–430.

    • Search Google Scholar
    • Export Citation
  • 24

    Edwards G, 2003. Ivermectin: does P-glycoprotein play a role in neurotoxicity? Filaria J 2 :S8.

  • 25

    Roulet A, Puel O, Gesta S, Lepage JF, Drag M, Soll M, Alvinerie M, Pineau T, 2003. MDR-1 deficient genotype in Collie dogs hypersensitive to the P-glycoprotein substrate ivermectin. Eur J Pharmacol 460 :85–91.

    • Search Google Scholar
    • Export Citation
  • 26

    Kwei GY, Alvaro RF, Chen Q, Jenkins HJ, Hop CE, Keohane CA, Ly VT, Strauss JR, Wang RW, Wang Z, Pippert TR, Umbenhauer DR, 1999. Disposition of ivermectin and cyclosporin A in CF-1 mice deficient in mdr1a P-glycoprotein. Drug Metab Dispos 27 :581–587.

    • Search Google Scholar
    • Export Citation
  • 27

    Rothova A, van der Lelij A, Stilma JS, Wilson WR, Barbe RF, 1989. Side-effects of ivermectin in treatment of onchocerciasis. Lancet 1 :1439–1441.

    • Search Google Scholar
    • Export Citation

 

 

 

 

PARENTERAL ADMINISTRATION OF IVERMECTIN IN A PATIENT WITH DISSEMINATED STRONGYLOIDIASIS

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  • 1 Division of Infectious Diseases, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada; McGill University Center for Tropical Diseases, McGill University Health Center, Montreal, Quebec, Canada; College of Pharmacy, University of Iowa, Iowa City, Iowa

We report the case of a 23-year-old Caribbean man with disseminated strongyloidiasis (co-infected with human T cell lymphotropic virus I/II)), severe hypoalbuminemia, and a paralytic ileus. Subcutaneous ivermectin (200 μg/kg) was administered daily for 14 days because of the inability to effectively administer oral albendazole and oral ivermectin. Three hours after the third daily dose of oral ivermectin, the serum ivermectin concentration was only 0.8 ng/mL, but it increased several fold to 5.8 ng/mL 16 hours after the first dose of subcutaneous ivermectin. During the course of subcutaneous treatment, ivermectin clearance was higher than expected (46.0 L/hour, normal = 31.8 L/hour). This is likely the result of severe hypoalbuminemia since ivermectin is highly protein bound. The ability to achieve adequate levels of ivermectin after oral administration in patients with disseminated strongyloidiasis may be impaired, highlighting the need for alternative routes of administration of ivermectin in these patients.

INTRODUCTION

Strongyloides stercoralis infects at least 30 million people worldwide.1 Most individuals infected with intestinal strongyloides are asymptomatic or have minor gastrointestinal symptoms. However, immunosuppressed individuals, particularly those co-infected with human T cell lymphotropic virus I/II with hematologic malignancies or those receiving corticosteroids, are at high risk for developing disseminated disease with a mortality rate up to 70%. In disseminated disease, there is extensive larval infiltration of the small bowel and migration to many other organs.2 Impaired oral absorption of antihelmintic agents in those with a paralytic ileus and disseminated strongyloidiasis may compromise effective delivery of treatment of this life-threatening condition.3,4 Unfortunately, there are no parenteral formulations of these drugs approved for use in humans and the appropriate dose, pharmacokinetics, and potential toxicity are unknown. There are only two previous case reports of ivermectin administered by other than the oral route (one subcutaneous5 and one rectal3), but neither reported pharmacokinetic data.

We describe the clinical course of a patient with disseminated strongyloidiasis who was treated for two weeks with oral albendazole and a veterinary formulation of subcutaneous ivermectin. To assess the pharmacokinetics and potential for toxicity, ivermectin levels in the serum and cerebrospinal fluid (CSF) were determined.

