Evaluation of ketamine, ketamine-xylazine and ketamine-diazepam anesthesia in the ferret

Ketamine, ketamine-xylazine, and ketamine-diazepam were evaluated clinically in 15 ferrets, and safe dosage was determined for each. All of the three regimens provided excellent immobilization. However, muscle rigidity and incomplete analgesia were noted in ketamine alone and in ketamine-diazepam respectively. It was concluded that 25 mg/kg ketamine and 2 mg/kg xylazine intramuscularly provided acceptable analgesia, muscle relaxation, duration and smooth recovery, although cardiac arrhythmias were a concern and require careful observation.     

Evaluation of medetomidine/ketamine for short-term immobilization of variable flying foxes (Pteropus hypomelanus)

Four medetomidine/ketamine (M/K) doses (30 microg/kg/3 mg/kg; 40/4; 50/5; 60/6), administered by intramuscular injection, were evaluated for short-term immobilization of adult male variable flying foxes (Pteropus hypomelanus). The highest dose (60 microg/kg/6 mg/kg) produced a significantly faster induction (31 +/- 46 sec) than the lowest dose (30/3) (125 +/- 62 sec). The highest dose levels (50/5, 60/6) produced significantly longer immobilization times (52.5 +/- 25.7 min and 60.6 +/- 20.8 min, respectively) than did the lower doses (30/3, 40/4) (18.8 +/- 8.7 min and 31.0 +/- 14.3 min, respectively). The dose at which 50% of the bats were immobilized for > or = 30 min (ED(50)) was approximately 40 microg/kg/4 mg/kg. This dose produced a mean immobilization time of 31 +/- 14 min, bradypnea and bradycardia. In conclusion, a M/K dose of 50 microg/kg/5 mg/kg is recommended for greater than 30 min of relaxed immobilization in free-living variable flying foxes and is sufficient for safe collection of samples.     

Comparison of intravenous medetomidine and medetomidine/ketamine for immobilization of free-ranging variable flying foxes (Pteropus hypomelanus)

Medetomidine (0.03 mg/kg) and medetomidine/ketamine (0.05/5.0 and 0.025/2.5 mg/kg), administered by intravenous injection, were evaluated for short-term immobilization of wild-caught variable flying foxes (Pteropus hypomelanus). Medetomidine alone produced incomplete chemical restraint and a stressful, prolonged induction. Both ketamine/medetomidine doses produced a smooth induction and complete immobilization. The combined medetomidine/ketamine dose of 0.025/2.5 mg/kg produced a rapid induction (232±224 sec) with minimal struggling and vocalization, a complete and effective immobilization period, and tended to lead to a faster and better quality recovery than medetomidine alone or a higher dose of medetomidine and ketamine (0.05/5.0 mg/kg), thus reducing holding time and permitting an earlier release of the bat back into the wild.     

Reversible immobilization of free-ranging African lions (Panthera leo) with medetomidine-tiletamine-zolazepam and atipamezole

A combination of medetomidine-tiletamine-zolazepam was used to conduct six immobilizations of free-ranging lions (Panthera leo) in Waza National Park, Cameroon, during 1999 and 2000. Drugs were administered by dart injection at 0.07+/-0.01 (mean+/-SD) mg/kg of medetomidine and 1.8+/-0.5 mg/kg of tiletamine-zolazepam. Chemical immobilization was characterized by smooth inductions (14.1+/-6 min), satisfactory analgesia, and muscle relaxation. One animal was treated for bradypnea. No major alterations of physiologic parameters (heart and respiratory rates, rectal temperature) were seen during immobilization in the other lions. Relative arterial oxygen saturation was measured in two animals and revealed mild hypoxemia. The animals received atipamezole at 0.3+/-0.1 mg/kg intramuscularly for reversal of anesthesia. Recoveries were uneventful. All animals were radiocollared, and no mortalities occurred during an 18-mo follow-up period. Use of medetomidine-tiletamine-zolazepam for anesthesia and reversal of anesthesia with atipamezole appear to be useful for reversible immobilization of free-ranging lions.     

