Papers by Montip Gettayacamin
APMIS, 2013
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Contemporary topics in laboratory animal science / American Association for Laboratory Animal Science
The lesser bandicoot rat (Bandicota savilei) is a wild field rat commonly found in Thailand. Vagi... more The lesser bandicoot rat (Bandicota savilei) is a wild field rat commonly found in Thailand. Vaginal smears were obtained from five colony-born animals twice daily for 28 days and stained with Giemsa stain. The external appearance of the vulva and appearance of the tip of vaginal swabs were recorded. All cells, including nucleated or keratinized epithelial cells and leukocytes, were quantified by percentage. No changes of the external genitalia were observed. The gross appearance of the vaginal swab may distinguish estrus and diestrus. Vaginal swabs contained a white or yellow material during estrus or diestrus, respectively. Changes in vaginal cytology at each stage of the estrous cycle of the lesser bandicoot rat were similar to those of the common laboratory rat. Estrus stages of the five rats occurred every 3 or 4 days. One female was introduced to a male after diestrus and produced a litter of six pups 27 days after pairing.
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The American journal of tropical medicine and hygiene
Male rhesus monkeys (Macaca mulatta) were administered daily doses of the antimalarial drug artee... more Male rhesus monkeys (Macaca mulatta) were administered daily doses of the antimalarial drug arteether. The 14-day treated group received either 24 mg/kg/day, 16 mg/kg/day, or 8 mg/kg/day. The seven-day treatment group received either 24 mg/kg/day or 8 mg/kg/day. All control cases in each group received the sesame oil vehicle alone. Neurologic signs were absent for animals in the seven and 14-day treatment groups except for one monkey which showed diffuse piloerection on day 14, and another monkey receiving 24 mg/kg/day for seven days showed mild lethargy after the fourth day. Mild, sporadic anorexia was noted in all animals by day 14, and a single animal showed diffuse piloerection on day 14. Surgical anesthesia preceded killing by exsanguination and was accompanied by perfusion fixation of the central nervous system. Brain sections were cut and then stained for study by light microscopy. Evidence of neuronal pathology, both descriptive and numerical, was collected. The neuroanatomic and neuropathologic findings demonstrated that arteether produced extensive brainstem injury when administered for 14 days. The magnitude of brainstem neurotoxicity was dose-dependent, where injury was greatest at the 24 mg/kg/day dose level, less at the 16 mg/kg/day dose level, and least at the 8 mg/kg/day dose level. Arteether induced multiple systems injury to brainstem nuclei of 1) the reticular formation (cranial and caudal pontine nuclei, and medullary gigantocellular and paragigantocellular nuclei); 2) the vestibular system (medial, descending, superior, and lateral nuclei); and 3) the auditory system (superior olivary nuclear complex and trapezoid nuclear complex). The vestibular nuclei and the reticular formation were most severely injured, with the auditory system affected less. The cranial nerve nuclei (somatic and splanchnic) appeared to escape damage, with the exception of the abducens nerve nucleus. The same brainstem nuclear groups of seven-day treated monkeys appeared normal. The statistical data are concordant with the descriptive data in demonstrating neurotoxic effects. In summary, no neurologic deficits were detected in any of the vehicle control monkeys (14-day and seven-day cases). Monkeys in the 14-day treatment group were free of clinical neurologic signs throughout the first week. At day 14, fine horizontal nystagmus was seen in one monkey, and another monkey exhibited diffuse piloerection. Monkeys in the seven-day treatment group were free of clinical neurologic signs except for one case. This monkey was treated with 24/mg/kg/day of arteether and exhibited lethargy after the fourth day. These indications of dysfunction arose too late to be practical indicators of neurotoxicity.
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The American journal of tropical medicine and hygiene, 1999
Twelve rhesus macaques (Macaca mulatta) challenged intranasally with a wild-type Japanese encepha... more Twelve rhesus macaques (Macaca mulatta) challenged intranasally with a wild-type Japanese encephalitis virus (JEV) developed clinical signs 11-14 days later. Tissues from the cerebral cortex, cerebellum, brainstem, thalamus, meninges, and all levels of the spinal cord were stained for JEV antigen with hyperimmune mouse ascitic fluid and streptavidin-alkaline phosphatase; immunofluorescent staining was also done on frozen sections. Viral antigen was found in all cell layers of the cerebellum, the gray matter of the thalamus and brainstem, and the ventral horn of all levels of the spinal cord. Staining was limited to neurons and their processes. Histopathologic changes were limited to the nervous system and characterized by nonsuppurative meningoencephalitis. These results were comparable with those of previous studies done with human autopsy tissues. Intranasal inoculation of rhesus monkeys with JEV was effective in producing clinical disease comparable with natural disease in humans...
