MOD-4023, a long-acting carboxy-terminal peptide-modified human growth hormone: results of a Phase 2 study in growth hormone-deficient adults.

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.

Effect of growth hormone replacement therapy on plasma brain natriuretic peptide concentration, cardiac morphology and function in adults with growth hormone deficiency.

OBJECTIVE: The impact of growth hormone (GH) replacement on plasma brain natriuretic peptide (BNP) in association with cardiac morphology and function in adults with growth hormone deficiency (GHD) was evaluated. SUBJECTS AND METHODS: Fifty nine adult patients with GHD (29 men, age 19-59 years) received a starting dose of 0.1-0.2 mg/day recombinant GH, which was subsequently adjusted to the 50th percentile of normal serum insulin-like growth factor (IGF-1) over a 6 month period. Plasma BNP and IGF-I levels before, 3 and 6 months after treatment were determined, as were the echocardiographic data, such as ejection fraction (EF), left ventricular end-diastolic volume (LVEDV), left ventricular end-diastolic diameter (LVEDD), interventricular septal thickness (IVST), posterior wall thickness (PWT), left ventricular mass (LVM), E/A wave and deceleration time (DT). RESULTS: Mean plasma BNP levels (53.1+/-8 pg/ml) and echocardiographic parameters were within the normal range at baseline, although men had higher LVM, IVST, PWT, LVEDV and LVEDD, respectively. A significant decrease in plasma BNP was observed after 6 months (27+/-5.6 pg/ml, P<0.05). No significant changes in echocardiographic parameters were observed except for a mild tendency to increase in LVM, and a borderline decrease in DT (181+/-8.1 vs. 155+/-9 ms, P<0.01). CONCLUSIONS: Six months GH replacement therapy induced a significant decrease in plasma BNP levels despite the majority of patients having plasma BNP within the normal range at baseline. A borderline decrease in diastolic deceleration time was observed, the clinical significance of which is unclear.

[Prolactin levels before and after stimulation with thyroliberin in primary hypothyroidism]. / Koncentrácie PRL pred a po stimulácii tyreoliberínom u primárnych hypotyreóz.

The authors examined the concentration of thyrotropic hormone (TSH) and prolactin (PRL) before and after stimulation with synthetic thyroliberine (0.2 mg TRH i.v.) in a group of 72 women with primary hypothyroidism (mean age 45 years, range 17-69 years) and 12 controls (mean age 35 years, range 17-49 years). According to the total thyroxin concentrations (TT4) and TSH they divided the group into three smaller subgroups: developed primary hypothyroidism (n = 8, mean age 50 years, TT4 < 65 nmol/l, basal TSH concentration > 15.0 mIU/l nmol/l), subclinical hypothyroidism, severe grade (n = 23, mean age 36 years, TT4 > 65 nmol/l, basal TSH concentration < 4.5 mIU/l), subclinical hypothyroidism mild degree (n = 39, mean age 42 years, TT4 > 65 nmol/l, basal TSH concentration < 4.5 mIU/l, TSH after TRH stimulation > 25 mIU/l). Mean basal PRL concentrations were in all three patient groups significantly higher than in the control group (P < 0.01) but mutually they did not differ significantly. Poststimulation PRL concentrations were also significantly higher than in controls however the values in developed hypothyroidism were significantly higher than in subclinical patients. No correlation was found between TSH and PRL concentrations.

[Incidence of primary hyperaldosteronism in hospitalized patients with hypertension]. / Výskyt primárneho hyperaldosteronizmu u hospitalizovaných hypertonikov.