CASE REPORT

A 23-year-old man from St. Vincent came to our hospital with a two-week history of epigastric pain, weight loss of 15 pounds, nausea, vomiting, and not having passed stools for three days prior to admission. On admission, he was hypotensive, afebrile, and dehydrated, and had severe, generalized abdominal tenderness with guarding. Initial blood tests showed significant leukocytosis (but a normal eosinophil count of 0.2 × 109/L [reference range < 0.5 × 109/L]), pre-renal azotemia, mildly abnormal liver enzyme levels, and significant hypoalbuminemia (albumin = 7 g/L, reference range = 35–51 g/L]). Intravenous fluids and ticarcillin-clavulanate were administered and the patient underwent an emergency laparotomy for a suspected bowel perforation. During surgical exploration, diffuse, severe distension and thickening of the small bowel, enlarged mesenteric lymph nodes, and ascites were found, but there was no evidence of mechanical obstruction or bowel perforation. A lymph node biopsy was performed for diagnostic purposes.

Four days after admission, the lymph node biopsy showed S. stercoralis larvae. Treatment with albendazole (400 mg twice a day) and ivermectin (15 mg [200 μg/kg] once a day) was initiated and administered via a nasogastric tube. Abundant, motile larvae were subsequently observed in nasogastric aspirate fluid and sputa. On the sixth day after admission, 48 hours after starting antihelmintic therapy, the patient became drowsy, hypoxic, hypotensive, and febrile, which necessitated intubation, mechanical ventilation, and vasopressor support. During the next 24 hours, the gastric output was extremely high (the nasogastric tube could not be clamped even for 15 minutes) and the effectiveness of administering albendazole and ivermectin by nasogastric tube was questioned. A veterinary formulation of subcutaneous ivermectin (Ivomec, Merial Canada Inc., Victoriaville, Quebec, Canada) was therefore obtained and administered on the seventh day after admission (Table 1). Albendazole was administered for 13 days though a nasogastric tube and ivermectin (15 mg [200 μg/kg]) was administered undiluted (1.5 mL of a 10 mg/mL solution) subcutaneously.

On day 10 after admission, three days after subcutaneous ivermectin and four days after treatment with vancomycin and meropenum was started, the fever resolved, oxygen requirements decreased, and treatment with vasopressors was discontinued. The acute deterioration was likely the result of nosocomial pneumonia. Despite clinical and parasitologic improvement (Table 1), the patient remained in an unexplained coma (Glasgow coma score = 5). No cause was identified despite extensive investigations: normal results were obtained with two computed tomographic scans of the head, one un-infused magnetic resonance image of the head, three cerebrospinal fluid (CSF) examinations (normal protein, glucose, and cell counts and the absence of larvae), and an electroencephalogram that showed nonspecific encephalopathic changes but no seizure activity.

After 10 days of subcutaneous ivermectin, the patient began to hypersalivate, remained comatose, but had a normal pupil size (~ 4 mm). Because of concerns of potential ivermectin central nervous system (CNS) toxicity that manifests in humans with mydriasis, ataxia, tremors, emesis, lethargy and coma,6,7 subcutaneous ivermectin was discontinued after 14 days. Over the following week and a half, the patient was weaned from the ventilator and the salivation decreased. The patient remained comatose and died of an aspiration pneumonia 35 days after coming to the hospital. Consent for postmortem examination was denied.

Serum ivermectin concentration.

