Zinc ligand-disrupted recombinant human Endostatin: Potent inhibition of tumor growth, safety and pharmacokinetic profile

Endostatin, a potent endogenous inhibitor of angiogenesis, inhibits the growth of primary tumors without induction of acquired drug resistance in mice. We report that a soluble recombinant human (rh) Endostatin produced with characteristics of the native Endostatin, effectively inhibited the growth of primary tumors and pulmonary metastases in a dose-dependent manner. We also show that deletion of two of the four zinc ligands of rhEndostatin did not affect this potent tumor inhibiton. The growth of established Lewis lung primary tumors implanted into mice was inhibited (80–90%) upon systemic treatment with 50 mg/kg/12 h of rhEndostatin. Using the B16-BL6 murine experimental pulmonary metastases model, rhEndostatin administered at 1.5 mg/kg/day or 4.5 mg/kg/day beginning 3- or 11-days post tumor cell injection, respectively, resulted in an approximate 80% inhibition of tumor growth. At effective anti-tumor doses of 1.5 and 50 mg/kg, pharmacokinetic modeling in mice showed (a) the protein was 100% bioavailable, (b) the AUC ranged from 16 to 700 ngml/h and (c) the C_max ranged from 161 to 4582 ng/ml. At the highest dose tested (300 mg/kg), delivered as a single bolus, no drug-related toxicity was observed in a Cynomolgus monkey infused with rhEndostatin. No toxicity was observed even at AUC and C_max values that were 1.3- to 56-fold higher than those observed in mice with tumors that were potently inhibited. Our production system yields a well characterized, soluble and potent rhEndostatin at quantities sufficient for human use. The preclinical studies described herein are an important first step toward the assessment of Endostatin in the clinic. This revised version was published online in June 2006 with corrections to the Cover Date.     

Twenty-four hour ambulatory blood pressure profile of a new,sustained-release preparation of nicardipine

Summary The 24-hour blood pressure (BP) profile of a new sustained-release preparation of nicardipine was assessed in 16 patients with essential hypertension (supine cuff diastolic BP>95 mmHg). Twenty-four hour ambulatory intraarterial BP monitoring (Oxford system) before treatment revealed a mean (SD) daytime BP of 174 (19) mmHg systolic and 105 (8) mmHg diastolic, and a mean nighttime BP of 142 (26) mmHg systolic and 83 (12) mmHg diastolic. Sustained release nicardipine (60 mg) was administered twice daily for 4–6 weeks and the ambulatory BP monitoring repeated. No significant change in heart rate occurred throughout the 24-hour period. However, there was a significant reduction (p<0.0001) in the mean daytime BP of 21 (13) mmHg systolic and 12 (9) mmHg diastolic and of mean nighttime BP of 21 (15) mmHg systolic and 13 (11) mmHg diastolic. A similar reduction in hourly mean BP occurred throughout the whole 24-hour period, including the steep early morning rise in BP. Although vasodilatory-type side effects occurred, they were generally mild to moderate and transient. This preparation produces a significant reduction in BP throughout the 24-hour period without reflex tachycardia.     

The pharmacokinetic and pharmacodynamic characteristics of a long-acting growth hormone (GH) preparation (nutropin depot) in GH-deficient adults

A pharmacokinetic-pharmacodynamic study of a long-acting GH [Nutropin Depot; somatropin (rDNA origin) for injectable suspension] was performed in 25 patients with adult GH deficiency. Single doses of 0.25 mg/kg and 0.5 mg/kg, based on ideal body weight, were administered sc. After either dose, serum GH concentrations rose rapidly in both sexes. In men, the lower dose maintained serum IGF-I levels within 1 SD of the mean for age and sex for 14-17 d; the higher dose raised IGF-I levels 2 SD above the mean. In most women, all of whom were receiving oral estrogen, the lower dose did not normalize IGF-I levels; the higher dose maintained IGF-I near the mean for approximately 14 d. Increases in IGF binding protein-3 and acid-labile subunit levels were observed in both sexes; however, a sex-related difference was not obvious. Fasting glucose and insulin concentrations were transiently elevated in men receiving the higher dose. Patients tolerated the injections well. We concluded that a single injection of Nutropin Depot at these doses in patients with adult GH deficiency increased serum IGF-I to within normal limits for 14-17 d. Estrogen-treated women required approximately twice the dose needed in men to produce comparable IGF-I concentrations.     