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The American journal of tropical medicine and hygiene, 1999
Placebo-controlled field efficacy trials of new Japanese encephalitis (JE) vaccines may be imprac... more Placebo-controlled field efficacy trials of new Japanese encephalitis (JE) vaccines may be impractical. Therefore, an animal model to evaluate efficacy of candidate JE vaccines is sought. Previous work has shown that exposure of monkeys to JE virus (JEV) via the intranasal route results in encephalitis. Here we report the further development of this model and the availability of titered virus stocks to assess the protective efficacy of JE vaccines. To determine the effective dose of our JE challenge virus, dilutions of a stock JEV (KE-93 isolate) were inoculated into four groups of three rhesus monkeys. A dose-dependent response was observed and the 50% effective dose (ED50) was determined to be 6.0 x 10(7) plaque forming units (pfu). Among animals that developed encephalitis, clinical signs occurred 9-14 days postinoculation. Infection with JEV was confirmed by detection of JEV in nervous tissues and IgM to JEV in the cerebrospinal fluid. Viremia with JEV was also detected intermit...
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Journal of Medicinal Chemistry, 2011
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Journal of Parasitology, 2014
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Abstract. The neurotoxicity,of,-arteether (AE) is related to drug accumulation,in blood due to sl... more Abstract. The neurotoxicity,of,-arteether (AE) is related to drug accumulation,in blood due to slow and prolonged absorption from the intramuscular injection sites. In this efficacy and toxicity study of AE, the traditional sesame oil vehicle was replaced with cremophore to decrease the accumulation and toxicity of AE. Dihydroartemisinin (DQHS), a more toxic and active metabolite of AE, was also analyzed. When
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Malaria Journal, 2014
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Malaria Journal, 2011
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Journal of Medicinal Chemistry, 2007
A series of acid-stable carboxamide derivatives of 2-guanidinoimidazolidinedione (5a-c and 6a-c) ... more A series of acid-stable carboxamide derivatives of 2-guanidinoimidazolidinedione (5a-c and 6a-c) were prepared as potential malaria prophylactic and radical cure agents. The new compounds showed moderate to good causal prophylactic activity in mice infected with Plasmodium yoelii sporozoites. Three compounds were further tested for causal prophylactic activity in Rhesus monkeys infected with Plasmodium cynomolgi sporozoites, and all showed a delay in patency from 13 to 40 days at 30 mg/kg/day x 3 days by IM dosing. Two out of four compounds tested for radical curative activity in Rhesus showed cure at 30 mg/kg/day x 3 days. The other two compounds showed delay in relapse from 16 to 68 days. Conversion of new carboxamides (5 and 6) to s-triazine derivatives (7) was demonstrated in mouse and human microsomal preparations and in rat plasma. The results suggest the metabolites, s-triazine derivatives 7, may be the active species of the new carboxamides 5a-c and 6a-c prepared in this study.
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Journal of Medicinal Chemistry, 2011
A library of diamine quinoline methanols were designed based on the mefloquine scaffold. The syst... more A library of diamine quinoline methanols were designed based on the mefloquine scaffold. The systematic variation of the 4-position amino alcohol side chain led to analogues that maintained potency while reducing accumulation in the central nervous system (CNS). Although the mechanism of action remains elusive, these data indicate that the 4-position side chain is critical for activity and that potency (as measured by IC(90)) does not correlate with accumulation in the CNS. A new lead compound, (S)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(2-(cyclopropylamino)ethylamino)ethanol (WR621308), was identified with single dose efficacy and substantially lower permeability across MDCK cell monolayers than mefloquine. This compound could be appropriate for intermittent preventative treatment (IPTx) indications or other malaria treatments currently approved for mefloquine.