The primary site of ivermectin toxicity in humans and animals is the CNS.6,7 We investigated the potential role of ivermectin toxicity in the persistent coma and excessive salivation of the patient by determination of ivermectin concentration in serum and CSF using high-performance liquid chromatography (HPLC). The analysis used an analytical method similar to that described for moxidectin,8 a related avermectin drug. Briefly, Oasis™ HLB 30-mg cartridges (Waters, Milford, MA) were used for solid-phase extraction of plasma, serum, and CSF. Extracted samples were derivatized with 100 μL of N-methylimidazole in acetonitrile (1:1 v/v) and 150 μL of trifluoroaceticanhydride in acetonitrile (1:2 v/v). Derivatized samples were transferred to autoinjector vials and placed on a 717 plus autosampler with a 501 pump (Waters). Twenty microliters was injected into an Ultrasphere® C18 5 μm 4.6 × 250 mm column (Alltech, Deerfield, IL). The mobile phase was tetrahydrofuran-acetonitrile-water (40:38:22, v/v/v) with a flow rate of 1.0 mL/minute. An RF10AxL detector (Shimadzu, Kyoto, Japan) was used for fluorescence detection with excitation at 365 nm and emission at 475 nm. Moxidectin was the internal standard in the analysis and the assay had a detection limit of 0.2 ng/mL. The results of ivermectin analysis are shown in Table 1.

Plasma levels of ivermectin were very low (0.8 ng/mL) three hours after the third daily dose of ivermectin administered by nasogastric tube. However, within 12 hours of having received one subcutaneous dose of ivermectin, serum levels were several-fold higher (5.8 ng/mL). Over the next 14 days, subcutaneous ivermectin (15 mg [200 μg/kg]) a day produced serum ivermectin levels between 11.4 and 17.2 ng/mL with no significant accumulation. The ivermectin level was still 14.8 ng/mL 48 hours after the last dose of subcutaneous ivermectin because the peak absorption is slow after a subcutaneous dose of ivermectin (in animals ranges = 1–4 days).914 Ivermectin and its metabolites were not detected in CSF after five subcutaneous doses.

DISCUSSION

Disseminated strongyloidiasis is frequently fatal. This may be partly explained by impaired absorption of orally administered antihelmintics.35 The very low concentration of ivermectin (0.8 ng/mL) achieved in our patient after administration of ivermectin through a nasogastric tube confirms that oral bioavailability is inadequate in patients with an ileus. Conversely, subcutaneous administration produced significantly higher ivermectin levels (11.4–17.2 ng/mL) than oral administration.

The pharmacokinetics of orally administered ivermectin in humans is well known. Fifty to sixty percent of ivermectin administered as a tablet or capsule is absorbed.7 Ivermectin is detectable in plasma within one hour15 and reaches peak levels ranging from 20 to 54.4 ng/mL 4–5 hours after a single dose of 200 μg/kg.7,15,16 Ivermectin is metabolized in the liver and its metabolites are excreted primarily in the bile. In some patients, an enterohepatic cycle produces a secondary plasma peak between 6 and 12 hours after dosing.7,15 The half-life of the parent drug is 12–56 hours6,7,15,17 and the half-life of its metabolites is up to three days.7 The therapeutic plasma ivermectin range for intestinal strongyloides is not known, but at a dose of 200 μg/kg/day for 1–2 days, parasitologic cure rates range from 83% to 97%.1820

Unfortunately, parenterally administered antihelminthics have not been approved for use in humans, and the experience with alternatives to oral administration is limited to one report of rectal thiabendazole,4 one report of rectal ivermectin,3 and one report of subcutaneous ivermectin.5 There are no pharmacokinetic data on subcutaneous ivermectin in humans but the kinetics have been studied extensively in large animals. The time to maximum concentration (Cmax) in large animals ranges from 1.2 to 4 days.914 Assuming an absorption half-life in humans of approximately one day (extrapolated from animal data)914 and a relatively short elimination half-life of 12–56 hours, steady state should be reached within one week of multiple dosing. In this patient (Table 1), the mean steady-state serum ivermectin concentration was approximately 13.6 ng/mL with an estimated clearance of 46.0 L/hour (calculated by dividing the dose rate [15 mg/24 hours] by the steady-state concentration). The estimated ivermectin clearance is higher than expected for a healthy male subject (31.8 L/hour) (Vanapalli S and others, unpublished data) and may explain why the steady-state serum ivermectin levels were lower than those observed after oral dosing (mean Cmax = 87 ng/mL after 7 days of 30 mg given orally every 72 hours in healthy fasting volunteers).6

