Two studies on reversal of opioid-induced respiratory depression by BK-channel blocker GAL021 in human volunteers.

BACKGROUND: Opioid-induced respiratory depression is potentially lethal. GAL021 is a calcium-activated potassium (BKCa) channel blocker that causes reversal of opioid-induced respiratory depression in animals due to a stimulatory effect on ventilation at the carotid bodies. To assess in humans whether GAL021 stimulates breathing in established opioid-induced respiratory depression and to evaluate its safety, a proof-of-concept double-blind randomized controlled crossover study on isohypercapnic ventilation (study 1) and subsequent double-blind exploratory study on poikilocapnic ventilation and nonrespiratory end points (study 2) was performed. METHODS: In study 1, intravenous low- and high-dose GAL021 and placebo were administrated on top of low- and high-dose alfentanil-induced respiratory depression in 12 healthy male volunteers on two separate occasions. In study 2, the effect of GAL021/placebo on poikilocapnic ventilation, analgesia, and sedation were explored in eight male volunteers. Data are mean difference between GAL021 and placebo (95% CI). RESULTS: Study 1: Under isohypercapnic conditions, a separation between GAL021 and placebo on minute ventilation was observed by 6.1 (3.6 to 8.6) l/min (P < 0.01) and 3.6 (1.5 to 5.7) l/min (P < 0.01) at low-dose alfentanil plus high-dose GAL021 and high-dose-alfentanil plus high-dose GAL021, respectively. Study 2: Similar observations were made on poikilocapnic ventilation and arterial pCO2. GAL021 had no effect on alfentanil-induced sedation, antinociception and no safety issues or hemodynamic effects became apparent. CONCLUSION: GAL021 produces respiratory stimulatory effects during opioid-induced respiratory depression with containment of opioid-analgesia and without any further increase of sedation. Further studies are needed to confirm these preliminary data.

Respiratory stimulant drugs in the post-operative setting.

Drug-induced respiratory depression (DIRD) is a common problem encountered post-operatively and can persist for days after surgery. It is not always possible to predict the timing or severity of DIRD due to the number of contributing factors. A safe and effective respiratory stimulant could improve patient care by avoiding the use of reversal agents (e.g., naloxone, which reverses analgesia as well as respiratory depression) thereby permitting better pain management by enabling the use of higher doses of analgesics, facilitate weaning from prolonged ventilation, and ameliorate sleep-disordered breathing peri-operatively. The purpose of this review is to discuss the current pharmaceutical armamentarium of drugs (doxapram and almitrine) that are licensed for use in humans as respiratory stimulants and that could be used to reverse drug-induced respiratory depression in the post-operative period. We also discuss new chemical entities (AMPAkines and GAL-021) that have been recently evaluated in Phase 1 clinical trials and where the initial regulatory registration would be as a respiratory stimulant.

Clinical pharmacokinetics of nateglinide: a rapidly-absorbed, short-acting insulinotropic agent.

The prevalence and medical and economic impact of type 2 diabetes mellitus is increasing in Western societies. New agents have been developed that act primarily to reduce postprandial glucose excursions, which may be of particular significance now that postprandial glucose excursions are known to be correlated with cardiovascular morbidity and mortality. Nateglinide is a phenylalanine derivative that blocks K+ channels in pancreatic beta-cells, facilitating insulin secretion. Nateglinide sensitises beta-cells to ambient glucose, reducing the glucose concentration needed to stimulate insulin secretion. The pharmacokinetics of nateglinide are characterised by rapid absorption and elimination, with good (73%) bioavailability. Nateglinide is more rapidly absorbed when given 0-30 minutes prior to meal ingestion than if given during the meal. Nateglinide is extensively metabolised, primarily by cytochrome P450 2C9, and eliminated primarily by the kidney. Nateglinide pharmacokinetics are linear over the dose range 60-240 mg. No significant pharmacokinetic alterations occur in renally impaired patients, in the elderly, or in mildly hepatically impaired patients. Nateglinide administered prior to meals stimulates rapid, short-lived insulin secretion in a dose-dependent manner, thus decreasing mealtime plasma glucose excursions. Its effects on insulin secretion are synergistic with those of a meal. With increasing nateglinide doses, the risk of hypoglycaemia also increases, but its incidence is low. Even if a meal is missed, and the patient skips the dose of nateglinide (as recommended in the event of a missed meal), the incidence of subsequent hypoglycaemia remains low compared with long-acting agents. The postprandial insulinotropic effects of nateglinide are more rapid than those of repaglinide and more rapid and greater than those of glibenclamide (glyburide), while producing less prolonged insulin exposure and less risk of delayed hypoglycaemia. Further investigation is required to determine if nateglinide inhibition of postprandial glucose excursions will help to prevent diabetic complications or preserve pancreatic beta-cell function.

