Diagnosis and treatment of endometriosis in a hooded capuchin (Sapajus apella).

Spontaneous endometriosis is common in women, great apes and Old World monkeys, but rare in New World monkeys. We report on the clinical diagnosis and successful combination of surgical and medical treatment in a case of spontaneous endometriosis in a diabetic hooded capuchin. Addressing this painful condition had a positive welfare impact.

Treatment of primate platynosomosis: A word of caution about the use of praziquantel in marmosets.

BACKGROUND: The successive reports of Platynosomum illiciens in Neotropical captive primates have increased interest in platynosomosis; however, its treatment is little known. METHODS: Callithrix penicillata (n = 10) naturally and chronically infected with P. illiciens were treated with praziquantel (25 mg/kg BW, three s.c. doses at 24 hours intervals), and coproparasitological tests performed over 67 days. The proportions of primates with a reduction in fecal egg counts (FEC) or negative results progressively increased after treatment, and at the last fecal tests, marmosets were negative. RESULTS AND CONCLUSIONS: Although all primates tolerated the initial days of study well, 40% (4/10) of them died between the 8th and 16th days after the onset of treatment. Clinical signs and necropsies indicated the occurrence of hepatic involvement, biliary obstruction, and cholangitis. Marmosets with a higher previous FEC were more likely to die after treatment. Use of praziquantel should be considered carefully on a case-by-case basis.

Remdesivir (GS-5734) Is Efficacious in Cynomolgus Macaques Infected With Marburg Virus.

Marburg virus (MARV) is a filovirus with documented human case-fatality rates of up to 90%. Here, we evaluated the therapeutic efficacy of remdesivir (GS-5734) in nonhuman primates experimentally infected with MARV. Beginning 4 or 5 days post inoculation, cynomolgus macaques were treated once daily for 12 days with vehicle, 5 mg/kg remdesivir, or a 10-mg/kg loading dose followed by 5 mg/kg remdesivir. All vehicle-control animals died, whereas 83% of animals receiving a 10-mg/kg loading dose of remdesivir survived, as did 50% of animals receiving a 5-mg/kg remdesivir regimen. Remdesivir-treated animals exhibited improved clinical scores, lower plasma viral RNA, and improved markers of kidney function, liver function, and coagulopathy versus vehicle-control animals. The small molecule remdesivir showed therapeutic efficacy in this Marburg virus disease model with treatment initiation 5 days post inoculation, supporting further assessment of remdesivir for the treatment of Marburg virus disease in humans.

Paromomycin sulfate is an effective treatment for balantidiasis in captive cynomolgus monkeys.

There are few effective antimicrobial agents against Balantidium coli infection. The effect of paromomycin sulfate (PS) against B. coli was confirmed in this study of 596 captive cynomolgus monkeys. In several trials, the minimum dose and duration of oral administration of PS were 25 mg/day for 5 + 5 days, with a 2-day withdrawal interval. To facilitate daily PS administration, pumpkin cakes supplemented with PS were made, which not only resulted in precise effects but also increased the efficiency of preparation and administration of PS by the animal care staff. No cysts or trophozoites were detected at 14 or 16 days after the last treatments. There were no obvious differences in blood and biochemical parameters between before and after administration of PS. These results indicate that PS is effective for elimination of B. coli without hematological side effects. These data could contribute to the control of microbiological pathogens during veterinary care and colony management in primate facilities.

Critical analysis of a doxycycline treatment trial of rhesus macaques infected with Borrelia burgdorferi.

A critical analysis was conducted of a doxycycline treatment trial of Indian rhesus macaques. In this treatment trial, the investigators attempted to infect the primates with Borrelia burgdorferi sensu stricto by at least 10 tick bites from artificially infected ticks. None of the primates became ill; nevertheless, 5 primates were treated with a 28-day course of oral doxycycline. In contrast to the conclusions of the authors, the data did not convincingly document the existence of viable B. burgdorferi in antibiotic-treated primates. The investigators were unable to cultivate the spirochete from any animal after treatment using highly sensitive in vitro methods. Like many prior animal studies, the current study also did not document that the doxycycline exposure in these animals was similar to that expected in humans. Numerous additional methodologic problems are discussed.