The elevated clearance of ivermectin in this patient may have been the result of his extremely low albumin level 7 g/L [reference range = 35–51 g/L] shortly after admission, which increased slowly to only 22 g/L over the course of the next three weeks. Hypoalbuminemia is common in disseminated strongyloidiasis and was found in 67% of patients in one series from the Dominican Republic.21 Ivermectin is highly bound to human serum albumin22 and the percentage of free drug therefore increases with decreasing albumin level.23 The extent of protein binding in the plasma or tissues also affects the volume of distribution of ivermectin. Individuals with low plasma protein binding will have a greater volume of distribution and lower steady-state concentrations.

The major side effect of ivermectin is neurotoxicity that usually manifests in animals and humans as mydriasis, ataxia, tremors, and emesis, followed by lethargy, coma, and death.6,7,2426 Humans can tolerate relatively high doses of ivermectin. In healthy, human volunteers, single doses of up to 2,000 μg/kg, and doses up to 1,091 μg/kg administered three times at 72-hour intervals produced no evidence of toxicity.6 A child who accidentally ingested 6,600–8,600 μg/kg had emesis, mydriasis, and sedation, but eventually recovered.7

The patient in this report had possible clinical signs of ivermectin toxicity (coma and hypersalivation). However, the plasma ivermectin concentrations in this patient were almost 20-fold lower than those that were well tolerated in human safety studies.6 Furthermore, ivermectin was undetectable in the CSF after five doses of subcutaneous ivermectin when the serum level was 12.1 ng/mL. Although ivermectin is well tolerated in healthy adults, approximately 10% of ivermectin-treated (150 μg/kg) patients with onchocerciasis showed adverse reactions that required additional medical treatment.27 In addition, in onchocerciasis patients in Sierra Leone, serum ivermectin levels did not correlate with adverse reactions.17 We therefore cannot rule out the possibility that the coma was due to either ivermectin or its metabolites (whose pharmacodynamic properties are unknown). Two metabolite peaks were noted on all chromatograms analyzed from post-admission days 16–23 in serum specimens, but not in CSF specimens. They were present in significant amounts with peak area ratios of 0.54–0.85 and 0.24–0.38 ng/mL relative to an ivermectin of 1 area ratio.

Disseminated strongyloidiasis is a challenging disease with a high mortality rate despite available effective therapy. This case highlights the need for the availability of alternative routes of administration of ivermectin given its poor oral bio-availability in the presence of an ileus. The severe hypoalbuminemia in this patient, which occurs commonly in disseminated strongyloidiasis, also raises the concern that increased clearance of ivermectin will further decrease the ability to achieve adequate levels after oral dosing. It was not completely excluded that this patient had serious CNS toxicity due to parenteral ivermectin. It would therefore be prudent for other clinicians considering using subcutaneous ivermectin in a patient with disseminated strongyloidiasis to carefully monitor signs and symptoms consistent with ivermectin CNS toxicity and to measure ivermectin levels.

Table 1

Antihelminthic therapy, parasitology, and serum ivermectin concentration

Table 1

*

Address correspondence to Christina Greenaway, Department of Microbiology, Division of Infectious Diseases, Room G-143, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Côte St., Catherine Road, Montreal, Quebec, Canada, H3T 1E2. E-mail: ca.greenaway@mcgill.ca

Authors’ addresses: Stephen A. Turner and Christina Greenaway, Department of Microbiology, Division of Infectious Diseases, Room G-143, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Côte St., Catherine Road, Montreal, Quebec, Canada, H3T 1E2, E-mails: trnrstephen@aol.com and ca.greenaway@mcgill.ca. J. Dick MacLean, McGill University for Tropical Diseases, Montreal General Hospital, 1650 Cedar Avenue, Montreal, Quebec, Canada, H3G 1A4, E-mail: dick.maclean@mcgill.ca. Lawrence Fleckenstein, University of Iowa College of Pharmacy, S-427-Phar, 115 South Grand Ave, Iowa City, IA 52242, E-mail: l-fleckenstein@uiowa.edu.