AIMS: To detect the incidence of primary hyperaldosteronism (PH) in hospitalized hypertensive patients. METHODS: Authors assessed plasma renin activity (PRA) and plasma aldosterone (PA) in 100 patients with arterial hypertension hospitalized at the II. department of Internal medicine in Kosice because of resistance to ambulatory treatment, eventually with the aim of differential diagnosis of arterial hypertension. RESULTS: From 100 hypertensive patients 90 (90%) have had essential hypertension (EH), 8 (8%) PH, 2 (2%) renovascular hypertension and 1 patient (1%) pheochromocytoma. Aldosterone-renin ratio was in PH patients 10-fold higher comparing with EH patients. From the 8 patients with PH 4 have had adenoma and in 3 patients hyperplasia was diagnosed with the use of CT or histology, 1 case was idiopathic hyperaldosteronism without CT hyperplasia evidence. In all PH patients the level of kalemia was less than 4 mmol/l, i.e. kalemia 4.0 mmol/l has 100% sensitivity for PH detection. CONCLUSION: Introduction of PRA and PA examinations in the diagnostic process of arterial hypertension led to more frequent diagnosis of PH, which may probably represent the most frequent form of endocrine hypertension. Although ARR is a reliable test for PH screening, routine ARR examinations in ambulatory practice are technically complicated and connected with high costs. Increasing the threshold level of kalemia for PH detection led to higher sensitivity and that is why the authors consider ARR examination rational in every patient with kalemia level less than 4 mmol/l. (Tab. 4, Ref. 18.)

[Changes in thrombocyte aggregation in primary hypothyroidism]. / Zmeny agregability trombocytov pri primárnej hypotyreóze.

The authors examined the thrombocyte aggregation in 10 controls and 17 patients with the diagnosis of primary hypothyroidism before and after 2 months substitution treatment with levothyroxine. They recorded a significantly reduced intensity of the aggregation response in untreated patients as compared with controls after adrenaline (p < 0.01), ADP (p < 0.01) but not after ristocetin. Impaired thrombocyte aggregation was observed in 11 of 17 patients, i.e. in 65%. After treatment the thrombocytopathy improved in 7 of 11 patients (63%), in four it persisted. Except one female patient the thrombocytopathy improved in all patients with manifest hypothyroidism. In patients with the latent form of hypothyroidism probably an independent coincidence of elevated TSH levels and impaired thrombocyte function was involved. The authors did not detect any cases of acquired von Willebrand's disease. In the conclusion the authors mention that impaired thrombocyte aggregation is a frequent phenomenon after thyroxine treatment. It may be of clinical significance when combined with other changes of haemostasis or in conjunction with the use of some drugs.

[The clinical picture of latent hypothyroidism in women]. / Klinický obraz pri latentnej hypotyreóze u zien.

The authors investigated the most frequent clinical symptoms in a group of 132 women with latent hypothyroidism (mean age 40.2 years, incl. 102 women younger than 45 years). They assessed the diagnosis on the basis of an excessive TSH response after administration of 0.2 mg thyreoliberin by the i.v. route (TRH test), while the thyroxine values were normal (TSH 0 min.: 4.93 +/- 3.55, TSH after 20 min. following TRH: 39.27 +/- 18.28 mIU/ml, T4: 102.0 +/- 25.02 nmol/l). Forty-one patients (31%) had goitrectomy in the case-history. USG examination of 70 patients revealed goitre in 13 (18.6%) reduced echogenity of the thyroid gland in 20 (28.6%) and microcysts in 31 (44.2%) of the patients. Analysis of the clinical symptoms revealed manifestations of a depressive symptomatology in 56 patients (40.3%), benign mammary dysplasia in 39 patients (29%). In the subgroup of women younger than 45 years an impaired menstrual cycle was recorded in 49 (48%) and galactorrhoea in 10 patients (9.8%). After thyroid substitution (L-thyroxine 50 micrograms/day) they observed in the majority normalization of the menstrual cycle and partial improvement of depressive manifestations.

[Latent hypothyroidism--a minor laboratory variation or a disease?]. / Latentná hypotyreóza--nezávazná laboratórna odchýlka alebo choroba?