Evaluation of a combination of tiletamine and zolazepam as an anesthetic for laboratory rodents

A combination of equal parts of tiletamine hydrochloride and zolazepam hydrochloride was evaluated as an injectable anesthetic for rats, mice, and hamsters. The drug produced satisfactory anesthesia and analgesia in rats when given either intraperitoneally or intramuscularly at concentrations of 20 or 40 mg/kg body weight. The length of anesthesia was dose dependent and was somewhat longer in females as compared to males, and inbreds compared to outbreds. Incisions through the peritoneum of anesthetized rats evoked little or no response, whereas cervical skin incisions evoked a slight response in many rats. Anesthesia without analgesia occurred in mice at dosages of 80 mg/kg body weight and higher, however, many animals developed respiratory distress and died at dosages of 100 to 160 mg/kg body weight. In hamsters, anesthesia but not analgesia occurred at drug concentrations of 50 to 80 mg/kg body weight. It was concluded that a tiletamine and zolazepam combination was an effective anesthetic for rats, but not for mice or hamsters.     

Anesthesia of boma-captured Lichtenstein's hartebeest (Sigmoceros lichtensteinii) with a combination of thiafentanil,medetomidine, and ketamine

A dose range was determined for anesthesia of recently boma-captured Lichtenstein's hartebeest (Sigmoceros lichtensteinii) (n = 13) with the synthetic opiate thiafentanil (THIA) (formerly called A3080) combined with medetomidine (MED) and ketamine (KET) in the Kasungu National Park, Malawi on 4 to 5 September 1999. The dose range of 11-29 micrograms/kg THIA (mean +/- SD = 21 +/- 4 micrograms/kg) combined with 5-10 mg/kg MED (8 +/- 1 micrograms/kg) plus 0.7-1.4 mg/kg KET (1.1 +/- 0.2 mg/kg) was found to be safe and effective for the field conditions associated with this study. The anesthesia produced by this drug combination was very predictable and characterized by a short induction time (3:34 +/- 1:20 min:sec), good muscle relaxation, and acceptable physiologic parameters for anesthesia periods ranging from 22:30-35:00 min:sec (31:14 +/- 2:50). Within the range of doses used in this study, times to onset of initial effects and recumbency were not dependent on THAI, MED, or KET doses. Anesthesia was rapidly and completely reversed by intravenous injections of naltrexone at 30 times the THAI dosage (0.69 +/- 0.19 mg/kg) and atipamezole at about four times the MED dosage (38 +/- 14 micrograms/kg). There was no residual effect from ketamine noted following reversal of THIA and MED and no mortality or morbidity was associated with this anesthetic regimen.     

Immobilization of Chacoan peccaries (Catagonus wagneri) using medetomidine, Telazol, and ketamine

A combination of medetomidine, Telazol, and ketamine hydrochloride was used to immobilize captive Chacoan peccaries (Catagonus wagneri) for translocation within Paraguay during August-October 2002. Animals were darted in enclosed areas of varying size. The average dose used was 32.5+/-7.2 microg/kg of medetomidine, 0.63+/-0.2 mg/kg of Telazol, and 3.9+/-0.65 mg/kg of ketamine. First effects were noted at 4.3+/-2.1 min, and ability to handle the animals was achieved by 12.6+/-3.7 min. Heart and respiratory rates declined and oxygen saturation increased during anesthesia. Muscle relaxation was good. Atipamezole was used to antagonize the medetomidine, although recoveries were still slow. This drug combination provided adequate immobilization of Chacoan peccaries; however, this protocol would not be considered to be reversible, and confinement during recovery is recommended.     

Immobilization of polar bears (Ursus maritimus Phipps) with a mixture of tiletamine hydrochloride and zolazepam hydrochloride

A 1:1 mixture of tiletamine hydrochloride and zolazepam hydrochloride was tested on 39 polar bears in and near Churchill, Manitoba, Canada during October 1983. The mean dose for satisfactory immobilization with a single injection was 5.1 mg/kg. Bears showed signs of ataxia from 1-3 min following injection and were usually sitting within 4 min. The mean induction time, taken as the adoption of sternal recumbency, was 5.1 min. Maximum relaxation was usually seen by about 20 min post-injection. The duration of immobilization appeared to be related to the dose of drug received. In bears that received a dose near the mean, recumbency lasted about 2 hr. Cubs of the year recovered more quickly than adults. Preliminary results indicated that the bears did not suffer respiratory depression and were able to thermoregulate while immobilized. Bears could be handled safely while under the effects of the drug and workers could readily evaluate the state of their sedation by their reactions. The drug did not appear to provide good analgesia at the doses tested.     