Efficacy and safety of a new ready-to-use recombinant human growth hormone solution

We report 24-month interim results of two multicenter phase III studies in previously untreated children with growth failure secondary to GH deficiency (GHD) that were paramount to the development of a new recombinant human GH (rh- GH, somatropin), approved as the first 'biosimilar' in Europe. Study 1 consisted of 3 parts performed in 89 children. The objective was to compare efficacy and safety of the lyophilized formulation of the new somatropin [Somatropin Powder (Sandoz)] with a licensed reference rhGH preparation and the liquid formulation of the new somatropin [Somatropin Solution (Sandoz)] and to assess long-term efficacy and safety of this ready-to-use Somatropin Solution. Study 2 was performed in 51 children and designed to demonstrate efficacy and safety of Somatropin Powder and to confirm its low immunogenic potential; rhGH was given sc at a daily dose of 0.03 mg/kg. Primary [body height, height SD score (HSDS), height velocity, and height velocity (HV) SD score (HVSDS)] and secondary [IGF-I and IGF binding protein 3 (IGFBP-3)] efficacy endpoints and safety parameters were assessed regularly. In study 1, all treatments showed comparable increases in growth. The baseline-adjusted difference between Somatropin Powder and the reference rhGH product in mean HV was -0.20 cm/yr (95% confidence interval (CI) [-1.34;0.94]) and in mean HVSDS was 0.76 (95% CI [-0.57;2.10]) after 9 months. These very small differences demonstrate comparable therapeutic efficacy between the two treatments. The results of study 2 were consistent with those seen in study 1. Equivalent therapeutic efficacy and clinical comparability in terms of safety and immunogenicity between Somatropin Powder and the reference rhGH product and between Somatropin Powder and Somatropin Solution was demonstrated. The safety and immunogenicity profiles were similar and as expected from experience with rhGH preparations.     

Corticosteroid pharmacokinetic/pharmacodynamic parameters and their relationship to safety and efficacy.

All inhaled corticosteroids (ICSs) exert their pharmacologic effects through the same mechanism. This review examines pharmacokinetic profiles of ICSs to explain the variations in efficacy and adverse effects seen with these agents and identify ideal properties for an optimal ICS. For optimum efficacy and safety, the ideal ICS would have high pulmonary bioavailability with pulmonary activation for targeted delivery, negligible oral bioavailability, high plasma protein binding, rapid systemic clearance, and sustained pulmonary residence to permit once-daily dosing.     

基因重组人生长激素在儿童中长期应用的安全性

自美国食品药品管理局(FDA)批准将重组人生长激素(rhGH)用于儿童后,20多年来美国已有数十万生长障碍患儿接受了rhGH治疗.由于参加临床试验的患者人数相对较少,一些少见的不良事件(AEs)可能无法发现,因而自1985年起,由Cenentech公司启动了一项开放式、多中心的售后调查,"全国生长协作研究"(NCGS),以监测其rhGH产品的疗效和安全性.自1985年12月至2006年1月1日,累计有54 996例患者(男性65%,女性35%)参加了NCGS,使用rhGH治疗的人年数达195 419,共有900多名医师参与了此项研究.     

Pharmacological profile of a new orally active growth hormone secretagogue, SM-130686.

