Inhibitory Sigmoid Emax Model Research Articles

Pharmacokinetics and hypotensive effect of deacetyl N-monodesmethyl diltiazem (M2) in rabbits after a single intravenous administration.

Deacetyl N-monodesmethyl diltiazem (M2) is a major metabolite of the widely used calcium antagonist diltiazem (DTZ). In order to study the pharmacokinetic and haemodynamic effects of this metabolite, M2 was administered as a single 5 mg/kg dose intravenously (i.v.) to New Zealand white rabbits (n = 5) via a marginal ear vein. Blood samples, blood pressure (SBP and DBP), and heart rate (HR) recordings were obtained from each rabbit up to 8 h, and urine samples for 48 h post-dose. Plasma concentrations of M2 were determined by HPLC. The results showed that there were no identifiable basic metabolites which could be quantified and characterized in the plasma. The apparent terminal t1/2 and AUC were 2.8 +/- 0.7 h and 2000 +/- 290 ng x h/ml, respectively. The Cl and Clr of M2 were 38 +/- 4.8 ml/min/kg and 0.57 +/- 0.23 ml/min/kg, respectively. M2 significantly decreased blood pressure (SBP and DBP) for up to 2 h post-dose (P < 0.05), but had no significant effect on the heart rate (P > 0.05). The Emax and EC50 as estimated by the inhibitory sigmoidal Emax model were 15 +/- 7% and 450 +/- 46 ng/ml, respectively, for SBP; 15 +/- 20% and 430 +/- 120 ng/ml for DBP.

Pharmacokinetics and haemodynamic effect of deacetyl diltiazem (M1) in rabbits after a single intravenous administration.

Deacetyl diltiazem (M1) is a major metabolite of the widely used calcium antagonist diltiazem (DTZ). In order to study the pharmacokinetic and haemodynamic effects of this metabolite, M1 was administered as a single 5 mg kg-1 dose intravenously (i.v.) to New Zealand white rabbits (n = 5) via a marginal ear vein. Blood samples, blood pressure (SBP and DBP), and heart rate (HR) recordings were obtained from each rabbit up to 8 h, and urine samples for 48 h post-dose. Plasma concentrations of M1 and its metabolites were determined by HPLC. The results showed that the only quantifiable basic metabolite in the plasma was deacetyl N-monodesmethyl DTZ (M2). The t1/2 and AUC of M1 and M2 were 2.1 +/- 0.5 and 3.0 +/- 1.1 h, and 1300 +/- 200 and 240 +/- 37 ng h mL-1, respectively. The Cl and Clr of M1 were 60 +/- 10 and 0.81 +/- 0.63 mL min-1 kg-1, respectively. M1 significantly decreased blood pressure (SBP and DBP) for up to 1 h post-dose (p < 0.05), but had no significant effect on the heart rate (P > 0.05). The Emax and EC50 as estimated by the inhibitory sigmoidal Emax model were 20 +/- 18% 620 +/- 310 ng mL-1, respectively for SBP; 20 +/- 8.3% and 420 +/- 160 ng mL-1 for DBP.