Interaction between GABAergic anticonvulsants and the NMDA receptor antagonist MK 801 against MES- and picrotoxin-induced convulsions in rats

The interaction between GABAergic (barbiturates, diazepam, ethanol) and other (phenytoin) anticonvulsants and the N-methyl-D-aspartate (NMDA) receptor antagonist MK 801 in protecting rats against maximal electroshock (MES)- and picrotoxin-induced (10 mg/kg) convulsions was studied. MK 801 (0.1 to 5 mg/kg) showed anticonvulsant responses against MES-induced convulsions in a dose dependent manner, higher doses showing severe muscle relaxation, motor incoordination, and anticonvulsant action. It also produced stereotypic head movement, circling behavior, and affected locomotion. When subanticonvulsant dose (1 mg/kg) of MK 801 was simultaneously administered with subprotective doses of GABAergic anticonvulsants, it significantly potentiated the effects of barbiturates, as compared to other agents. At 1 mg/kg, MK 801 did not offer protection against tonic convulsions though protected (100%) the animals from mortality due to picrotoxin-induced convulsions. It potentiated the effect of a subprotective dose (5 mg/kg) of pentobarbital, but not of diazepam, against tonic convulsions. However, no mortality was observed in either group. The antiglutamate action of barbiturates, particularly that of pentobarbital, may contribute to the observed potentiating response between pentobarbital and MK 801.     

Salicylate-induced teratogenesis in the ferret

A single subcutaneous injection of 400 mg/kg sodium salicylate produced a high resorption rate on day 13 (91%) and on day 18 (66%) of gestation. Malformations were seen in the surviving fetuses. Pregnant ferrets injected with 250 mg/kg salicylate produced a lower resorption rate of between 31% and 43%. Malformations were seen in the surviving fetuses of animals injected with lower doses of sodium salicylate both at 13 and 18 days of gestation.Salicylate-induced teratogenicity at 400 mg/kg was compared with that produced in a closed colony of Wistar rats. The concentration of salicylate in whole blood (and serum) was determined after a single injection of 125 mg/kg or 400 mg/kg sodium salicylate. Although salicylate concentration in the blood in both species showed remarkable similarity at the doses tested and the times of sampling, the results indicated that the drug was far more embryo-toxic in ferrets than in rats. The inter-order variation in the embryotoxicity of sodium salicylate is such that it would be unwise to ignore its possible teratogenic activity in man.     

Immobilization of Norwegian Reindeer (Rangifer tarandus tarandus) and Svalbard Reindeer (R. t. platyrhynchus) with Medetomidine and Medetomidine-Ketamine and Reversal of Immobilization with Atipamezole

The sedative action of medetomidine (-ketamine) was studied in 12 captive Norwegian semidomesticated reindeer (NR), including 4 newborn calves, and in 7 free-living Svalbard reindeer (SR). Medetomidine, with or without ketamine, caused effective, reliable immobilization in NR. Doses of 50–200 µg/kg medetomidine alone or 30-125 µg/kg medetomidine combined with ⩾ 300 µg/kg ketamine induced complete immobilization, good muscle relaxation and persistent, deep sedation with little respiratory depression in NR; SR required higher doses. Atipamezole successfully antagonized medetomidine (-ketamine) resulting in rapid and persistent reversal of immobilization in all cases (NR and SR). Both medetomidine and atipamezole had wide safety margins and no conspicuous lasting side effects after reversal.     

A comparison of carfentanil/xylazine and Telazol/xylazine for immobilization of white-tailed deer

October 2001 to January 2002, captive free-ranging white-tailed deer (Odocoileus virginianus) were immobilized with a combination of carfentanil citrate and xylazine hydrochloride. From this study, we selected a dose of carfentanil/xylazine for the purpose of comparing immobilization parameters and physiologic effects with those of a combination of tiletamine and zolazepam (Telazol) and xylazine. Animals were initially given intramuscular injections of 10 mg xylazine and one of four doses of carfentanil (i.e., 0.5, 1.0, 1.5, and 2.0 mg). A carfentanil dose of 1.2 mg (x +/- SD = 23.5 +/- 3.2 microg/kg) and 10 mg xylazine (0.2 +/- 0.03 mg/kg) were selected, based on induction times and previously published reports, to compare with a combination of 230 mg of Telazol (4.5 +/- 0.6 mg/kg) and 120 mg xylazine (2.3 +/- 0.3 mg/kg). Time to first observable drug effects and to induction were significantly longer for deer treated with carfentanil/xylazine than with Telazol/xylazine (P < 0.01). Hyperthermia was common in deer immobilized with carfentanil/xylazine, but heart rate, respiration rate, and hemoglobin saturation were within acceptable levels. Degree of anesthesia of deer immobilized with Telazol/xylazine was superior to deer immobilized with carfentanil/xylazine. The combination of 120 mg of naltrexone hydrochloride and 6.5 mg of yohimbine hydrochloride provided rapid and complete reversal (1.9 +/- 1.1 min) of carfentanil/xylazine immobilization. Animals immobilized with Telazol/xylazine had long recovery times with occasional resedation after antagonism with 6.5 mg of yohimbine. The combination of carfentanil and xylazine at the doses tested did not provide reliable induction or immobilization of white-tailel (leer even though drug reversal was rapid and safe using naltrexone and yohimbine.     