SUCCESSFUL TREATMENT OF GENERALIZED DEMODICOSIS IN RED-HANDED TAMARINS ( SAGUINUS MIDAS) USING A SINGLE ADMINISTRATION OF ORAL FLURALANER.

Two adult sibling red-handed tamarins ( Saguinus midas) presented with weight loss and multifocal skin masses. A skin biopsy revealed pyogranulomatous dermatitis with intrafollicular Demodex sp. mites. Subsequent skin scrapes confirmed the presence of live mites within lesions. Initial treatment with topical and oral ivermectin was unsuccessful, and lesions continued to progress. A single dose of fluralaner (Bravecto®, Merck Animal Health, Kenilworth, New Jersey, 07033, USA; 28.125 mg po) was administered to each animal approximately 5 mo after initial presentation. Lesions resolved over the next 3 mo, and all follow-up skin scrapes were negative for both animals. No adverse effects were noted. A single oral administration of fluralaner at 30-35 mg/kg appears adequate and safe for the treatment of generalized demodicosis in red-handed tamarins.

Management of Ocular Human herpesvirus 1 Infection in a White-faced Saki Monkey (Pithecia pithecia).

A 20-y-old male intact white-faced saki monkey (Pithecia pithecia) presented with an acute ocular disease of the right eye. Clinical signs included periocular swelling, conjunctivitis, and anisocoria with a miotic right pupil. Conjunctival swabs were positive for Human herpesvirus 1 (HHV1) according to PCR amplification with sequencing. Initial clinical signs resolved with supportive treatment, and the animal was managed chronically by using acyclovir (5 mg/kg PO twice daily) during flare-ups. After more than 2 y, the progression of clinical disease led to enucleation of the right eye. At 2 mo after surgery, acute presentation of severe neurologic signs, including ataxia and blindness, resulted in euthanasia. Histopathology, PCR analysis, and sequencing results were consistent with viral encephalitis due to HHV1; coinfection with Pithecia pithecia lymphocryptovirus 1 was identified. This report describes the first case of managed HHV1 infection in a platyrrhine primate and the first case of HHV1 in a white-faced saki monkey that was not rapidly fatal.

A Surgical Procedure for the Administration of Drugs to the Inner Ear in a Non-Human Primate Common Marmoset (Callithrix jacchus).

Hearing research has long been facilitated by rodent models, although in some diseases, human symptoms cannot be recapitulated. The common marmoset (Callithrix jacchus) is a small, easy-to-handle New World monkey which has a similar anatomy of the temporal bone, including the middle ear ossicular chains and inner ear to humans, than in comparison with that of rodents. Here, we report a reproducible, safe, and rational surgical approach to the cochlear round window niche for the drug delivery to the inner ear of the common marmoset. We adopted posterior tympanotomy, a procedure used clinically in human surgery, to avoid manipulation of the tympanic membrane that may cause conductive hearing loss. This surgical procedure did not lead to any significant hearing loss. This approach was possible due to the large bulla structure of the common marmoset, although the lateral semicircular canal and vertical portion of the facial nerve should be carefully considered. This surgical method allows us to perform the safe and accurate administration of drugs without hearing loss, which is of great importance in obtaining pre-clinical proof of concept for translational research.

PUSTULAR DERMATITIS CAUSED BY IMPETIGO IN RED-TAILED MONKEYS ( CERCOPITHECUS ASCANIUS).

Impetigo is a bacterial infection of the superficial layer of the epidermis with crusting or bullae caused by Streptococcus spp., Staphylococcus spp., or both. A 14-yr-old red-tailed monkey ( Cercopithecus ascanius) presented with recurrent scabbing and ulceration under the nares over an 8-yr period. Repeated cultures and biopsy samples led to a presumptive diagnosis of impetigo, later confirmed on necropsy. Multiple antibiotic regimens were employed with varying success during multiple episodes, while lesions resolved on their own at other times. This condition has not been previously reported in a nonhuman primate, although it is not uncommon in humans.

Whole body clonality analysis in an aggressive STLV-1 associated leukemia (ATLL) reveals an unexpected clonal complexity.