Latent hypothyreosis is a state which is characteristic by normal values of thyroid hormones (T3, T4) and moderately increased values of thyroid-stimulating hormone (TSH), or extensive response of TSH after stimulation with thyrotrophin-releasing hormone (TRH-test). The characteristic symptoms include goitre, symptoms of mammary glands (galactorrhea, benign mammary dysplasia), impairment of menstruation cycle and fertility and psychic disturbances (depressive symptomatology, deterioration of memory). The characteristic laboratory alterations include increased basal or stimulated values of prolactin and impairment of lipoprotein metabolism (significant decrease of HDL, increase of LDL). This aspect often makes the indication of substitution therapy justified in spite of normal concentrations of peripheral hormones. (Ref. 26).

Central hypothyroidism--various types of TSH responses to TRH stimulation.

Thyrotropin (TSH) levels in serum before and 20 and 60 min after the administration of 0.2 mg TRH i.v. as well as thyroid hormone (T3, T4) levels were studied in 39 patients with organic diencephalo-pituitary lesions and 27 healthy subjects. All participants gave their informed consent with the study. By the type of TSH response to TRH stimulation all patients were divided into 4 groups: 1. Normal response (n = 10): basal TSH 2.31 +/- 1.51, peak TSH 20 min after TRH 12.17 +/- 6.53, TSH 60 min after TRH 8.43 +/- 4.65 microU/ml; T3 2.02 +/- 0.48 and T4 95.9 +/- 27.73 nmol/l; 2. Blunted or absent TSH response (n = 8): basal TSH 0.82 +/- 0.42, peak TSH 20 min after TRH 1.51 +/- 0.66, TSH 60 min after TRH 1.35 +/- 0.51 microU/ml; T3 1.6 +/- 0.49 and T4 86.63 +/- 16.49 nmol/l; 3. Delayed ("diencephalic") TSH response (n = 16): basal TSH 2.69 +/- 1.27, peak TSH 20 min after TRH 7.96 +/- 3.35, TSH 60 min after TRH 10.0 +/- 3.97 microU/ml; T3 1.30 +/- 0.63 and T4 65.85 +/- 21.13 nmol/l; 4. Higher basal or stimulated TSH (n = 10): basal TSH > 10 mU/ml or stimulated values above 25 mU/ml. Mean T3 and T4 values in patients with normal or blunted TSH response did not differ significantly from the controls. Mean T3 and T4 in the group with delayed TSH response were significantly lower (P < 0.01). High TSH and low T3 and T4 levels were found in the patient with large meningioma sellae.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma cortisol and prolactin response to insulin-induced hypoglycemia in neurosis.

Prolactin (PRL) and plasma cortisol response to insulin induced hypoglycemia were studied in 14 patients with various somatic and vegetative complaints of neurotic character and in 12 controls. In all examined subjects glucose level fell below 50% of basal values and below 2.2 mmol/l. Significant PRL and plasma cortisol response were present in all controls. Plasma cortisol increase in control group was at least 1.5 fold higher than basal values and the difference between basal concentrations and highest values after stimulation was at least 0.25 mumol. Individual peak of PRL values in group of controls was 1.8-10 fold greater than basal levels. In the group of 14 patients in 11 cases no PRL response to challenge was found and in 4 cases also plasma cortisol response was blunted. In two patients extremely exaggerated PRL reaction was found. Different PRL responses to insulin-induced hypoglycemia are probably a manifestation of different types of neurotransmitter metabolism breakdown.

[The prolactin and TSH response to stimulation in patients with hypophyseal tumors]. / Odpovede prolaktínu a TSH na stimuláciu u chorých s tumorom hypofýzy.

The authors examined the prolactin (PRL) and thyrotropin (TSH) response to stimulation with chloropromazine and thyreoliberin in 10 patients with pituitary tumours. They observed a hypothalamic response instead of the expected pituitary response. These findings may be of importance for the understanding of the aetiopathogenesis of pituitary tumours. As we are able to influence nowadays some expansive pituitary processes by conservative treatment, these findings may in the near future be important in clinical practice.