Effects of systemically administered monoamine reuptake blocking agents on patterns of buspirone-induced analgesia in rats

We have recently shown the serotonin 5-HT1A receptor agonist buspirone to produce analgesia in several pain tests in rats. As a 5-HT1A agonist, buspirone may change serotonergic (5-HT) tone to alter the balance of central monoaminergic (MA) systems that function in analgesia. MA-reuptake blocking drugs have been shown to produce analgesia, both when given alone and in combination with a variety of other agents, presumably via their action upon MA neurochemistry. The present study was undertaken to examine the effect of systemic administration of the 5-HT-reuptake blocker amitriptyline (AMI: 10 mg/kg), NE-reuptake blocker desipramine (DMI: 10 mg/kg) or DA-reuptake blocker GBR-12909 (7.5 mg/kg) on patterns of analgesia produced by buspirone (1-5 mg/kg) in thermal and mechanical pain tests in rats. Neither reuptake blocking agents or buspirone, when administered alone or in combination, produced overt changes in motor activity at the doses tested. AMI alone was not analgesic in either thermal or mechanical pain tests. In both assays, AMI reduced the analgesic action of buspirone, with greater effects seen in the thermal test. When administered alone, DMI produced significant analgesia against thermal and mechanical pain. DMI significantly attenuated the analgesic action of all doses of buspirone in both pain tests. Alone, GBR-12909 did not affect nociception in thermal or mechanical tests. GBR-12909 decreased buspirone-induced analgesia at all doses in the thermal test, while having no effect on buspirone-induced analgesia against mechanical pain. These results demonstrate that facilitation of 5-HT, NE and DA function with reuptake blocking drugs did not enhance the analgesic action of buspirone. These data indicate against the adjuvant use of reuptake blocking compounds and buspirone as analgesics. Furthermore, such findings may suggest other possible non-MA substrates of buspirone-induced analgesia.     

Central effects of citral, myrcene and limonene, constituents of essential oil chemotypes from Lippia alba (Mill.) n.e. Brown.

Citral, myrcene and limonene (100 and 200 mg/kg body wt., i.p.), constituents of essential oils from Lippia alba chemotypes, decreased not only the number of crossings but also numbers for rearing and grooming, as measured by the open-field test in mice. Although muscle relaxation detected by the rota rod test was seen only at the highest doses of citral (200 mg/kg body wt.) and myrcene (100 and 200 mg/kg body wt.), this effect was observed even at the lowest dose of limonene (50 mg/kg body wt.). Also, citral and myrcene (100 and 200 mg/kg body wt.) increased barbiturate sleeping time as compared to control. Limonene was also effective at the highest dose, and although citral did not increase the onset of sleep, it increased the duration of sleep, which is indicative of a potentiation of sleeping time. Citral (100 and 200 mg/kg body wt.) increased 2.3 and 3.5 times, respectively, the barbiturate sleeping time in mice. Similar effects were observed for myrcene and limonene at the highest dose (200 mg/kg body wt.) which increased the sleeping time around 2.6 times. In the elevated-plus maze, no effect was detected with citral up to 25 mg/kg body wt., while at a high dose it decreased by 46% the number of entries in the open arms. A smaller but significant effect was detected with limonene (5 mg/kg body wt.). While myrcene (10 mg/kg body wt.) decreased only by 22% the number of entries in the open arms, this parameter was decreased by 48% at the highest dose. Our study showed that citral, limonene and myrcene presented sedative as well as motor relaxant effects. Although only at the highest dose, they also produced a potentiation of the pentobarbital-induced sleeping time in mice, which was more intense in the presence of citral. In addition, neither of them showed an anxiolytic effect, but rather a slight anxiogenic type of effect at the higher doses.     