SM-130686, an oxindole derivative, is a novel orally active GH secretagogue (GHS) which is structurally distinct from previously reported GHSs such as MK-677, NN703 and hexarelin. SM-130686 stimulates GH release from cultured rat pituitary cells in a dose-dependent manner. Half-maximum stimulation was observed at a concentration of 6.3+/-3.4 nM. SM-130686-induced GH release was inhibited by a GHS antagonist, but not by a GH-releasing hormone antagonist. SM-130686 dose-dependently inhibited the binding of radiolabeled ligand, (35)S-MK-677, to human GHS receptor 1a (IC(50)=1.2 nM). This indicates that SM-130686 stimulates GH release through the GHS receptor. The effect of a single oral administration of SM-130686 on GH release in pentobarbital-anesthetized rats was studied. After treatment with 10 mg/kg SM-130686, plasma GH concentrations measured by radioimmunoassay significantly increased, reaching a peak at 20-45 min, and remained above baseline during the experimental period (60 min). The anabolic effect of repetitive SM-130686 administration was studied in rats. Rats received 10 mg/kg SM-130686 orally twice a day and were weighed every day for 9 days. At day 9 there was a significant increase in both the body weight and the fat free mass (19.5+/-2.1 and 18.1+/-7.5 g respectively). Serum IGF-I concentration was also significantly elevated 6 h after the last dose of SM-130686. An endogenous GHS ligand for the GHS receptor has recently been identified from stomach extract and designated as ghrelin. The GH-releasing activity in vitro relative to ghrelin (100%) was about 52% for SM-130686. It is likely that SM-130686 is a partial agonist for the GHS receptor. In summary, we describe here an orally active GHS, SM-130686, which acts through the GHS receptor. Repetitive administration of SM-130686 to rats, similar to repetitive administration of GH, significantly increased the fat free mass by an amount almost equal to the gain in body weight.     

Long-term safety of recombinant human growth hormone in turner syndrome

CONTEXT: Turner syndrome (TS) affects more than 50,000 girls and women in the United States. The National Cooperative Growth Study (NCGS) has collected efficacy and safety data for 5220 TS children treated with recombinant human GH (rhGH) during the last 20 yr. OBJECTIVES: Our objective was to determine frequencies of specific targeted adverse events (AEs) and additional AEs of interest in TS patients. Corresponding safety data in non-TS patients or normal populations were compared for selected AEs. METHODS: Patients may be enrolled at rhGH initiation and followed until discontinuation. Investigators submit AE reports describing any event that is potentially rhGH related or is a targeted event. RESULTS: The Genentech Drug Safety department received 442 AE reports for TS NCGS patients as of June 30, 2006, including 117 serious AEs. Seven deaths occurred; five resulted from aortic dissections/ruptures. The incidence of certain events known to be associated with rhGH (targeted events), including intracranial hypertension, slipped capital femoral epiphysis, scoliosis, and pancreatitis, was increased compared with other non-TS patients in NCGS. There were 10 new-onset malignancies that occurred, including six in patients without known risk factors. Type 1 diabetes also appeared to be increased compared with other NCGS groups. CONCLUSIONS: Children with TS who were treated with rhGH exhibit an increased underlying risk for selected AEs associated with rhGH and for type 1 diabetes, which is likely unrelated to rhGH. The aortic dissection/rupture incidence reflects the higher baseline risk for these events in TS, was consistent with current epidemiological data in smaller TS populations, and is likely unrelated to rhGH. It is not known whether the reported malignancies represent an inherently increased risk in TS patients. Twenty years of experience in 5220 patients indicates no new rhGH-related safety signals in the TS population. The NCGS and similar registries, although focused on the years during rhGH treatment, may also be a window into the natural history of TS in childhood.     

Regulation of human growth hormone secretion and its disorders

Growth hormone (GH) secretion from anterior pituitary is regulated by the hypothalamus and the mediators of GH actions. Major regulatory factors include GH releasing hormone (GHRH), somatostatin (SRIF), GH releasing peptide (ghrerin) and insulin-like growth factor (IGF-I). The principal physiological regulation mechanisms of GH secretion are neural endogenous rhythm, sleep, stress, exercise, and nutritional and metabolic signals. GH deficiency results from various hereditary or acquired causes, which may be isolated or combined with other pituitary hormone deficiencies. GH deficiency can be treated with recombinant human GH, which results in accelerating growth in children and normalization of intermediary metabolism in adults. GH hypersecretion mostly results from a pituitary tumor and causes acromegaly or gigantism. Hypersecretion of GH can be treated by transshenoidal surgery. Medical treatment with octreotide and analogs is also effective to reduce GH secretion in combination with or without the surgery.     

