Toxicity of TXU-PAP in chimpanzees
| System | Maximum Toxicity Grade (Onset and Duration) | |||||
|---|---|---|---|---|---|---|
| 10 μg/kg/day × 10 days | 20 μg/kg/day × 5 days | |||||
| C-291 | C-294 | C-881 | C-1150 | C-138 | C-144 | |
| Activity/feeding | 0 | 0 | 3 (day 13)1-a | 0 | 0 | 0 |
| Fever | 0 | 0 | 0 | 0 | 0 | 0 |
| Weight loss | 0 | 0 | 0 | 0 | 0 | 0 |
| Weight gain | 0 | 0 | 0 | 0 | 0 | 0 |
| Cardiac | ||||||
| Tachycardia | 0 | 2 (day 12, 13, 21) | 3 (day 12) | 0 | 0 | 0 |
| Hypotension | 2 (day 1, 3–4) | 01-e | 1 (day 6, 7, 12) | 01-f | 0 | |
| Hypertension | 0 | 0 | 0 | 0 | 0 | 0 |
| Pulmonary | ||||||
| Clinical | 0 | 0 | 2 (day 12)1-b 1-c 1-d | 0 | 0 | 0 |
| Respiratory rate | 0 | 2 (day 11–13) | 4 (day 11–13, 15) | 0 | 0 | 0 |
| Renal | ||||||
| Creatinine | 0 | 0 | 1 (day 15)1-a | 0 | 0 | 0 |
| BUN | 0 | 0 | 4 (day 15)1-a | 1 (day 12, 13) | 0 | 1 (day 4, 5) |
| Electrolytes | 1 (day 2–5, 8–10, 14) | 1 (day 4, 8, 14, 21) | 4 (day 15)1-a | 2 (day 13, 14) | 1 (day 4, 5) | 1 (day 2, 3, 5) |
| Liver | ||||||
| ALT | 1 (day 2–7, 11–12) | 1 (day 11–14, 21) | 3 (day 6, 22, 29) | 2 (day 2–15, 22, 29) | 1 (day 2–5) | 2 (day 3–5) |
| Bili | 0 | 0 | 0 | 0 | 0 | 0 |
| Gastrointestinal | ||||||
| Nausea/vomiting | 0 | 0 | 3 (day 13)1-a | 0 | 0 | 0 |
| Diarrhea | 0 | 0 | 0 | 0 | 0 | 0 |
| Nervous system | ||||||
| Central | 0 | 0 | 0 | 0 | 0 | 0 |
| Peripheral | 0 | 0 | 0 | 0 | 0 | 0 |
| Infection | 0 | 0 | 2 (day 57)1-f | 2 (day 13–15, 29)1-g | 0 | 0 |
| Hematology | ||||||
| Leukopenia | 1 (day 1, 28, 62) | 0 | 0 | 0 | 0 | 0 |
| Anemia | 0 | 1 (day 1, 2, 5, 7–14, 217) | 1 (day 9, 10, 22, 29) | 1 (day 10, 13–15, 22, 29) | 0 | 0 |
| Thrombocytopenia | 0 | 0 | 1 (day 6–8, 11, 12, 15, 22) | 0 | 0 | 1 (day 1–5) |
| Hyperleukocytosis | 0 | 0 | 0 | 0 | 0 | 0 |
| VLS | 1 (day 9–14) | 1 (day 6–14) | 1 (day 5–28) | 1 (day 7–15) | 1 (day 5–28) | 1 (day 5–28) |
↵1-a On day 12, no peristalsis was evident by auscultation of the abdomen (grade 2). On day 13, a severe ileus developed, and 350 to 450 ml of slightly opaque fluid along with a large amount of gas was evacuated by slow suction via a gastric tube. Dehydration was also noted.
↵1-b On day 8, hyperventilation was observed during the induction of anesthesia.
↵1-c On day 12, a labored, biphasic respiration with marked expiratory stridor was recorded. During the larygoscopy, a 4 × 4-mm dark submucosal lesion was found at the center of the glottis; glottis appeared markedly hyperemic and mildly edematous. The roof of the oropharynx and soft palate was mildly swollen, hyperemic, and covered by mucous; Breath sounds were decreased over the left lung.
↵1-d C-881 repeatedly exhibited adverse reactions to the anesthetic agent being used. Beginning on day 12 and continuing on through days 13, 22, and 29, this chimpanzee became cyanotic during induction of anesthesia. A full recovery was observed at each time after the administration of oxygen. On day 13, cyanosis was combined with rapid shallow respirations (64 respirations/min) with significant laryngeal edema.
↵1-e Anesthesia-related hypotension evident on days 7 and 8 (grade 3).
↵1-f On day 57, physical examination revealed an erosion of the tip of toes II to V with complete loss of epithelium on toe II, with pus draining from under the nail; possible reepithelialization was observed on toes III, IV, and V.
↵1-g On day 13, an area of approximately 2.5-cm diameter along the right ventral mandible branch lacked an epidermis; dermis was raw; and a mild yellow, mucous exudation was present. A pinpoint area with mild mucous exudation along the ventral edge of the last rib on the right side was also found. On day 14, three areas with epidermal loss and mild mucopurulent secretions were found: right side of face over ventral edge of mandible, right thorax over the last rib, and central part of the left pinna. On day 15, the three areas indicated above showed increased loss of epidermis and inflamed dermis (2.5–3.0-cm diameter along ventral edge of right mandible with increasing mucopurulent exudation, edge of the last rib on the right side with a 5-mm-long pustule, and 5-mm diameter of central part of left pinna). By day 29, only the 2.5-cm-diameter abrasion, circular with loss of epidermis on the right ventral mandibular branch was noted.
The numbers in parentheses indicate the day of onset of the toxicity and its duration.