Myocardial Infarction after Long-Term Treatment with a Tyrosine Kinase Inhibitor (TKI) with Anti-VEGF Receptor Activity.

TKIs including anti-VEGF receptor activity have been approved for the treatment of patients with radioiodine resistant thyroid carcinomas. For lenvatinib arterial thromboembolic events are listed as adverse events of special interest with lenvatinib. In the phase III study, arterial thromboembolic events were reported in 3% of lenvatinib-treated patients and 1% in the placebo group. Most of the patients had predisposing factors. Only one myocardial infarct was reported in the lenvatinib phase III study. We report a 73-year-old female patient with metastatic thyroid papillary carcinoma who was treated with total thyroidectomy. The operation was followed by four radioiodine therapies over a period of 6 years. At 6 years she developed lung metastasis without radioiodine uptake, one solitary liver metastasis and one solitary right renal metastasis. One year after the first diagnosis of radioiodine resistant lung metastasis the lung metastasis showed progression according to RECIST criteria. This treatment was resulting in prolonged partial response with disappearance of a hepatic and renal metastasis. A myocardial infarction occurred after 39 months of lenvatinib treatment resulting in implantation of 3 stents and a two chamber pacemaker. The treatment was discontinued. Except for well controlled hypertension there were neither predisposing diseases like diabetes nor symptoms of cardiac ischemia on exertion. However, the family history for cardiovascular diseases was positive for cardiac infarction reported for one brother. Another brother was treated for hypertension and the patient's mother suffered from a cerebral infarction at the age of 60. While only one myocardial infarct was reported in the lenvatinib phase III study with 392 patients this case suggests that long-term treatment with lenvatinib may be associated with an increased risk for myocardial infarct also in patients with no predisposing diseases except well controlled hypertension and positive family history for cardiovascular diseases.

Impulsivity, self-control, and hypnotic suggestibility.

Hypnotic responding might be due to attenuated frontal lobe functioning after the hypnotic induction. Little is known about whether personality traits linked with frontal functioning are associated with responsiveness to hypnotic suggestions. We assessed whether hypnotic suggestibility is related to the traits of self-control and impulsivity in 154 participants who completed the Brief Self-Control Scale, the Self-Regulation Scale, the Barratt Impulsiveness Scale (BIS-11), and the Harvard Group Scale of Hypnotic Susceptibility (HGSHS:A). BIS-11 non-planning impulsivity correlated positively with HGSHS:A (Bonferroni-corrected). Furthermore, in the best model emerging from a stepwise multiple regression, both non-planning impulsivity and self-control positively predicted hypnotic suggestibility, and there was an interaction of BIS-11 motor impulsivity with gender. For men only, motor impulsivity tended to predict hypnotic suggestibility. Hypnotic suggestibility is associated with personality traits linked with frontal functioning, and hypnotic responding in men and women might differ.

The developmental toxicity of orally administered oxytetracycline in rats and mice.

Timed-pregnant CD rats and CD-1 mice were dosed by gavage with oxytetracycline hydrochloride (OXT) in corn oil on gestational days (gd) 6-15 (0, 1200, 1350, or 1500 mg/kg/day for rats; 0, 1325, 1670, or 2100 mg/kg/day for mice). Deaths among treated females occurred in a dose-related manner in all OXT dose groups (2-7%, mice; 5-24%, rats), but no maternal deaths occurred in the vehicle control groups. Significant dose-related decreases in maternal weight gain during treatment, as well as for corrected gestational weight gain (i.e., maternal gestational weight gain minus gravid uterine weight), were observed at all doses in rats but not in mice. Gravid uterine weight was reduced in a dose-related manner only in mice, with the high-dose group significantly reduced compared to the control group. At termination (gd 20, rats; gd 17, mice), the status of uterine implantation sites was recorded and live fetuses were weighed. Fetuses were examined for external, visceral, and skeletal abnormalities. There were no significant effects of OXT in either species on the incidence of postimplantation loss (resorptions plus dead fetuses) or malformations. In both species, there was a significant trend toward reduced fetal body weight, and each group of rats receiving OXT was significantly reduced compared to the control group. Administration of OXT during organogenesis at doses exceeding the therapeutic range for humans produced maternal and fetal toxicity, but did not produce any treatment-related increase in malformations.

Teratologic evaluation of dinitrotoluene in the Fischer 344 rat.

Technical grade dinitrotoluene (DNT) was administered by gavage (po) to timed-pregnant Fischer 344 rats on Gestational Days (gd) 7 through 20. Mortality rates for the DNT (14, 35, 37.5, 75, 100, or 150 mg/kg/day) groups were 4.5, 7.7, 0.0, 0.0, 4.3, and 46.2% of treated females, respectively. No deaths occurred in the positive control (hydroxyurea, 200 mg/kg/day) or vehicle control (corn oil) groups. At sacrifice on gd 20, the hematological profile for dams in the 100-mg/kg/day group exhibited characteristic signs of DNT toxicity. Treatment-related increases in maternal relative liver and spleen weight (% body weight), and a dose-related decrease in absolute maternal weight gain during gestation (i.e., minus gravid uterine weight) were observed across all DNT groups. A notable increase in prenatal mortality occurred at the high dose (16.8% resorptions or late fetal deaths per litter for controls vs 49.6% for DNT), but but did not reach statistical significance. No statistically significant effects on fetal growth or morphological development as a result of DNT treatment were observed. Hydroxyurea produced mild hematoxicity in dams and fetuses. Effects of hydroxyurea on fetal growth and morphological development included decreased fetal body weight and crown-rump length, and an increased percentage of malformed fetuses (30% per litter). In conclusion, DNT was not found to be teratogenic following oral administration to Fischer 344 rats; embryo/fetal toxicity was observed only at a dose which also produced 46.2% maternal mortality.

Teratologic and postnatal evaluation of aniline hydrochloride in the Fischer 344 rat.

Timed-pregnant Fischer 344 rats were dosed by gavage with aniline hydrochloride (10, 30, or 100 mg/kg/day), a positive control agent (hydroxyurea, 200 mg/kg/day), or vehicle (distilled water) on gestational days (gd) 7 through 20 or gd 7 through parturition. At termination on gd 20 confirmed-pregnant dams exhibited characteristic signs of aniline HCl toxicity, i.e., methemoglobinemia, increased relative spleen weight, decreased red blood cell (RBC) count, and hematological changes indicative of increased hematopoietic activity. High-dose dams exhibited mild methemoglobinemia, increased relative spleen weight, and increased RBC size at termination on postnatal day (pnd) 30. At termination on gd 20, fetuses from aniline-treated dams exhibited increased relative liver weight and enhanced hematopoietic activity, but no evidence of an embryolethal or teratogenic effect was observed. Postnatal signs of toxicity in litters from aniline-treated dams (i.e., decreased body weight, elevated relative liver weight, and elevated relative spleen weight) were transient, and no evidence of toxicity was observed in pups surviving to pnd 60. Hydroxyurea (200 mg/kg/day) administered by gavage proved to be an excellent positive control for embryotoxicity, maternal toxicity, teratogenicity, and postnatal maturational deficits in the Fischer 344 rat. In conclusion, aniline hydrochloride was not teratogenic to Fischer 344 rats, even at maternally toxic doses; transient signs of toxicity were observed postnatally in the offspring in conjunction with mild, but persistent signs of maternal toxicity through pnd 30.