CORRELATION OF BISPECTRAL INDEX (BIS) WITH END-TIDAL SEVOFLURANE CONCENTRATIONS IN INFANTS AND CHILDREN

S396 Introduction: BIS has been used to determine the hypnotic effects of several intravenous and volatile agents, including sevoflurane, but data have not been collected in children. We maintained various steady-state end-tidal concentrations of sevoflurane in N2 O and documented the corresponding BIS in infants (0 - 2 yr) and children (2 - 12 yr). Methods: Twenty-two unpremedicated patients undergoing elective surgery were enrolled in this institutionally-approved protocol. Anesthesia was induced with sevoflurane in 60% N2 O/O2 with or without propofol. BIS measurements were delayed at least 20 min following propofol. Opioids and muscle relaxants were given as clinically indicated. BIS was recorded on an ASPECT Medical Systems Model A1050 EEG monitor. End-tidal sevoflurane concentrations were measured with a Datex Ultima Capnomac[registered sign] or Ohmeda RGM 5250[registered sign] monitor and maintained within 0.1% of these targets: 4, 3, 2, 1.5, 1, 0.5%. BIS was stable for at least 5 min at each concentration before it was recorded. Data for each group were fit to an inhibitory sigmoid Emax model (SlideWrite Plus[copyright sign]. Results: Table 1 shows the demographics of the 2 groups. BIS fell with increasing concentrations of sevoflurane (see Figure 1). Overall responses and awake values (not shown) did not appear to differ from those reported in adults. The sevoflurane concentration for a half-maximal response (95% C.I.) was significantly different between groups: 1.55% (1.40 - 1.70) for infants vs. 1.25% (1.12 - 1.37) for children.Table 1Figure 1Conclusion: BIS correlates with sevoflurane concentration in children and infants. This is similar to the correlation in adults. The concentration-response difference between infants and children is consistent with data showing that MAC (minimum alveolar concentration) is higher in children less than one year of age. [1,2]

Establishing the dose response curve for metabolic control with troglitazone, an insulin action enhancer, in type 2 diabetes patients

Troglitazone is a novel once-daily oral antidiabetic agent for the treatment of type 2 diabetes patients. Here, we report the overall dose response characteristics of troglitazone, with respect to effects on metabolic control, using a pharmacodynamic model. Data from week 12 from two previously reported double-blind, randomized, parallel-group, placebo-controlled, dose-ranging multicentre studies examining once-daily doses of 10, 30, 100, 200, 400, 600 and 800 mg of troglitazone were combined for the analyses. The pharmacodynamic relationships for relevant parameters of metabolic control were modelled using a nonlinear regression modelling programme. The troglitazone dose-concentration relationship was linear over 10–800 mg. Using an inhibitory sigmoid Emax model, ED50 values of approximately 100 mg and 200 mg were found for fasting serum glucose and triglycerides, respectively. The 200 mg dose for HbAlc showed an inconsistent reduction compared with placebo between the two studies; this illustrates the difficulties associated with comparing results from different assay techniques. Insulin and nonesterified fatty acid reductions compared with placebo were not consistent between studies, and no pharmacodynamic modelling was possible. No changes in body weight were observed at any dose. Troglitazone was as well tolerated as placebo across the dose range investigated. This pharmacodynamic analysis has established that 200–600 mg once daily can be considered the therapeutic dose range of troglitazone that significantly improves metabolic control in type 2 diabetes patients.

Pharmacodynamic modelling of the analgesic effects of piritramide in postoperative patients.

The concentration-effect relationship of piritramide, a synthetic opioid analgesic predominantly used for postoperative analgesia and analgosedation, has not been reported so far. Twenty-four patients of both genders aged 58.1 (11.7) yr (mean (SD)) received inhalational anaesthesia for abdominal surgery. Postoperative pain was assessed with a visual analogue scale (VAS). Analgesia was provided with piritramide, infused at a rate of 7 micrograms.kg-1.min-1 until analgesia was considered sufficient (VAS < 25) or up to a maximum dose of 0.2 mg/kg. The plasma concentrations of piritramide were determined by gas chromatography. An inhibitory fractional sigmoid Emax-model was used to describe the relation between effect site concentration and perceived pain. The equilibration half-life between plasma and effect site concentrations (T1/2 (keo)) was 16.8 min (median; range: 4.4-41.6 min). The steady-state plasma concentration required to produce 50% of maximum analgesia (EC50) was 12.1 ng/ml (range: 2.9-29.8 ng/ml) and correlated with initial pain intensity. The slope factor gamma was 1.9 (range: 0.5-6.1) and increased with age. Clinically relevant respiratory depression did not occur. Due to the relatively large equilibration half-life of the effect compartment, the context-sensitive half-time of the effect site concentrations after short-time administration (< 2 h) clearly exceeded those of alfentanil, sufentanil, and fentanyl. The analgesic effect of piritramide was adequately described by an inhibitory fractional Emax-model. In order to overcome the pronounced hysteresis, piritramide should initially be administered as an intravenous bolus of at least 5 mg.