Analgesia and pharmacodynamics of Wutou injection in mice
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OBJECTIVE To study the analgesia effects and pharmacodynamics of Wutou injection.METHODS The mice were treated ip once with Wutou injection (2 mg·kg -1 ) and morphine (10 mg·kg -1 ) was used as the positive control.The changes of reactive latent period on hot-plate were observed.The apparent parameters of pharmacodynamics were estimated based on the time-effect curve.RESULTS The Wutou injection had analgesic effect obviously.Its effect-time curve ws conformed to one-compartment modle of extravascular administration.The apparent parameters of the pharmacodynamics were: K a=0.026539 min -1 ; t 1/2a =26.12 min; k e=0.007968 min -1 ; t 1/2E =87 min; t max =80.16 min; E max =149.24 ΔE%(58.27 s),respectively.CONCLUSION The Wutou injection had analgesic effect obviouly.The parameters of pharmacodynamics may be helpful for physicians clinic.Keywords:
Pharmacodynamics
Negative control
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The pharmacokinetics of lidocain injected intramuscularly in doses of 300-600 mg was studied and compared to that on its intravenous administration in a dose of 80 mg in the same patients with acute myocardial infarction. When injected intramuscularly the drug rapidly and safely reached the systemic circulation. The relationship between the lidocain plasma concentration and time could be depicted adequately by an open one-compartmental model to determine the parameters of the model. The maximum concentration (2.34 micrograms/kg for a dose of 400 mg) was attained 44 min after the injection. The half-life was 101 min, and the total clearance 0.67 l/min. Analysis of the model curves concentration--time for the doses 400 and 600 mg showed that in the former case the effective concentration (2 micrograms/kg or more) was maintained for 1 h, whereas in the latter one for 2.3 h.
Systemic circulation
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Intravenous bolus
Half-life
Bolus (digestion)
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Epidural (E.D.) and intrathecal (I.T.) morphine (M) analgesia were studied in patients with pain after thoracotomy. The role of the pharmacokinetic properties of M. for the associated analgesia was also evaluated. M. concentrations in CSF and plasma were assayed using gas chromatography with EC detection. Analgesia was evaluated as the time postoperative until the patients again required analgetics and were given meperidine intramuscularly (I.M.) for thoracic pain. A lumbar site of E.D. and I.T. injection of M. resulted in a variable but in general longlasting postoperative analgesia although delayed after I.T. administration. The mean duration of analgesia after E.D. administration was dose-related (8.6 +/- 2.0 h, 13.0 +/- 3.5 h, and 15.6 +/- 2.6 h; means +/- SEM for the 2, 4 and 6 mg groups, respectively), which was comparable to that achieved after I.T. administration of 0.25 to 0.50 mg M. M. concentrations in plasma after E.D. administration were comparable in variability and magnitude to those found after I.M. administration. The concentrations of M. in plasma were not related to the long duration of analgesia and may only contribute to analgesia shortly after the E.D. administration. The reported time course of analgesia after E.D. injection with a delayed onset corresponded with the appearance of M. in the CSF. Fifteen min after E.D. administration, M. was found in higher concentrations in CSF than in plasma, but peak levels were not seen until 2 h after the injection. Both the high content of M. in CSF as expressed by AUC, as well as peak concentrations in CSF, were related to the longlasting analgesia after E.D. administration. A protracted clearance of M. from the CSF as a cause of longlasting analgesia was not found, M. was eliminated with a similar half-life from CSF and plasma. The high CSF concentrations of M. seen after E.D. administration were the result of a direct uptake across the dura. In contrast, the appearance of M. in CSF after I.M. administration of 10 mg was slower. Maximal concentration of M. in the CSF was reached after 3 h and the peak levels were on average about 100 times less than those found after E.D. injection of 6 mg morphine. CSF and plasma reached pseudoeliquilibrium at a ratio around 0.9 after I.M. administration. This is to be compared with a CSF/plasma concentration ratio around 100 after E.D. administration. A comparison of M. concentrations in the CSF after thoracic and lumbar E.D. injection showed that spinal CSF rapidly yielded comparable concentrations at the lumbar level.(ABSTRACT TRUNCATED AT 400 WORDS)