HTLV-1 causes Adult T cell Leukemia/Lymphoma (ATLL) in humans. We describe an ATL-like disease in a 9 year-old female baboon naturally infected with STLV-1 (the simian counterpart of HTLV-1), with a lymphocyte count over 1010/L, lymphocytes with abnormal nuclear morphology, and pulmonary and skin lesions. The animal was treated with a combination of AZT and alpha interferon. Proviral load (PVL) was measured every week. Because the disease continued to progress, the animal was euthanized. Abnormal infiltrates of CD3+CD25+ lymphocytes and Tax-positive cells were found by histological analyses in both lymphoid and non-lymphoid organs. PVL was measured and clonal diversity was assessed by LM-PCR (Ligation-Mediated Polymerase Chain Reaction) and high throughput sequencing, in blood during treatment and in 14 different organs. The highest PVL was found in lymph nodes, spleen and lungs. One major clone and a number of intermediate abundance clones were present in blood throughout the course of treatment, and in organs. These results represent the first multi-organ clonality study in ATLL. We demonstrate a previously undescribed clonal complexity in ATLL. Our data reinforce the usefulness of natural STLV-1 infection as a model of ATLL.

TREATMENT OF DIABETES MELLITUS IN A GOLDEN LION TAMARIN (LEONTOPITHECUS ROSALIA) WITH THE GLUCAGON-LIKE PEPTIDE-1 MIMETIC EXENATIDE.

An 8-yr-old male golden lion tamarin ( Leontopithecus rosalia ) was diagnosed with diabetes mellitus based on hyperglycemia and persistent glycosuria. Initial treatment consisted of the oral antihyperglycemic medications glipizide and metformin that resulted in decreased blood glucose concentrations; however, marked glycosuria persisted. Insufficient improvement on oral antihyperglycemic therapy and poor feasibility of daily subcutaneous insulin therapy led to an investigation into an alternative therapy with extended-release exenatide, a glucagon-like peptide-1 (GLP-1) mimetic, at a dosage of 0.13 mg/kg subcutaneously once per month. Following treatment with exenatide, the persistent glycosuria resolved, the animal maintained normal blood glucose concentrations, and had lower serum fructosamine concentrations compared to pretreatment levels. Based on these findings, extended-release exenatide could be considered as a therapeutic option in nonhuman primates with diabetes mellitus that do not respond to oral antihyperglycemics and in which daily subcutaneous insulin is not feasible.

Therapy of calcium oxalate urolithiasis in a rhesus macaque (Macaca mulatta).

A rhesus macaque (Macaca mulatta) was presented for anuria. Examination revealed calcium oxalate concrements in the bladder. A cystotomy was performed, and a therapy with alfuzosin was conducted. Over 1 year after the treatment, the rhesus macaque had not shown any more signs of stranguria. This is the first case reporting the successful treatment of urolithiasis in a rhesus macaque.

MEDICAL MANAGEMENT OF LEIOMYOMATA AND SUSPECTED ENDOMETRIOSIS IN AN ALLEN'S SWAMP MONKEY (ALLENOPITHECUS NIGROVIRIDUS).

A 13-yr-old female nulliparous Allen's swamp monkey (Allenopitchecus nigroviridis) presented with intermittent excessive vaginal bleeding, cyclical lethargy, and a history of irregular menstrual cycles. Abdominal ultrasonography revealed a subjectively thickened, irregular endometrium, multiple leiomyomata (uterine fibroids), and bilateral anechoic foci on the ovaries. Treatment was initiated with leuprolide acetate i.m. monthly for 6 mo. Recheck ultrasound at 3 mo showed a decrease in leiomyoma diameter and no evidence of active follicles on the ovaries. Eleven months following completion of treatment, clinical signs recurred and the animal was treated with a deslorelin implant. Since implant placement, no vaginal bleeding has been noted.

Protection from pulmonary tissue damage associated with infection of cynomolgus macaques by highly pathogenic avian influenza virus (H5N1) by low dose natural human IFN-α administered to the buccal mucosa.

Using an established nonhuman primate model for H5N1 highly pathogenic influenza virus infection in humans, we have been able to demonstrate the prophylactic mitigation of the pulmonary damage characteristic of human fatal cases from primary influenza virus pneumonia with a low dose oral formulation of a commercially available parenteral natural human interferon alpha (Alferon N Injection®). At the highest oral dose (62.5IU/kg body weight) used there was a marked reduction in the alveolar inflammatory response with minor evidence of alveolar and interstitial edema in contrast to the hemorrhage and inflammatory response observed in the alveoli of control animals. The mitigation of severe damage to the lower pulmonary airway was observed without a parallel reduction in viral titers. Clinical trial data will be necessary to establish its prophylactic human efficacy for highly pathogenic influenza viruses.