"Cocktail" approaches and strategies in drug development: valuable tool or flawed science?

There is an increasing interest in the simultaneous administration of several probe substrates to characterize the activity of multiple drug-metabolizing enzymes, the so-called "cocktail" approach. However, this method remains controversial and is being investigated more extensively. No general consensus has emerged on the applicability of this approach in clinical investigation and during drug development. The objective of the article is to review this important yet specialized technique, as well as its merits, drawbacks, and potential application in drug development. Among the two-, three-, four-, five-, and six-drug in vivo cocktails previously evaluated in humans, a variety of substrate probe combinations have been studied. Some probe combinations have been validated not to interact in vivo and have been useful in characterizing drug-drug interaction potential and metabolic enzyme induction in humans. For drug candidates that affect two or more in vitro pathways or are potential gene inducers, the use of a cocktail approach may facilitate the rapid delineation of the drug candidate's drug interaction potential. It may also offer the potential of providing clear guidance on safely conducting larger clinical studies and limiting comedication restrictions to only those likely to be clinically relevant.

Tegaserod pharmacokinetics are similar in patients with severe renal insufficiency and in healthy subjects.

Tegaserod (HTF 919), a selective 5-HT4 receptor partial agonist with promotile activity throughout the gastrointestinal tract, is in development for the treatment of irritable bowel syndrome. In an open-label, parallel-group study, the pharmacokinetics of a single 12-mg oral dose of tegaserod in patients with severe renal insufficiency requiring hemodialysis were compared with data obtained from healthy subjects matched for age, weight, height, and gender (n = 10, both). The pharmacokinetics of tegaserod were similar in both groups (AUC(0h-tz), ng.h/ml: 14.6 +/- 8.5 vs. 14.3 +/- 7.1; Cmax, ng/ml: 4.6 +/- 2.3 vs. 5.1 +/- 2.2; tmax, h: 1.0, for both). Tegaserod had similar tolerability in renally impaired patients and healthy volunteers, with adverse events largely related to the gastrointestinal pharmacological actions of the drug. Therefore, no dose adjustment of tegaserod is necessary for patients with renal insufficiency.

Pharmacokinetics of nateglinide in renally impaired diabetic patients.

Treatment of hyperglycemia in patients with diabetes mellitus and renal insufficiency is complicated by altered pharmacokinetics of hypoglycemic agents. This study evaluated the pharmacokinetic profile and safety of nateglinide, an amino acid derivative that improves early phase insulin secretion and reduces mealtime glucose excursions. This open-label, single-dose, two-center study included patients (mean age = 57 +/- 10 years) with type 1 or 2 diabetes with impaired renal function (IRF) (n = 10) or with renal failure undergoing hemodialysis (n = 10). Both groups were compared with age-, sex-, height-, and weight-matched healthy controls (n = 20). All participants received a single 120-mg dose of nateglinide immediately before breakfast. Pharmacokinetic and safety evaluations were undertaken up to 48 hours postdose. All 40 subjects completed the study. Plasma nateglinide concentrations increased rapidly in patients undergoing dialysis and matched healthy subjects (tmax = 0.95 vs. 0.78 h, respectively) and was comparable with patients with IRF and matched healthy subjects (tmax = 0.80 vs. 0.65 h, respectively). There were no statistically significant differences for Cmax or AUC0-t between the groups. Nateglinide was eliminated rapidly in all groups (t1/2 = 1.9-2.8 h). There was no correlation between the level of renal function and systemic exposure. There was a low extent of renal excretion of nateglinide in healthy subjects (11%) and diabetic patients with IRF (3%). Nateglinide was well tolerated. These data suggest that nateglinide is suitable for use in diabetic patients with IRF or with renal failure undergoing dialysis. Given the comparable absorption and elimination profiles of nateglinide in renally impaired and healthy subjects, no dose adjustment appears necessary in the renally impaired.