Arteether: Risks of two-week administration in Macaca mulatta

被引:62
作者
Petras, JM
Kyle, DE
Gettayacamin, M
Young, GD
Bauman, RA
Webster, HK
Corcoran, KD
Peggins, JO
Vane, MA
Brewer, TG
机构
[1] USA, CTR HLTH PROMOT & PREVENT MED, ABERDEEN PROVING GROUND, MD 21010 USA
[2] BECTON DICKINSON CO, ASIA PACIFIC REG, SINGAPORE 2263, SINGAPORE
[3] FITZSIMONS ARMY MED CTR, DEPT CLIN INVEST, AURORA, CO 80045 USA
[4] WALTER REED ARMY INST RES, DEPT PHARMACOL, WASHINGTON, DC 20307 USA
[5] WALTER REED ARMY INST RES, DIV EXPT THERAPEUT, WASHINGTON, DC 20307 USA
[6] ARMED FORCES RES INST MED SCI, US MED COMPONENT, APO, AP 96546 USA
关键词
D O I
10.4269/ajtmh.1997.56.390
中图分类号
R1 [预防医学、卫生学];
学科分类号
1004 ; 120402 ;
摘要
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 syste. 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 ar the 24 mg/kg/day dose level, less at the 10 mg/kg/day dose level, and feast 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 an 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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页码:390 / 396
页数:7
相关论文
共 28 条
[1]  
[Anonymous], 1982, CYTOARCHITECTURE HUM
[2]  
BEALES PF, 1988, MALARIA PRINCIPLES P, V2, P1287
[3]   PHARMACOKINETICS OF ARTEETHER IN DOG [J].
BENAKIS, A ;
SCHOPFER, C ;
PARIS, M ;
PLESSAS, CT ;
KARAYANNAKOS, PE ;
DONDAS, I ;
KOTSARELIS, D ;
PLESSAS, ST ;
SKALKEAS, G .
EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, 1991, 16 (04) :325-328
[4]  
Bjorkman A., 1991, Malaria: waiting for the vaccine. London School of Hygiene and Tropical Medicine First Annual Public Health Forum, P105
[5]  
BRADLEY DJ, 1991, MALARIA : WAITING FOR THE VACCINE, P11
[6]   NEUROTOXICITY IN ANIMALS DUE TO ARTEETHER AND ARTEMETHER [J].
BREWER, TG ;
PEGGINS, JO ;
GRATE, SJ ;
PETRAS, JM ;
LEVINE, BS ;
WEINA, PJ ;
SWEARENGEN, J ;
HEIFFER, MH ;
SCHUSTER, BG .
TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE, 1994, 88 :33-36
[7]   FATAL NEUROTOXICITY OF ARTEETHER AND ARTEMETHER [J].
BREWER, TG ;
GRATE, SJ ;
PEGGINS, JO ;
WEINA, PJ ;
PETRAS, JM ;
LEVINE, BS ;
HEIFFER, MH ;
SCHUSTER, BG .
AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 1994, 51 (03) :251-259
[8]   ARTEMISININ (QINGHAOSU) - A NEW TYPE OF ANTIMALARIAL DRUG [J].
BUTLER, AR ;
WU, YL .
CHEMICAL SOCIETY REVIEWS, 1992, 21 (02) :85-90
[9]  
CAMMERMEYER J, 1962, Ergeb Anat Entwicklungsgesch, V36, P1
[10]   THE POST-MORTEM ORIGIN AND MECHANISM OF NEURONAL HYPERCHROMATOSIS AND NUCLEAR PYKNOSIS [J].
CAMMERMEYER, J .
EXPERIMENTAL NEUROLOGY, 1960, 2 (04) :379-405