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The pharmacokinetics of meptazinol (3 mg kg-1 i.v.), a centrally acting opioid agonist-antagonist, were studied in six male and six female patients during anaesthesia with 1-3 vol.% enflurane and an infusion of 10-30 micrograms kg-1 min-1 etomidate. Arterial blood samples were taken up to 300 min postinjection. The plasma meptazinol concentrations, determined by HPLC, best fitted to a three-compartment open mamillary model with central elimination using a non-linear extended least-squares regression analysis. Derived pharmacokinetic parameters indicated a rapid distribution (T1/2 pi = 1.24 +/- 0.83 min, T1/2 alpha = 7.55 +/- 3.97 min), a short elimination half-life (T1/2 beta = 86.9 +/- 15.6 min), a volume of the central compartment twice as large in females (Vc = 0.557 +/- 0.237 l kg-1) as in males (Vc = 0.274 +/- 0.144 l kg-1), a small distribution volume at steady state (Vss = 2.52 +/- 0.66 l kg-1) and a high total plasma clearance (ClP = 1547 +/- 385 ml min-1). The elimination rate microconstant in females (k10 = 0.0577 +/- 0.0337 min-1) was significantly lower than in males (k10 = 0.1093 +/- 0.0437 min-1 with a lower drug fraction in the central compartment in the post-distributive phase (Fc = males: 0.08 +/- 0.02, females 0.19 +/- 0.11). As Vss and ClP were similar in both groups, sex-related differences were only observed in the dynamics of distribution of the drug. From a pharmacokinetic point of view we suspect that meptazinol shows very little cumulation on repeated i.v. administration as necessary during anaesthesia.
Sufentanil
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Hydromorphone
Pharmacodynamics
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Hydromorphone
Crossover study
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Twelve healthy volunteers received single iv doses of either 500 and 1000 mg or 750 and 1500 mg of the sodium salt of FCE 22101; in addition, five of the volunteers received a further dose of 2000 mg. In the second part of the study, 11 of the volunteers received 1000 mg doses of FCE 22101 in a four-way randomized fashion by iv bolus (1000 mg, with and without probenecid), im injection (1000 mg plus lignocaine) and a continuous infusion (280 mg/h) to steady state. All doses were well tolerated by the volunteers with no serious side effects and no significant haematological or biochemical changes following drug administration. Plasma and urine concentrations of FCE 22101, and in the cross-over study also its open ring metabolites P1 and P2, were determined by HPLC. Good linearity was observed between the peak plasma levels or AUC and the dose given. Plasma concentrations were fitted to a two-compartment model and the mean pharmacokinetic parameters determined after iv bolus were: Cmax 117 mg/l, T ½ β 36 min, Vss 181, AUC 2179 mg/min/l with urinary recoveries of FCE 22101 37%, P1 36% and P2 6%. With probenecid the values were Cmax 116 mg/l, T ½ β 47min, Vss 141, AUC 4540 mg/min/l and urinary recoveries of FCE 22101 20%, P1 40% and P2 7%. Following im injection the mean values were Cmax 15 mg/l, Tmax 30 min, Tmax 14 min, T ½ β 61 min, AUC 2117 mg/min/l and urinary recoveries of FCE 22101 33%, P1 37% and P2 6%. At steady state during continuous infusion, mean values were Css 12.7 mg/l, Vss 131 and T ½ β after steady state was 22 min. Although urinary recoveries varied widely between volunteers there was a tendency towards consistency of recovery within individual volunteers. We conclude that FCE 22101 is a well tolerated penem with pharmacokinetic properties broadly similar to those of other penem and carbapenem antibiotics.
