Ectopic invasive ACTH-secreting pituitary adenoma mimicking chordoma: a case report and literature review.

BACKGROUND: Ectopic pituitary adenoma (EPA) is defined as a special type of pituitary adenoma that originates outside of the sellar region, is extra- or intra-cranially located, and without connection to normal pituitary tissue. EPA is extremely rare, with most cases presented as case reports or small case series. Due to nonspecific symptoms and laboratory indicators, the preoperative diagnosis, treatment and management for EPA remain challenging. CASE PRESENTATION: Here, we report the imaging phenotype and pathological findings of a case of invasive EPA in a 47-year-old woman. A preoperative non-contrast CT scan revealed a 5.8 × 3.6 × 3.7 cm soft tissue mass located in the sphenoid sinus and clivus. MRI showed an ill-defined solid mass with heterogeneous signals on T1-weighted and T2-weighted images. The mass displayed infiltrative growth pattern, destroying bone of the skull base, invading adjacent muscles and encasing vessels. The patient underwent partial tumor resection via transsphenoidal endoscopic surgery. Pathological examination led to diagnosis of ectopic ACTH-secreting pituitary adenoma. Post-surgery, the patient received external beam radiotherapy. CONCLUSION: EPA with invasive growth pattern has rarely been reported. The imaging phenotype displays its relationship to the pituitary tissue and surrounding structures. Immunohistochemical examination acts as a crucial role in differentiating EPA from other skull base tumors. This case report adds to the literature on EPA by summarizing its characteristics alongside a review of the literature.

A First-in-Human Safety, Tolerability, and Pharmacokinetics Study of Benapenem in Healthy Chinese Volunteers.

The objective of this trial was to investigate the safety, tolerability, and pharmacokinetics (PK) of benapenem administered by single or multiple intravenous infusions in healthy Chinese volunteers. The trial was divided into 3 parts. In part A, 94 subjects were enrolled in a double-blind, placebo-controlled, sequential-ascending-single-dose study. The subjects were randomly assigned to groups receiving placebo or benapenem for injection at doses of 62.5, 125, 250, 500, 1,000, 2,000, or 3,000 mg. The effects of intravenous infusion time on the subjects of 250-, 500-, and 1,000-mg groups were explored. In part B, 12 subjects were enrolled in a single-dose PK study under fasting conditions and received 250, 500, or 1,000 mg of benapenem for injection. In part C, 36 subjects were given 250, 500, and 1,000 mg of benapenem for injection once daily for 7 consecutive days. The results showed that benapenem for injection was well tolerated during the studies. The major observed adverse events were mild, and all were resolved spontaneously without any medical intervention. Benapenem was mainly excreted through the kidneys in the form of parent molecule and metabolites. The PK and safety profiles of benapenem in healthy Chinese volunteers support its once-daily dosing in future clinical investigations. (Part A, part B, and part C have been registered at ClinicalTrials.gov under identifiers NCT03588156, NCT03578588, and NCT03570970, respectively.).