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Bioorganic & Medicinal Chemistry Letters, 2010
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American Journal of Tropical Medicine and Hygiene, 2012
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APMIS, 2013
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Antimicrobial agents and chemotherapy, 2014
Hematotoxicity in individuals genetically deficient in glucose-6-phosphate dehydrogenase (G6PD) a... more Hematotoxicity in individuals genetically deficient in glucose-6-phosphate dehydrogenase (G6PD) activity is the major limitation of primaquine (PQ), the only antimalarial drug in clinical use for treatment of relapsing Plasmodium vivax malaria. PQ is currently clinically used in its racemic form. A scalable procedure was developed to resolve racemic PQ, thus providing pure enantiomers for the first time for detailed preclinical evaluation and potentially for clinical use. These enantiomers were compared for antiparasitic activity using several mouse models and also for general and hematological toxicities in mice and dogs. (+)-(S)-PQ showed better suppressive and causal prophylactic activity than (-)-(R)-PQ in mice infected with Plasmodium berghei. Similarly, (+)-(S)-PQ was a more potent suppressive agent than (-)-(R)-PQ in a mouse model of Pneumocystis carinii pneumonia. However, at higher doses, (+)-(S)-PQ also showed more systemic toxicity for mice. In beagle dogs, (+)-(S)-PQ cau...
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Clinical Pharmacology & Therapeutics, 2004
Purpose: Methylene blue has antimalarial activity in vitro and in vivo in rats and humans. The pu... more Purpose: Methylene blue has antimalarial activity in vitro and in vivo in rats and humans. The purpose of this study is to characterize the pharmacokinetics and pharmacodynamics of intravenous methylene blue in healthy rhesus monkeys.Methods: Methylene blue 1% USP solution was administered as a single 30-second intravenous infusion at doses of 2.5 mg/kg, 5.0 mg/kg and 10.0 mg/kg to healthy
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Clinical Pharmacology & Therapeutics, 2005
Background/Aims: Methylene blue (MB), an FDA approved drug for methemoglobinemia, also demonstrat... more Background/Aims: Methylene blue (MB), an FDA approved drug for methemoglobinemia, also demonstrates in vitro and in vivo antimalarial activity. Artesunate (AS) is widely used to treat malaria in malaria-endemic countries. The purpose of this study was to evaluate the anti-malarial efficacy and safety of intravenous MB when given alone and in combination with intravenous AS in rhesus monkeys.Methods: A Rhesus/P. cynomolgi model of uncomplicated blood stage malaria was used to evaluate different combinations of MB and AS. The study was conducted under an approved protocol in an AAALAC accredited animal facility. The study design used a 3 by 3-factorial design to compare 3 doses of MB (0, 2 and 8 mg/kg) in combination with 3 doses of AS (0, 1 and 8 mg/kg). Thirty-four healthy rhesus monkeys were randomly assigned to one of 8 different treatment groups or to an infection control group. Study drugs were administered as three once-daily intravenous injections after threshold parasitemia levels were attained.Results: Parasitemia clearance and cure rates demonstrated dose-dependency. Combinations were much more likely to result in cure. Four monkeys died with clinical and necropsy findings consistent with severe malaria that were not considered to be related to study drugs. All remaining study animals recovered with no adverse sequelae.Conclusions: Intravenous methylene blue was well tolerated and demonstrated dose-dependent anti-malarial efficacy, as well as apparent synergy with intravenous artesunate.
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The American journal of tropical medicine and hygiene, 1999
Two poxvirus-vectored vaccines for Japanese encephalitis (JE), NYVAC-JEV and ALVAC-JEV, were eval... more Two poxvirus-vectored vaccines for Japanese encephalitis (JE), NYVAC-JEV and ALVAC-JEV, were evaluated in rhesus monkeys for safety, immunogenicity, and protective efficacy. The vaccines were given to four monkeys each on study days 0 and 28 along with saline placebo on day 7. For controls, the licensed BIKEN JE vaccine and a saline placebo were given to other groups of four monkeys on days 0, 7, and 28. No systemic effects were observed. All injection site reactions were mild. All vaccines elicited appreciable JE-specific neutralizing antibody responses. However, a more rapid increase and higher peak level of antibody were seen in the BIKEN group as compared with the NYVAC-JEV and ALVAC-JEV groups. The peak neutralizing antibody level in the NYVAC-JEV group was higher than that of the ALVAC-JEV group. Antibody persisted in all four BIKEN recipients through 273 days of follow-up, whereas, the antibody level decreased to the threshold of detection in two NYVAC-JEV and all four ALVAC-...
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