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Simultaneous pharmacokinetic‐pharmacodynamic (PK‐PD) models of meperidine in Soats were established by utilizing the P 3 wave of the cerebral evoked potentials as an analgesic measurement. An effect compartment linked to the central compartment was postulated in the models. The hypothetical drug amount in the effect compartment was related to the observed analgesia through the Hill equation. After intramuscular (i. m., n = 16) and intravenous (i. v., n = 13) dosing (5 mg/kg), the elimination rate constants of meperidine in the effect compartment ( K eO ) were 0.3744 ± 0.2546 and 0.1123 ± 0.0428 min ‐1 , drug concentrations in the effect compartment generating half maximal analgesia (EC (50) ) were 0.70 ± 0.33 and 0.41 ± 0.26 μg/ml, the maximal effects (E max ) were 89.63 ± 15.63 and 85.92 ± 9.64%, and the Hill coefficients (S) were 2.61 ± 1.21 and 2.37 ± 1.15, respectively. K eO and EC (50) with i.m. dosing were significantly greater than with i.v. injection. However, administration route had no influence on S, E max and the total amount of effect ( AUE ). The predicted peak effect (E max ^) of 64.44 ± 14.64 and 66.02 ± 11.51% were achieved at 14.7 ± 7.4 and 8.5 ± 2.2 min after i.m. and i.v. dosing, respectively. Peak analgesia appeared much later than peak plasma concentration, but simultaneously with peak CSF level both after i.m. and i.v. dosing. An obvious hysteresis was demonstrated between plasma concentration and analgesic effect. This study demonstrates that meperidine analgesia can be predicted using a PK‐PD model, but not by PK data alone. Both i.m. and i.v. administration routes were evaluated kinetically and dynamically.
Pharmacodynamics
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Pharmacokinetics of morphine, buprenorphine and pethidine were determined in 10 cats. Six cats received morphine (0.2 mg/kg) intravenously and four intramuscularly. Five received buprenorphine (0.01 mg/kg) intravenously and six intramuscularly. Six received pethidine (5 mg/kg) intramuscularly. Jugular venous blood samples were collected at time points to 24 h, and plasma morphine concentrations were measured by high performance liquid chromatograpy (HPLC), buprenorphine by radioimmunoassay (RIA) and pethidine by gas chromatography. Our data for morphine show elimination half-life (t1/2el) 76.3 min intravenous (i.v.) and 93.6 min intramuscular (i.m.); mean residence time (MRT) 105.0 and 120.5 min; clearance (Clp) 24.1 and 13.9 mL/kg/min; and volume of distribution (V(dss)) 2.6 and 1.7 L/kg, respectively. Comparable data for buprenorphine are t1/2el 416.8 and 380.2 min; MRT 417.6 and 409.8 min; Clp 16.7 and 23.7 mL/kg/min; and V(dss) 7.1 and 8.9 L/kg. For i.m. pethidine, t1/2el 216.4 min; MRT 307.5 min; Clp 20.8 mL/kg/min and V(dss) 5.2 L/kg. For i.m. dosing, the tmax for morphine, buprenorphine and pethidine were 15, 3 and 10 min, respectively. The pharmacokinetics of the three opioids in cats are broadly comparable with those of the dog, although there is a suggestion that the cat may clear morphine more slowly.
Pethidine
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The pharmacokinetics of 3-O-demethylfortimicin A were evaluated in 16 healthy adult male volunteers after bolus intramuscular (i.m.) and 30-min intravenous (i.v.) infusion administration of doses ranging from 0.25 to 16 mg/kg. Mean calculated peak levels of the drug in plasma after the 0.25-, 0.5-, 1-, 2-, 4-, 8-, and 16-mg/kg i.m. doses were 1.1, 1.9, 3.5, 4.9, 11.0, 21.8, and 41.3 micrograms/ml, respectively, occurring about 60 min after dosing. The biphasic decline in levels of the drug in plasma after i.v. administration was not apparent after i.m. dosing, presumably because absorption of the drug from the injection site obscured the alpha elimination phase. Mean calculated peak levels for the 1-, 2-, 4-, 8-, and 16-mg/kg 30-min i.v. infusions were 5.9, 12.2, 20.1, 36.7, and 66.4 micrograms/ml, respectively. A statistically significant trend of increasing apparent volume of distribution with increasing dose size was noted for the i.m. dose group only. Plasma drug clearance was dose level and route independent, with an excellent linear relationship between the area under the plasma drug level curve and the dose. The mean 0- to 48-h urinary recoveries of 3-O-demethylfortimicin A after the i.m. injections and i.v. infusions were 90 and 102%, respectively. After the i.m. dosings, the half-life of the drug in plasma averaged 2.0 h, and after the i.v. dosings it averaged 2.7 h. The results of the study indicated that most of the drug was cleared by renal mechanisms.
Intravenous bolus
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Intramuscular injection
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