Safety, Pharmacokinetics and Pharmacodynamics of Multiple Escalating Doses of PEGylated Exenatide (PB-119) in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: At present, the deficiency of ß-cell function is progressive in patients with type 2 diabetes mellitus. Exenatide cannot only control blood glucose well, but also promotes the regeneration and proliferation of islet ß-cells and improves the function of ß cells. However, it needs to be given twice a day, and there are many adverse reactions such as nausea. PEGylated exenatide (study code: PB-119) needs to be administered only once a week. The purpose of this experiment was to evaluate the safety, pharmacokinetics and pharmacodynamics of an escalating dose regimen of subcutaneous PEGylated exenatide injections in healthy subjects. METHODS: Twelve healthy young adult subjects in each group received once-weekly subcutaneous injections of 165 µg, 330 µg, and 660 µg PEGylated exenatide for 6 weeks. Plasma drug concentration was determined in venous blood collected across selected time points. Safety and tolerability were evaluated by monitoring adverse events, laboratory parameters, and electrocardiogram. Blood glucose, insulin,  glucagon and C peptide were monitored at different time points to evaluate the pharmacodynamics of PEGylated exenatide. RESULTS: A total of 11, 10, and 12 subjects completed the study in 165 µg, 330 µg, and 660 µg dose groups, respectively. After 6 consecutive weeks of administration, the t1/2 in the 165 µg, 330 µg, and 660 µg dose groups was 55.67 ± 11.03 h, 56.99 ± 21.37 h, and 54.81 ± 13.87 h, respectively. The Cavg was 4.22 ± 0.78 ng/ml, 6.03 ± 1.43 ng/ml, and 10.50 ± 3.06 ng/ml, respectively. AUCss was 708.59 ± 131.87 h•ng/ml, 1012.63 ± 240.79 h•ng/ml, and 1763.81 ± 514.50 h•ng/ml, respectively. The accumulation index was 1.15 ± 0.07, 1.17 ± 0.11, and 1.14 ± 0.07. The CLss/F was 241.25 ± 51.13 ml/h, 341.53 ± 73.62 ml/h, and 450.06 ± 313.76 ml/h, respectively. A total of 10 of 36 (27.78%) subjects in the three dose groups developed specific antibodies after consecutive subcutaneous injections of PEGylated exenatide. The Cavg and Cmax were higher than those of antibody-negative subjects. Furthermore, in antibody-positive subjects, CLss/F, t1/2, AUCτ, accumulation index, MRT(0-inf) and other parameters were lower than those of antibody-negative subjects. In the 165 µg dose group, two subjects (16.67%) experienced 4 adverse events. In the 330 µg dose group, no subjects reported adverse events. In the 660 µg dose group, 8 subjects (66.67%) reported 16 adverse events, which were mostly gastrointestinal. There were no significant changes in the pharmacodynamic parameters except the glucagon level at day 36 in the 660 µg dose group, the 2h postprandial insulin and C peptide levels at day 36 and day 50 in the 165 µg dose group compared with baseline (- 1 day). CONCLUSION: A once-weekly subcutaneous injection of 165 µg and 330 µg PEGylated exenatide is safe. No significant effects on blood glucose or pancreatic hormone levels were observed in the subjects within these dose groups. The pharmacokinetic parameters of PEGylated exenatide may be affected by immunogenicity. CLINICAL TRIALS REGISTRATION: The study is registered at clinicaltrials.gov (No. NCT03062774).

Correction to: Safety, Tolerability and Pharmacokinetics of Single Dose Polyethylene Glycolated Exenatide Injection (PB-119) in Healthy Volunteers.

The original version of this article unfortunately contained a mistake.

Safety, Tolerability and Pharmacokinetics of Single Dose Polyethylene Glycolated Exenatide Injection (PB-119) in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: Exenatide promotes insulin secretion and inhibits postprandial glucagon secretion. Polyethylene glycolated exenatide injection (PB-119), a derivative obtained by modification of exenatide, is more stable in metabolic behavior than exenatide in vivo. Our study aimed to evaluate the safety, tolerability and pharmacokinetic characteristics of polyethylene glycolated exenatide as a single subcutaneous injection in healthy volunteers. METHODS: Seventy subjects were randomly assigned to 8 incremental dosage groups (2, 5, 10, 25, 50, 100, 200 and 400 µg). The 2- to 50-µg groups had 8 subjects in each group (the ratio of test preparation to placebo was 3:1), and the 100- to 400-µg groups had 10 subjects in each group (the ratio of test preparation to placebo was 4:1). All the subjects received a single subcutaneous injection of polyethylene glycolated exenatide and placebo according to the dosage groups. The tolerability test was conducted in the 2- to 10-µg groups. The pharmacokinetic test was carried out in the 25- to 400-µg groups, and plasma samples were collected to determine the pharmacokinetics of polyethylene glycolated exenatide. After medication, the vital signs of the subjects were monitored, and laboratory tests and electrocardiogram tests were carried out regularly in all the subjects. RESULTS: All 70 subjects completed the experiment. Except for the 5-µg and 10-µg groups, the safety and tolerability tests showed no adverse reactions in the 2-µg to 50-µg groups. Several subjects in the 100-µg and 200-µg groups had tolerable gastrointestinal tract reactions, and all subjects in the 400-µg group experienced adverse reactions, mainly gastrointestinal tract reactions and liver dysfunction. The pharmacokinetics of polyethylene glycolated exenatide was studied in 36 subjects, which showed slow absorption, a mean peak time of 20-40 h, and a mean elimination half-life of 51-64 h. CONCLUSION: The administration of polyethylene glycolated exenatide injection at a single dose of 2-200 µg is safe and tolerable for healthy volunteers. Once-weekly polyethylene glycolated exenatide injection can be recommended. CLINICAL TRIALS REGISTRATION: The study was registered at clinicaltrials.gov (No. NCT02084251).