Dose titration of deferasirox iron chelation therapy by magnetic resonance imaging for chronic iron storage disease in three adult red bald-headed uakari (Cacajao calvus rubicundus).

Iron overload is common in lemurs and some New World nonhuman primates raised in captivity, but there is no such documentation in the red bald-headed uakari (Cacajao calvus rubicundus). This study describes postmortem documentation of severe iron storage disease in one red bald-headed uakari and the use of iron chelation with oral deferasirox in the three surviving members of the colony. Magnetic resonance imaging was used to quantify pretreatment iron burden and to follow the response to therapy in two females, 22 and 28 yr of age, and one male 33 yr of age. Baseline liver iron concentrations ranged from 16 to 23 mg/g dry weight. In humans, a liver iron concentration greater than 15 mg/g is considered severe and associated with endocrine and cardiac toxicity. The uakaris were otherwise asymptomatic, generally healthy, nonpregnant, and on a stable, low-iron diet. Quantitative magnetic resonance imaging indicated that dosage escalations up to 100 mg/kg were needed to produce meaningful reductions in iron stores. After 5 yr of therapy, two animals continue at a dosage of 100 mg/kg per day, and the third was transitioned to twice-weekly maintenance dosing because of successful de-ironing. The animals tolerated iron chelation therapy well, having stable hematologic, renal, and hepatic function profiles before, during, and after treatment. Deferasirox monotherapy may represent a therapeutic option in primates with iron storage disease when dietary measures are ineffective and phlebotomy is logistically challenging.

Efficacy of antibiotic-impregnated polymethylmethacrylate beads in a rhesus macaque (Macaca mulatta) with osteomyelitis.

Here we describe the successful surgical implementation of antibiotic-impregnated polymethylmethacrylate beads in a rhesus macaque (Macaca mulatta) with marked osteomyelitis. The macaque presented to the veterinary clinic with grossly contaminated bite wounds in the left ankle secondary to conspecific trauma. Radiographic findings were highly suggestive of osteomyelitis. Additional differential diagnoses included bony infarct, fracture, and cellulitis. In light of the location of the lesion and extensive tissue trauma, the animal had a poor prognosis. Systemic, broad-spectrum antibiotics were instituted. After 2 wk of care, lesions did not respond to empirical therapies. On consultation, a veterinary orthopedic surgeon at another facility recommended placement of antibiotic-impregnated polymethylmethacrylate beads at the sites of osteomyelitis. The animal underwent minor surgery in which beads were introduced into the wound. The monkey had a positive response to therapy. The animal regained full function and was returned to outdoor social housing. Veterinarians are encouraged to consider using antibiotic-impregnated polymethylmethacrylate beads when treating osteomyelitis in other nonhuman primates and in other traditional laboratory animal species.

Chronic anemia and effects of iron supplementation in a research colony of adult Rhesus macaques (Macaca mulatta).

A cohort of rhesus macaques used in neuroscience research was found at routine examinations to have chronic anemia (spun Hct less than 30%). Four anemic (Hct, 24.8% ± 3.4%) and 10 control (39.6% ± 2.9%) macaques were assessed to characterize the anemia and determine probable cause(s); some animals in both groups had cephalic implants. Diagnostic tests included CBC, bone marrow evaluations, iron panels, and serum erythropoietin and hepcidin concentrations. Serum iron and ferritin were 15.8 ± 11.1 µg/dL and 103.8 ± 53.1 ng/mL, respectively, for the anemic group compared with 109.8 ± 23.8 µL/dL and 88.5 ± 41.9 ng/mL, respectively, for the control group. Erythropoietin levels were 16.2 to over 100 mU/mL for the anemic macaques compared with 0 to 1.3 mU/mL for the control group. Hepcidin results were similar in both groups. Because the findings of low iron, high erythropoietin, and normal hepcidin in the anemic macaques supported iron-deficiency anemia or anemia of chronic disease combined with iron-deficiency anemia, a regimen of 4 doses of iron dextran was provided. In treated macaques, Hct rose to 36.3% ± 6.8%, serum iron levels increased to 94.0 ± 41.9 µg/dL, and erythropoietin levels fell to 0.15 to 0.55 mU/mL. Maintenance of normal Hct was variable between macaques and reflected individual ongoing clinical events.

