10 research outputs found
Ivermectin treatment of Loa loa hyper-microfilaraemic baboons (Papio anubis): Assessment of microfilarial loads, haematological and biochemical parameters and histopathological changes following treatment.
Individuals with high intensity of Loa loa are at risk of developing serious adverse events (SAEs) post treatment with ivermectin. These SAEs have remained unclear and a programmatic impediment to the advancement of community directed treatment with ivermectin. The pathogenesis of these SAEs following ivermectin has never been investigated experimentally. The Loa/baboon (Papio anubis) model can be used to investigate the pathogenesis of Loa-associated encephalopathy following ivermectin treatment in humans. 12 baboons with microfilarial loads > 8,000mf/mL of blood were randomised into four groups: Group 1 (control group receiving no drug), Group 2 receiving ivermectin (IVM) alone, Group 3 receiving ivermectin plus aspirin (IVM + ASA), and Group 4 receiving ivermectin plus prednisone (IVM + PSE). Blood samples collected before treatment and at Day 5, 7 or 10 post treatment, were analysed for parasitological, hematological and biochemical parameters using standard techniques. Clinical monitoring of animals for side effects took place every 6 hours post treatment until autopsy. At autopsy free fluids and a large number of standard organs were collected, examined and tissues fixed in 10% buffered formalin and processed for standard haematoxylin-eosin staining and specific immunocytochemical staining. Mf counts dropped significantly (p0.05). All animals became withdrawn 48 hours after IVM administration. All treated animals recorded clinical manifestations including rashes, itching, diarrhoea, conjunctival haemorrhages, lymph node enlargement, pinkish ears, swollen face and restlessness; one animal died 5 hours after IVM administration. Macroscopic changes in post-mortem tissues observed comprised haemorrhages in the brain, lungs, heart, which seen in all groups given ivermectin but not in the untreated animals. Microscopically, the major cellular changes seen, which were present in all the ivermectin treated animals included microfilariae in varying degrees of degeneration in small vessels. These were frequently associated with fibrin deposition, endothelial changes including damage to the integrity of the blood vessel and the presence of extravascular erythrocytes (haemorrhages). There was an increased presence of eosinophils and other chronic inflammatory types in certain tissues and organs, often in large numbers and associated with microfilarial destruction. Highly vascularized organs like the brain, heart, lungs and kidneys were observed to have more microfilariae in tissue sections. The number of mf seen in the brain and kidneys of animals administered IVM alone tripled that of control animals. Co-administration of IVM + PSE caused a greater increase in mf in the brain and kidneys while the reverse was noticed with the co-administration of IVM + ASA. The treatment of Loa hyper-microfilaraemic individuals with ivermectin produces a clinical spectrum that parallels that seen in Loa hyper-microfilaraemic humans treated with ivermectin. The utilization of this experimental model can contribute to the improved management of the adverse responses in humans
Microscopic lesions present in the untreated and in the first 72 hours after treatment.
<p>A. Microfilariae in dermal vessels. B. Eosinophil accumulation in the tissues, a typical response in the first 24 hours, C. Blood vessel free of mf- many normal vessels can also be seen free of mf in this phase, D. Accumulation of mf in the lymphoid tissues, an event that is common within the first 2–3 days, E. Fibrin deposition (red) on the walls of a cerebral vessel. F. Area of mf degeneration and eosinophil accumulation/degranulation in a lymph node.</p
Potential pathogenesis of Loa encephalopathy following the ivermectin treatment of Loa hyper-microfilaraemic individuals.
<p>Potential pathogenesis of Loa encephalopathy following the ivermectin treatment of Loa hyper-microfilaraemic individuals.</p
Blood peripheral mf loads before and after different treatments.
<p>Blood peripheral mf loads before and after different treatments.</p
Presence and extent of histo-pathological changes in different organs (No. of animals per group).
<p>Presence and extent of histo-pathological changes in different organs (No. of animals per group).</p
Microscopic lesions present in the untreated and in the first 72 hours after treatment.
<p>A. Microfilariae in dermal vessels. B. Eosinophil accumulation in the tissues, a typical response in the first 24 hours, C. Blood vessel free of mf- many normal vessels can also be seen free of mf in this phase, D. Accumulation of mf in the lymphoid tissues, an event that is common within the first 2–3 days, E. Fibrin deposition (red) on the walls of a cerebral vessel. F. Area of mf degeneration and eosinophil accumulation/degranulation in a lymph node.</p
The typical behavioral response after treatment: Depression and reluctance to participate in normal activities.
<p>The typical behavioral response after treatment: Depression and reluctance to participate in normal activities.</p
Changes in <i>Loa</i> mf loads with different treatment regimes.
<p>: ivermectin alone (IVM), ivermectin and aspirin (IVM+ASA), and ivermectin and prednisone (IVM+PSE).</p
Microscopic lesions present in the treated animals more than 72 hours after treatment.
<p>A. Adult L. loa worm in connective tissue beneath the skin. B. Blocked CNS vessel comprised of eosinophils, fibrin, macrophages and parasite debris. C. Blocked CNS vessels with associated damage (vacuolation of the parenchyma). D. Intact microfilariae caught in a cellular intravascular mass in the CNS, E. A degenerating mf in a capillary of the CNS and surrounded by fibrin. F. Area of vascular and parenchymal damage in the CNS predominately filled with macrophages and eosinophils.</p
Distribution of L. loa mf in the tissues of different organs in the four experimental groups: Control animals, animals given ivermectin alone, animals given ivermectin and aspirin animals, and animals given ivermectin and prednisone.
<p>Distribution of L. loa mf in the tissues of different organs in the four experimental groups: Control animals, animals given ivermectin alone, animals given ivermectin and aspirin animals, and animals given ivermectin and prednisone.</p