Preclinical and clinical in vitro in vivo correlation of an hGH dextran microsphere formulation.

PURPOSE: To investigate the in vitro in vivo correlation of a sustained release formulation for human growth hormone (hGH) based on hydroxyethyl methacrylated dextran (dex-HEMA) microspheres in Pit-1 deficient Snell dwarf mice and in healthy human volunteers. MATERIALS AND METHODS: A hGH-loaded microsphere formulation was developed and tested in Snell dwarf mice (pharmacodynamic study) and in healthy human volunteers (pharmacokinetic study). RESULTS: Single subcutaneous administration of the microspheres in mice resulted in a good correlation between hGH released in vitro and in vivo effects for the hGH-loaded microsphere formulation similar to daily injected hGH indicating a retained bioactivity. Testing the microspheres in healthy volunteers showed an increase (over 7-8 days) in hGH serum concentrations (peak concentrations: 1-2.5 ng/ml). A good in vitro in vivo correlation was obtained between the measured and calculated (from in vitro release data) hGH serum concentrations. Moreover, an increased serum concentration of biomarkers (insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3) was found again indicating that bioactive hGH was released from the microspheres. CONCLUSIONS: Good in vitro in vivo correlations were obtained for hGH-loaded dex-HEMA microspheres, which is an important advantage in predicting the effect of the controlled drug delivery product in a clinical situations.

The effect of nimodipine monotherapy and combined treatment with ketamine and lignocaine in aneurysmal subarachnoid haemorrhage.

The clinical effects of nimodipine monotherapy were compared with the effects of nimodipine combined with ketamine and lignocaine (combination therapy) in a single-centre, one investigator, open study in patients with proven aneurysmal subarachnoid haemorrhage (aSAH). After clipping of the aneurysm, nimodipine was administered intravenously until day 5-7 after clipping. Thereafter the intravenous nimodipine was substituted by oral doses of nimodipine. These were decreased gradually and then discontinued within the following 6 days. For combination therapy, nimodipine was given together with both a bolus injection of 1 microgram/kg ketamine followed by an infusion of the drug at a rate of 3 micrograms/kg/min and a bolus injection of 1.5 mg/kg lignocaine followed by an infusion of the drug at a rate of 12 micrograms/kg/min. During the study period, 173 patients were admitted to the hospital with subarachnoid haemorrhage (SAH). Of these patients, 115 with a proven aneurysm were operated on and evaluated: 66 patients received nimodipine monotherapy and 49 were given nimodipine combined with ketamine and lignocaine. These subgroups were comparable in terms of the baseline characteristics (age, Hunt and Hess score). The (baseline corrected) Hunt and Hess scores after surgery and a 0-5 clinical outcome score were applied as indices for clinical effects. Patients receiving nimodipine monotherapy and combined therapy showed a significant clinical improvement compared to baseline (P = 0.001 and P = 0.006, respectively). The beneficial effect of nimodipine monotherapy is in line with previous double-blind, placebo-controlled studies. Although nimodipine monotherapy seems to be more effective than combined treatment, this was not statistically significant. Our data indicate that combined treatment with ketamine and lignocaine is not more effective than nimodipine monotherapy in patients with mild aSAH, but this does not rule out an effect in severe cases. There was no indication of a pharmacodynamic interaction between nimodipine and co-medication. No serious or clinically relevant adverse reactions were noted during the study.

Effects of early intervention with low-dose aspirin (100 mg) on infarct size, reinfarction and mortality in anterior wall acute myocardial infarction.

Recently, it was shown that aspirin given early in acute myocardial infarction (AMI) improves hospital survival, but the mechanisms involved are unclear. In a prospective, randomized placebo-controlled trial, the influence of early intervention with low-dose aspirin (100 mg/day) on infarct size and clinical outcome was studied in 100 consecutive patients with first anterior wall AMI. Infarct size was calculated by cumulative lactate dehydrogenase release in the first 72 hours after admission and was found to be (mean +/- standard deviation) 1,431 +/- 782 U/liter in the aspirin group (n = 50) and 1,592 +/- 1,082 U/liter in the placebo group (n = 50, p = 0.35). The study medication was given for 3 months, during which mortality was 10 (20%) in the aspirin patients and 12 (24%) in the placebo patients (p = 0.65). However, reinfarction occurred in 2 patients (4%) in the aspirin group and in 9 (18%) in the placebo group (p less than 0.03). Early intervention with low-dose aspirin showed, in comparison to placebo, a 10% decrease of infarct size, but this difference was not statistically significant. However, early low-dose aspirin effectively decreased the risk of reinfarction. Therefore, the favor able results of early aspirin on mortality in acute myocardial infarction are probably due more to prevention of reinfarction than to decrease of infarct size.

Emergency room infusion of intravenous streptokinase in acute myocardial infarction: feasibility, safety, and hemodynamic consequences.

Between September 1, 1986, and December 31, 1987, sixty-four consecutive patients younger than 70 years, with early (less than 4 hours) symptoms and signs of myocardial infarction, were treated with 1.5 million units streptokinase intravenously in the emergency room (ER group) before admission to the coronary care unit. Data from these patients were compared in retrospect to those of 66 consecutive patients with myocardial infarction who were treated with intravenous streptokinase in the coronary care unit (CCU group) before September 1, 1986. Time between first symptoms and initiation of fibrinolytic therapy was significantly shorter in the ER group: 114 +/- 53 minutes vs 150 +/- 56 minutes in the CCU group (p less than 0.001). The incidence of in-hospital complications was similar in both groups. However, left ventricular stroke work index during the stay in the coronary care unit was 50 +/- 19 gm/m2 in the ER group vs 42 +/- 14 in the CCU group (p = 0.02). Also the echocardiographic left ventricular wall motion score at 48 hours after admission tended to be better in the ER group: 6.7 +/- 4.0 compared to that in the CCU group (7.6 +/- 4.5; p = 0.29). In conclusion, infusion of intravenous streptokinase in the emergency room is feasible and safe and results in a significant time gain leading to a better hemodynamic profile. Within the hospital the emergency room is the ideal place for intravenous fibrinolytic therapy in eligible patients with acute myocardial infarction.