ABSTRACT
OBJECTIVE: Growth hormone (GH) replacement therapy currently requires daily injections, which may cause distress and low compliance. C-terminal peptide (CTP)-modified growth hormone (MOD-4023) is being developed as a once-weekly dosing regimen in patients with GH deficiency (GHD). This study's objective is to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of MOD-4023 administered once-weekly in GHD adults. DESIGN: 54 adults with GHD currently treated with daily GH were normalized and randomized into 4 weekly dosing cohorts of MOD-4023 at 18.5%, 37%, 55.5% or 123.4% of individual cumulative weekly molar hGH dose. The study included 2 stages: Stage A assessed the effectiveness and PK/PD profiles of the 4 dosing regimens of MOD-4023. Stage B was an extension period of once-weekly MOD-4023 administration (61.7% molar hGH content) to collect further safety data and confirm the results from Stage A. RESULTS: Dose-dependent response was observed for both PK and PD data of weekly MOD-4023 treatment. Insulin-like growth factor I (IGF-I) SDS levels were maintained within normal range. The 18.5% cohort was discontinued due to low efficacy. MOD-4023 was well tolerated and exhibited favorable safety profile in all dose cohorts. The reported adverse events were consistent with known GH-related side effects. CONCLUSIONS: Once-weekly MOD-4023 administration in GHD adults was found to be clinically effective while maintaining a favorable safety profile and may obviate the need for daily injections. Weekly GH injections may improve compliance and overall outcome. The promising results achieved in this Phase 2 study led to a pivotal Phase 3 trial, which is currently ongoing.
Subject(s)
Hormone Replacement Therapy/methods , Human Growth Hormone/deficiency , Human Growth Hormone/therapeutic use , Hypopituitarism/drug therapy , Adult , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Male , Middle Aged , Treatment Outcome , Young AdultABSTRACT
The authors present a case of an 82-year-old male patient who presented with frequent hypoglycaemia. Four years prior to the current evaluation the patient had been diagnosed with prostate carcinoma; however, he refused surgical treatment. Initial diagnostic tests indicated organic hypoglycaemia with low serum insulin levels. Insulinoma was excluded and further laboratory tests showed reduced serum insulin-like growth factor-II and normal serum chromogranin A levels as well as normal hypophysis and peripheral hormone values. The authors hypothesised that the severe hypoglycaemia might be the consequence of synthesis and secretion of insulin-like growth factor-II (or its prohormone) by the previously diagnosed prostate tumour. Insulin-like growth factor-II and its prohormone directly increases glucose uptake of the tumour, muscle and adipose tissue, decreases glucose release from the liver and downregulates insulin synthesis due to inhibition of the pancreatic beta cells. The patient required continuous intravenous glucose substitution initially with 5%, subsequently with 20% glucose infusion. Administration of other agents resulted only in temporary improvement. Prostatectomy was again considered but then excluded because of the recurrent hypoglycaemia and the poor general condition of the patient. Hypoglycaemia was finally controlled with glucose and diazoxide therapy, but no improvement in the general condition of the patients was observed and the patient deceased. Immunohistochemistry of the prostate sections showed a carcinoma with strong insulin-like growth factor-II staining, suggesting that insulin-like growth factor-II-secreting prostate tumour caused the severe hypoglycaemia.
Subject(s)
Adenocarcinoma/metabolism , Hypoglycemia/blood , Hypoglycemia/etiology , Insulin-Like Growth Factor II/metabolism , Prostatic Neoplasms/metabolism , Adenocarcinoma/complications , Aged, 80 and over , Diazoxide/administration & dosage , Fatal Outcome , Glucose/administration & dosage , Humans , Immunohistochemistry , Infusions, Intravenous , Male , Prostatic Neoplasms/complications , Severity of Illness IndexABSTRACT
Diagnosis and management of endocrine crises in adulthood. The homeostasis of the body is regulated by concerted action of the endocrine, nervous and immune systems. An imbalance in this equilibrium, as a consequence of disease or endocrine failure, may lead to crisis, characterized by sudden onset and severe symptoms. The classical endocrine emergencies are rare but life-threatening conditions. Prompt and aggressive treatment significantly reduces mortality. Immediate therapy might be necessitated in cases of suspected endocrine emergencies, even prior to laboratory confirmation. These patients generally require admittance to an intensive care unit. In the present review only the most severe forms of life-threatening endocrine emergencies, including acute adrenal insufficiency, pituitary apoplexy, pheochromocytoma crisis, thyroid storm and myxedema coma will be discussed.
