Treatment of kidney encapsulated rats with 850 µC. of radioactive iodine effectively prevented both the characteristic rise of blood pressure to hypertensive levels and cardiac hypertrophy. Iodine-deficient diet was ineffective under these conditions. Once hypertension was established, treatment with 850 µC. radioactive iodine lowered blood pressure toward normal levels although a significant decrease in heart weight was not observed. The iodine-deficient diet was also ineffective under these conditions. It is felt that hypothyroidism produced by administration of high doses of radioactive iodine is as effective in preventing blood pressure rise as that observed with propylthiouracil treatment. The antihypertensive effect of these antithyroid treatments appears to be the direct result of inhibition of secretion of thyroid hormone.
Surgical thyroparathyroidectomy (thyroidectomy) prevented the rise in systolic blood pressure to hypertensive levels in rats whose kidneys were bilaterally encapsulated with latex envelopes. This treatment also reduced the systolic blood pressure of ‘normal,’ nonencapsulated rats. The antithyroid drug, propylthiouracil (PTU), acted in the same fashion as surgical thyroidectomy on blood pressure of both kidney encapsulated and nonencapsulated rats. However, PTU appeared to be a more effective treatment than thyroidectomy since blood pressures of both PTU-treated, kidney encapsulated and PTU-treated, nonencapsulated rats were reduced to a greater extent than were the blood pressures of their surgically thyroidectomized counterparts. It was not possible to lower further the blood pressure of surgically thyroidectomized, kidney-encapsulated rats by treatment with PTU, even though the treatment was continued for 20 weeks. Other results of the two treatments were also similar and differed only in degree, viz. decreased growth rate, decreased food intake and anemia. Surgical thyroidectomy decreased water intake of nonencapsulated rats while PTU treatment increased it above that of controls. In the encapsulated groups, however, both treatments decreased water intake below that of control encapsulated rats. Thyroidectomy performed after the kidneys had been encapsulated for 9–19 weeks had only slight effect on blood pressure.
Background: An 18-year-old patient with atypical partial lipodystrophy had a transient initial metabolic response to metreleptin that deteriorated when neutralizing antibodies against metreleptin developed. A therapeutic trial with setmelanotide did not result in any metabolic benefit as desired. Because her status continued to deteriorate, we attempted to treat her with REGN4461, a fully human monoclonal antibody that is an agonist to the human leptin receptor (LEPR). Clinical Case: A compassionate use protocol (IND No. 144013) was initiated to treat the patient with REGN4461. The treatment consisted of 5 mg/kg intravenous infusion followed by 300 mg weekly subcutaneous injections of REGN4461. The primary endpoint was achievement of fasting triglycerides < 500 mg/dL without the need for ongoing plasmapheresis. Treatment-emergent adverse events were also followed. Here, we report her first 21-week response to treatment with REGN4461. The treatment resulted in a reduction of triglycerides from 1288 mg/dL to 344 mg/dl and allowed her to discontinue plasmapheresis. She lost 3.4 kilograms so far, and her liver size reduced per liver span measured by physical examination. Also, the liver MRI at week 12 showed a significant reduction in liver size and fat content (from 29.9% to 16.6%). Although her glucose control is still challenging, a slight reduction in her HbA1c was observed at week 12 along with improvements in her average glucose levels and total daily insulin requirement so far. No untoward signals were detected in her safety measurements. Conclusion: To date, treatment with REGN4461 offered substantial clinical benefit by improving the metabolic abnormalities in this unique patient. This experience represents the longest human exposure with REGN4461. The improvements noted in metabolic parameters and hepatic steatosis are similar to previous observations in lipodystrophic humanized LEPR mice. Our results suggest that REGN4461 showed clinical benefit even in the presence of neutralizing antibodies to metreleptin.
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