静注硫酸镁对腰硬联合麻醉患者术后疼痛和寒战反应的影响

目的:探讨腰硬联合麻醉中静脉输注50 mg/kg和25 mg/kg两种剂量的硫酸镁对术后镇痛和寒战的的影响。方法:90名腰硬联合麻醉(CSEA)下行全子宫切除术的患者随机分成3组。在腰麻注药后即刻,MGI组30分钟内静脉输注硫酸镁25 mg/kg继以10 mg/kg/h的速度输注至手术结束;MGⅡ组输注硫酸镁50 mg/kg,然后以10 mg/kg/h的速度输注;C组注入等量生理盐水。观察术后24小时的疼痛评分(视觉模拟评分法:VAS),术后镇痛药物的用量,寒战的发生率。结果:三组术后镇痛用药量由低到高依次为MGII组,MGI组,C组(P<0.001)。术后VAS评分,MGII组较C组减少,(P<0.05);在12 h,24 h,MGII组较MGI组减少,MGI组在2 h,4 h较C组减少(P<0.05)。术后寒战在C组发生率最高,在MGI组与MGII组发生率少,组间有统计学差异(P=0.007)。结论:腰硬联合麻醉中静脉输注两种剂量的硫酸镁均可以改善术后镇痛,减少术后寒战的发生率,大剂量硫酸镁更有效,但也可能伴随更大的血流动力学波动。     

In vivo postirradiation protection by a vitamin E analog, alpha-TMG

The water-soluble vitamin E derivative alpha-TMG is an excellent radical scavenger. A dose of 600 mg/kg TMG significantly reduced radiation clastogenicity in mouse bone marrow when administered after irradiation. The present study was aimed at investigating the radioprotective effect of postirradiation treatment with alpha-TMG against a range of whole-body lethal (8.5-12 Gy) and sublethal (1-5 Gy) doses of radiation in adult Swiss albino mice. Protection against lethal irradiation was evaluated from 30-day mouse survival and against sublethal doses was assessed from micronuclei and chromosomal aberrations in the bone marrow 24 h after irradiation. An intraperitoneal injection of 600 mg/kg TMG within 10 min of lethal irradiation increased survival, giving a dose modification factor (DMF) of 1.09. TMG at doses of 400 mg/kg and 600 mg/kg significantly reduced the percentage of aberrant metaphases, the different types of aberrations, and the number of micronucleated erythrocytes. DMFs of 1.22 and 1.48 for percentage aberrant metaphases and 1.6 and 1.98 for micronuclei were obtained for 400 mg/kg and 600 mg/kg TMG, respectively. No drug toxicity was observed at these doses. The effectiveness of TMG when administered postirradiation suggests its possible utility for protection against unplanned radiation exposures.     

Anesthesia of polar bears using xylazine-zolazepam-tiletamine or zolazepam-tiletamine

Immobilization features and physiologic effects of combinations of xylazine-zolazepam-tiletamine (XZT) and zolazepam-tiletamine (ZT or Telazol) were compared in nine captive and 17 free-ranging polar bears (Ursus maritimus) between 1998 and 2001. Although induction time was similar between drugs, induction dosage and volume were less with XZT. Induction of immobilization with XZT was predictable and smooth, muscle relaxation was good, and all bears remained completely immobilized and unresponsive to stimuli throughout a 1 hr handling period. The combination XZT was safely tolerated at two to three times the recommended dosage of 5 mg/kg (i.e., xylazine at 2 mg/kg + Telazol at 3 mg/kg). Bears immobilized with XZT had slower pulse rates, higher mean arterial pressures, and lower arterial oxygen tensions than bears immobilized with ZT. Rectal temperature increased slowly over time (approximately 0.5 C per hr) following immobilization with XZT. Based on response to a painful stimulus (compression of a claw bed), XZT was a more effective analgesic than ZT. Although the immobilization effects of XZT could not be reversed with the alpha 2-antagonist drug tolazoline, they were reversed with yohimbine or atipamezole. However, the time to complete reversal of effects (i.e., standing and ambulatory) was highly variable among bears.     