The pharmacodynamic inhibition of estrogen synthesis by fadrozole, an aromatase inhibitor, and its pharmacokinetic disposition

In this dose-ranging phase I study, the relationship between in vivo androgen to estrogen conversion kinetics and plasma concentrations of fadrozole was investigated in postmenopausal women receiving therapy with this aromatase inhibitor. Patients received ascending doses, ranging from 0.3-8 mg fadrozole twice daily, each for a period of 2 weeks. Drug kinetics and endocrine effects were evaluated specifically for the 2- and 8-mg twice daily treatment regimens. The in vivo activity of the drug was demonstrated by the suppression of estrone and estradiol biosynthesis from testosterone and androstenedione, respectively. The drug inhibitory constant, KI, for the estrone synthetic pathway, was 3.0 ng/mL (13.4 nmol/L) and was of similar magnitude as that determined under in vitro conditions. The KI for the estradiol synthetic pathway was 5.3 ng/mL (23.7 nmol/L). The disparity between KI values may indicate that the two pathways are not equivalent in terms of their inhibition by fadrozole. Pharmacokinetic data demonstrated tha the drug was rapidly absorbed after oral dosing, with peak plasma concentrations achieved in median times of 1 and 2 h, respectively, for the 2- and 8-mg twice daily treatment regimens. The average half-life and oral clearance values were 10.5 h and 621 mL/min, respectively. Oral clearance was independent of dose.     

Comparison of peginterferon pharmacokinetic and pharmacodynamic profiles

The pharmacokinetics and in dosing regimens of the currently available pegylated interferon (peginterferon) alfa molecules differ greatly, depending on the size and nature of their polyethylene glycol (PEG) moiety. Peginterferon alfa-2a has a branched 40 kDa PEG chain covalently attached to lysine residues and circulates as an intact molecule. On the other hand, peginterferon alfa-2b has a linear 12 kDa PEG chain covalently attached to interferon-a-2b via an unstable urethane bond that is hydrolysed after injection, releasing native interferon alfa-2b. The difference in pegylation between the two peginterferons has a significant impact on their pharmacokinetic properties. Data from comparative and non-comparative studies indicate that peginterferon alfa-2b has a shorter half-life in serum than peginterferon alfa-2a, and a significant proportion of patients receiving peginterferon alfa-2b may have trough concentrations below the limit of detection during the latter part of the 7-day dosing schedule. However, the pharmacodynamic parameters of the two drugs appear to be similar.     

The pharmacodynamic and pharmacokinetic profile of intranasal crushed buprenorphine and buprenorphine/naloxone tablets in opioid abusers

Aims Sublingual buprenorphine and buprenorphine/naloxone are efficacious opioid dependence pharmacotherapies, but there are reports of their diversion and misuse by the intranasal route. The study objectives were to characterize and compare their intranasal pharmacodynamic and pharmacokinetic profiles. Design A randomized, double‐blind, placebo‐controlled, cross‐over study. Setting An in‐patient research unit at the University of Kentucky. Participants Healthy adults (n = 10) abusing, but not physically dependent on, intranasal opioids. Measurements Six sessions (72 hours apart) tested five intranasal doses [0/0, crushed buprenorphine (2, 8 mg), crushed buprenorphine/naloxone (2/0.5, 8/2 mg)] and one intravenous dose (0.8 mg buprenorphine/0.2 mg naloxone for bioavailability assessment). Plasma samples, physiological, subject‐ and observer‐rated measures were collected before and for up to 72 hours after drug administration. Findings Both formulations produced time‐ and dose‐dependent increases on subjective and physiological mu‐opioid agonist effects (e.g. ‘liking’, miosis). Subjects reported higher subjective ratings and street values for 8 mg compared to 8/2 mg, but these differences were not statistically significant. No significant formulation differences in peak plasma buprenorphine concentration or time–course were observed. Buprenorphine bioavailability was 38–44% and T_max was 35–40 minutes after all intranasal doses. Naloxone bioavailability was 24% and 30% following 2/0.5 and 8/2 mg, respectively. Conclusions It is difficult to determine if observed differences in abuse potential between intranasal buprenorphine and buprenorphine/naloxone are clinically relevant at the doses tested. Greater bioavailability and faster onset of pharmacodynamic effects compared to sublingual administration suggests a motivation for intranasal misuse in non‐dependent opioid abusers. However, significant naloxone absorption from intranasal buprenorphine/naloxone administration may deter the likelihood of intranasal misuse of buprenorphine/naloxone, but not buprenorphine, in opioid‐dependent individuals.     