Mucocutaneous candidiasis in a mandrill (Mandrillus sphinx).

An adult male mandrill (Mandrillus sphinx) suffered from chronic ulceration of the facial and gluteal skin and the oral and nasal mucosa. The ulcers were resistant to therapy and led to deterioration in the general condition of the animal. Microscopical examination revealed a severe, chronic, multifocal, granulomatous and eosinophilic dermatitis and panniculitis. There was also stomatitis and rhinitis with numerous intralesional fungal elements. These organisms were identified by immunohistochemistry, transmission electron microscopy, polymerase chain reaction and fungal culture as Candida albicans. Species identification was confirmed by MALDI-TOF mass spectrometry. A specific predisposing immunosuppressive factor for the deep chronic mucocutaneous candidiasis was not identified; however, social stress and/or a primary defect in cell-mediated immunity could not be excluded as possible causes for a predisposing immunodeficiency in the animal.

Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys.

PURPOSE: Evaluate the efficacy of an SN-38-anti-Trop-2 antibody-drug conjugate (ADC) against several human solid tumor types, and to assess its tolerability in mice and monkeys, the latter with tissue cross-reactivity to hRS7 similar to humans. EXPERIMENTAL DESIGN: Two SN-38 derivatives, CL2-SN-38 and CL2A-SN-38, were conjugated to the anti-Trop-2-humanized antibody, hRS7. The immunoconjugates were characterized in vitro for stability, binding, and cytotoxicity. Efficacy was tested in five different human solid tumor-xenograft models that expressed Trop-2 antigen. Toxicity was assessed in mice and in Cynomolgus monkeys. RESULTS: The hRS7 conjugates of the two SN-38 derivatives were equivalent in drug substitution (∼ 6), cell binding (K(d) ∼ 1.2 nmol/L), cytotoxicity (IC(50) ∼ 2.2 nmol/L), and serum stability in vitro (t/(½) ∼ 20 hours). Exposure of cells to the ADC demonstrated signaling pathways leading to PARP cleavage, but differences versus free SN-38 in p53 and p21 upregulation were noted. Significant antitumor effects were produced by hRS7-SN-38 at nontoxic doses in mice bearing Calu-3 (P ≤ 0.05), Capan-1 (P < 0.018), BxPC-3 (P < 0.005), and COLO 205 tumors (P < 0.033) when compared to nontargeting control ADCs. Mice tolerated a dose of 2 × 12 mg/kg (SN-38 equivalents) with only short-lived elevations in ALT and AST liver enzyme levels. Cynomolgus monkeys infused with 2 × 0.96 mg/kg exhibited only transient decreases in blood counts, although, importantly, the values did not fall below normal ranges. CONCLUSIONS: The anti-Trop-2 hRS7-CL2A-SN-38 ADC provides significant and specific antitumor effects against a range of human solid tumor types. It is well tolerated in monkeys, with tissue Trop-2 expression similar to humans, at clinically relevant doses, and warrants clinical investigation.

Acute necrotic stomatitis (noma) associated with methicillin-resistant Staphylococcus aureus infection in a newly acquired rhesus macaque (Macaca mulatta).

BACKGROUND: A newly acquired rhesus macaque was suffering from rapid destruction of the left cheek caused by necrotizing stomatitis. METHODS: To restore reconstructive surgery and intensive care with antibiotics, wound protection, wound healing agents, and debridement were applied. RESULTS: Staphylococcus aureus and Enterococcus faecalis were isolated from the culture of the lesion, and the antibiotic susceptibility test revealed methicillin-resistant Staphylococcus aureus infection. Vancomycin and ampicillin-sulbactam effectively treated the bacterial infections, and reconstructive surgery was performed once the infection was cleared. Topical application of recombinant human epidermal growth factor (rhEGF) was useful to treat exposed wound of the noma lesion. CONCLUSIONS: Simian noma associated with methicillin-resistant Staphylococcus aureus (MRSA) had not previously been reported in non-human primates. Although noma associated with MRSA is hard to cure because of its rapid and destructive progress, the aggressive therapy used in this study led to the successful resolution of an acute necrotic stomatitis lesion in a rhesus macaque.