Ethanol-induced analgesia

The effect of ethanol (ET) on nociceptive sensitivity was evaluated using a new tail deflection response (TDR) method. The IP injection of ET (0.5-1.5 g/kg) produced rapid dose-dependent analgesia. Near maximal effect (97% decrease in TDR) was produced with the 1.5 g/kg dose of ET ten minutes after injection. At ninety minutes post-injection there was still significant analgesia. Depression of ET-induced nociceptive sensitivity was partially reversed by a 1 mg/kg dose of naloxone. On the other hand, morphine (0.5 or 5.0 mg/kg IP) did not modify ET-induced analgesia, while 3.0 minutes of cold water swim (known to produce non-opioid mediated analgesia) potentiated ET-induced analgesic effect. The 0.5 g/kg dose of ET by itself did not depress motor activity in an open field test, but prevented partially the depression in motor activity produced by cold water swim (CWS). Thus the potentiation by ET of the depression of the TDR produced by CWS cannot be ascribed to the depressant effects of ET on motor activity.     

Evaluation of three combinations of anesthetics for use in free-ranging alpine marmots (Marmota marmota)

From April 1998 to September 2000, 241 free-ranging alpine marmots (Marmota marmota) were anesthetized in the course of a field project using either xylazine plus ketamine (XK), medetomidine plus ketamine (MK), or xylazine plus a 1:1 mixture of zolazepam and tiletamine (XZT). For each of the combinations, the respective doses for short term and long-term surgery were established and seasonal variations in the amount of drugs needed were assessed. No fatalities occurred, and doses for efficient and safe anesthesia in spring were as follows (XK, MK, and XZT, respectively, in mg/kg body mass): short term surgery 3 + 40, 0.25 + 35, and 3 + 15; long term surgery 20 + 80, 0.5 + 70, and 10 + 20. In late summer/autumn, higher doses (20 + 60, 0.2 + 60, and 10 + 15 for short term surgery) had to be administered, probably due to increase of marmots' body fat content. Heart rate, respiratory rate, rectal temperature, palpebral reflex, muscle relaxation, and analgesia were monitored to evaluate the animals' responses to each of the drug combinations. Hypothermia was induced by all combinations and heart rate significantly decreased during anesthesia, especially in marmots receiving MK. Respiratory rate was highly variable and no significant differences between the drugs were found. Muscle relaxation was rather poor in marmots anesthetized with XK. The XZT combination tended to have a longer induction period but was found to subsequently depress the palpebral reflex and induce muscle relaxation and analgesia very efficiently. We conclude that, regardless of the anesthetics used, doses should always be adjusted to the planned manipulations, the marmots' nutritional state, and to the time of year. Furthermore, close monitoring of physiologic parameters, especially body temperature, should be guaranteed. On the basis of physiologic and behavioral responses, XZT is the most effective drug combination for anesthetizing alpine marmots, especially for long term, potentially painful procedures.     

TGF‐β1 monoclonal antibody: Assessment of embryo‐fetal toxicity in rats and rabbits

A humanized monoclonal antibody targeting transforming growth factor β1 (TGF‐β1 mab) has been used in development for the treatment of chronic kidney disease. Embryo‐fetal development studies were conducted in rats and rabbits using 30 and 25 animals per group, respectively. The TGF‐β1 mab was administered subcutaneously to rats at 0, 2, or 50 mg/kg/dose on gestation days (GDs) 6, 10, and 14 and intravenously to rabbits at 0 or 3 mg/kg/dose on GDs 7, 12 to 19, and at 30 mg/kg/dose on GDs 7, 12, 14, 16, and 18. Maternal reproductive endpoints and fetal viability, weight, and morphology were evaluated. There was no indication of maternal or embryo‐fetal toxicity in the rat. Effects in the rabbit were limited to the fetus where the 30 mg/kg TGF‐β1 mab dose produced a slight decrease in fetal weight and an increase in the incidence of retrocaval ureter and an absent and/or malpositioned kidney/ureter in two fetuses. In conclusion, TGF‐β1 mab produced no adverse maternal or embryo‐fetal findings in rats when administered ≤50 mg/kg on GDs 6, 10, and 14. TGF‐β1 mab did not demonstrate maternal toxicity or embryo‐fetal lethality at doses as high as 30 mg/kg when administered on GDs 7, 12, 14, 16, and 18 in rabbits. Fetal growth and morphology were affected only at 30 mg/kg; thus, the no observed adverse effect level was 3 mg/kg in rabbits. The margin of safety for both rats and rabbits was ≥37‐fold the clinical exposure level.