REFERENCES

  • 1

    Genta RM, 1989. Global prevalence of strongyloidiasis: critical review with epidemiologic insights into the prevention of disseminated disease. Rev Infect Dis 11 :755–767.

    • Search Google Scholar
    • Export Citation
  • 2

    Mahmoud AAF, 2000. Intestinal nematodes (roundworms). Mandell G, Douglas R, Bennett J, eds. Principles and Practice of Infectious Diseases. Volume 2. Philadelphia: Churchill Livingstone, 2938–2943.

  • 3

    Tarr P, Miele P, Peregoy K, Smith M, Neva F, Lucey D, 2003. Case report: rectal administration of ivermectin to a patient with Strongyloides hyperinfection syndrome. Am J Trop Med Hyg 68 :453–455.

    • Search Google Scholar
    • Export Citation
  • 4

    Boken D, Leoni P, Preheim L, 1993. Treatment of Strongyloides stercoralis hyperinfection syndrome with thiabendazole administered per rectum. Clin Infect Dis 16 :123–126.

    • Search Google Scholar
    • Export Citation
  • 5

    Chiodini P, Reid A, Wiselka M, Firmin R, Foweraker J, 2000. Parenteral ivermectin in Strongyloides hyperinfection. Lancet 355 :43–44.

  • 6

    Guzzo CA, Furtek CI, Porras AG, Chen C, Tipping R, Clineschmidt CM, Sciberras DG, Hsieh JY, Lasseter KC, 2002. Satety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. J Clin Pharmacol 42 :1122–1133.

    • Search Google Scholar
    • Export Citation
  • 7

    Fink D, Porras A, Pharmacokinetics of ivermectin in animals and humans. Campbell W, ed. Ivermectin and Abamectin. New York: Springer-Verlag, 1989:113–130.

  • 8

    Chen Y, Fleckenstein L, 2002. Liquid choromatographic assay of moxidectin in human plasma for application to pharmacokinetic studies. J Pharmaceut Biomed Anal 29 :917–926.

    • Search Google Scholar
    • Export Citation
  • 9

    Echeverria J, Mestorino N, Errecalade J, 2002. Comparative pharmacokinetics of ivermectin after its subcutaneous administration in healthy sheep and sheep infected with mange. J Vet Pharmacol Ther 25 :159–160.

    • Search Google Scholar
    • Export Citation
  • 10

    Lanusse C, Lifschitz A, Virkel G, Alvarez L, Sanchez S, Sutra JF, Galtier P, Alvinerie M, 1997. Comparative plasma disposition kinetics of ivermectin, moxidectin and doramectin in cattle. J Vet Pharmacol Ther 20 :91–99.

    • Search Google Scholar
    • Export Citation
  • 11

    Toutain P, Upson D, Terhune T, McKenzie M, 1997. Comparative pharmacokinetics of doramectin and ivermectin in cattle. Vet Parasitol 72 :3–8.

    • Search Google Scholar
    • Export Citation
  • 12

    Alvinerie M, Sutra J, Galtier P, 1993. Ivermectin in goat plasma and milk after subcutaneous injection. Vet Res 24 :417–421.

  • 13

    Barber S, Bowles V, Lespine A, Alvinerie M, 2003. The comparative serum disposition kinetics of subcuataneous administration of doramectin, ivermectin and moxidecin in the Australian Merino sheep. J Vet Pharmacol Ther 26 :343–348.

    • Search Google Scholar
    • Export Citation
  • 14

    Marriner S, McKinnon I, Bogan J, 1987. The pharmacokinetics of ivermectin after oral and subcuataneous administration to sheep and horses. J Vet Pharmacol Ther 10 :175–179.

    • Search Google Scholar
    • Export Citation
  • 15

    Baraka O, Mahmoud B, Marschke C, Gerary T, Homeida M, Williams J, 1996. Ivermectin distribution in the plasma and tissues of patients infected with Onchocerca volvulus. Eur J Clin Pharmacol 50 :407–410.