Pharmacokinetic and pharmacodynamic characteristics of a long-acting growth hormone (GH) preparation (nutropin depot) in GH-deficient children

Long-term GH replacement therapy is indicated for children with growth failure due to GH deficiency (GHD). We evaluated the feasibility of administering a long-acting GH preparation [Nutropin Depot (somatropin, rDNA origin) for injectable suspension] to prepubertal children with GHD by examining pharmacokinetic and pharmacodynamic response parameters after single or multiple doses. Data were collected from three studies involving 138 children treated with Nutropin Depot 0.75 mg/kg once per month, 0.75 mg/kg twice per month, or 1.5 mg/kg once per month. Twenty-two patients underwent intensive sampling to estimate mean peak serum GH concentrations (C(max)) and time to achieve C(max) for GH and IGF-I. Thereafter, weekly serum concentrations were measured and compared with baseline. C(max) and area under the curve were approximately proportional to the dose administered. Fractional area under the curve data indicate that at least 50% of GH exposure occurs during the first 2 d after administration. Serum GH levels remained above 1 microg/liter for 11-14 d. IGF-I levels remained above baseline for 16-20 d, but increases were not proportional to dose. After multiple doses over a 6-month period, peak and trough concentrations showed no progressive accumulation of GH, IGF-I, or IGF binding protein-3. Nutropin Depot administration once or twice per month provides serum levels of GH and IGF-I expected to promote growth, without accumulation of GH, IGF-I, or IGF binding protein-3, in children with GHD.     

Efficacy and safety of long-acting growth hormone in adult growth hormone deficiency: A systematic review and meta-analysis

Background & aimsNo meta-analysis has analysed efficacy and safety of long-acting growth hormone (GH) therapy in adult GH deficiency. We undertook this meta-analysis to address this gap in knowledgeMethodsElectronic databases were searched for RCTs involving adult GH deficiency patients receiving weekly long-acting GH as compared to daily GH/placebo controls. Primary outcome was to evaluate changes in body-composition parameters. Secondary outcomes were to evaluate alterations in glycaemia and adverse-events.ResultsData from 5 studies involving 648 patients were analysed (4 studies having daily GH as active controls; 1 study having placebo as passive controls). Over 24–34 weeks clinical use, patients receiving long-acting GH had comparable change in lean mass [MD-0.28 kg (95%CI: 0.94 – 0.38); P = 0.41; I² = 29% (low heterogeneity)] and fat mass [MD-0.10 kg (95%CI: 1.97–1.78); P = 0.92; I² = 77%(considerable heterogeneity)] as compared to daily GH injections. Long-acting GH use was associated with significantly lower visceral adipose tissue [MD-1.75 cm²(95%CI: 2.14 to ?1.35); P < 0.01; I² = 0% (low heterogeneity)] and higher gynoid fat-mass [MD 0.14 kg(95%CI:0.02–0.26); P = 0.03] compared to daily GH injections. Total adverse events [Risk ratio (RR) 1.65 (95% CI: 0.83–3.29); P = 0.15; I² = 68%] and severe adverse events [RR 0.60 (95% CI: 0.30–1.19); P = 0.14; I² = 0%] were not significantly different in long-acting GH group compared to controls. Occurrence of headache, arthralgia, nasopharyngitis, new onset diabetes, anti-GH antibodies were comparable among groups. Long-acting GH users had significantly higher treatment adherence compared to controls [OR 4.80 (95%CI:3.58–6.02); P < 0.01; I² = 0%].ConclusionLong-acting GH has comparable beneficial impact on body composition parameters in adult GH deficiency, is well tolerated without any increased adverse events.