    • Search Google Scholar
    • Export Citation
  • 16

    Edwards G, Dingsdale A, Helsby N, Orme M, Breckenridge A, 1988. The relative systemic availability of ivermectin after administration as capsule, tablet, and oral solution. Eur J Clin Pharmacol 35 :681–684.

    • Search Google Scholar
    • Export Citation
  • 17

    Njoo FL, Beek WM, Keukens HJ, van Wilgenburg H, Oosting J, Stilma JS, Kijlstra A, 1995. Ivermectin detection in serum of onchocerciasis patients: relationship to adverse reactions. Am J Trop Med Hyg 52 :94–97.

    • Search Google Scholar
    • Export Citation
  • 18

    Marti H, Haji HJ, Savioli L, Chwaya HM, Mgeni AF, Ameir JS, Hatz C, 1996. A comparative trial of a single-dose ivermectin versus three days of albendazole for treatment of Strongyloides stercoralis and other soil-transmitted helminth infections in children. Am J Trop Med Hyg 55 :477–481.

    • Search Google Scholar
    • Export Citation
  • 19

    Datry A, Hilmarsdottir I, Mayorga-Sagastume R, Lyagoubi M, Gaxotte P, Biligui S, Chodakewitz J, Neu D, Danis M, Gentilini M, 1994. Treatment of Strongyloides stercoralis infection with ivermectin compared with albendazole: results of an open stud of 60 cases. Trans R Soc Trop Med Hyg 88 :344–345.

    • Search Google Scholar
    • Export Citation
  • 20

    Toma H, Sato Y, Shiroma Y, Kobayashi J, Shimabukuro I, Takara M, 2000. Comparative studies on the efficacy of three antihelminthics on treatment of human strongyloidaisis in Okinawa, Japan. Southeast Asian J Trop Med Public Health 31 :147–151.

    • Search Google Scholar
    • Export Citation
  • 21

    Adedayo O, Grell G, Bellot P, 2002. Hyperinfective strongyloidiasis in the medical ward: review of 27 Cases in 5 years. South Med J 97 :711–716.

    • Search Google Scholar
    • Export Citation
  • 22

    Klotz U, Ogbuokir J, Okonkwo P, 1990. Ivermectin bindings avidly to plasma proteins. Eur J Clin Pharmacol 39 :607–608.

  • 23

    Okonkwo P, Ogbuokiri J, Ofoegbu E, Klotz U, 1993. Protein binding and ivermectin estimations in patients with onchocerciasis. Clin Pharmacol Ther 53 :426–430.

    • Search Google Scholar
    • Export Citation
  • 24

    Edwards G, 2003. Ivermectin: does P-glycoprotein play a role in neurotoxicity? Filaria J 2 :S8.

  • 25

    Roulet A, Puel O, Gesta S, Lepage JF, Drag M, Soll M, Alvinerie M, Pineau T, 2003. MDR-1 deficient genotype in Collie dogs hypersensitive to the P-glycoprotein substrate ivermectin. Eur J Pharmacol 460 :85–91.

    • Search Google Scholar
    • Export Citation
  • 26

    Kwei GY, Alvaro RF, Chen Q, Jenkins HJ, Hop CE, Keohane CA, Ly VT, Strauss JR, Wang RW, Wang Z, Pippert TR, Umbenhauer DR, 1999. Disposition of ivermectin and cyclosporin A in CF-1 mice deficient in mdr1a P-glycoprotein. Drug Metab Dispos 27 :581–587.

    • Search Google Scholar
    • Export Citation
  • 27

    Rothova A, van der Lelij A, Stilma JS, Wilson WR, Barbe RF, 1989. Side-effects of ivermectin in treatment of onchocerciasis. Lancet 1 :1439–1441.

    • Search Google Scholar
    • Export Citation
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