Francisco J. Flores-Murrieta

Evidence for the involvement of nitric oxide in the antinociceptive effect of ketorolac.

The involvement of nitric oxide in the antinociception produced by ketorolac was assessed using the pain-induced functional impairment model in the rat: 800 micrograms of NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, or saline was injected intra-articularly in a hind limb joint previously injured with uric acid. Animals then received ketorolac, dipyrone or no drug. Ketorolac and dipyrone produced a significant antinociceptive effect which was reduced by pretreatment with NG-nitro-L-arginine methyl ester, but not with saline. It is concluded that the antinociceptive effect of both drugs involves the local participation of nitric oxide.

Pharmacokinetic-Pharmacodynamic Modeling: Why?

At present, pharmacokinetic-pharmacodynamic (PK-PD) modeling has emerged as a major tool in clinical pharmacology to optimize drug use by designing rational dosage forms and dosage regimes. Quantitative representation of the dose-concentration-response relationship should provide information for prediction of the level of response to a certain level of drug dose. Several mathematical approaches can be used to describe such relationships, depending on the single dose or the steady-state measurements carried out. With concentration and response data on-phase, basic models such as fixed-effect, linear, log-linear, E(MAX), and sigmoid E(MAX) can be sufficient. However, time-variant pharmacodynamic models (effect compartment, acute tolerance, sensitization, and indirect responses) can be required when kinetics and response are out-of-phase. To date, methodologies available for PK-PD analysis barely suppose the use of powerful computing resources. Some of these algorithms are able to generate individual estimates of parameters based on population analysis and Bayesian forecasting. Notwithstanding, attention must be paid to avoid overinterpreted data from mathematical models, so that reliability and clinical significance of estimated parameters will be valuable when underlying physiologic processes (disease, age, gender, etc.) are considered.

The role of peripheral 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F serotonergic receptors in the reduction of nociception in rats

This study assessed the possible antinociceptive role of peripheral 5-HT(1) receptor subtypes in the rat formalin test. Rats were injected into the dorsum of the hind paw with 50 microl of diluted formalin (1%). Nociceptive behavior was quantified as the number of flinches of the injected paw. Reduction of flinching was considered as antinociception. Ipsilateral, but not contralateral, peripheral administration of the 5-HT(1) receptor agonists R(+)-UH-301 (5-HT(1A); 0.1-3 microg/paw), CGS-12066A (5-HT(1B); 0.01-0.3 microg/paw), GR46611 (5-HT(1B/1D); 0.3-10 microg/paw), BRL54443 (5-HT(1E/1F); 3-300 microg/paw) or LY344864 (5-HT(1F); 3-300 microg/paw) significantly reduced formalin-induced flinching. The corresponding vehicle was devoid of any effect by itself. The local antinociceptive effect of R(+)-UH-301 (0.3 microg/paw) was significantly reduced by WAY-100635 (30-100 microg/paw; a 5-HT(1A) receptor antagonist). Moreover, the antagonists GR55562 (30-100 microg/paw; 5-HT(1B/D)) or SB224289 (30-100 microg/paw; 5-HT(1B)) dose-dependently reduced the antinociceptive effect of CGS-12066A (0.3 microg/paw) whereas GR55562 (30-100 microg/paw) or BRL15572 (30-100 microg/paw, 5-HT(1D)) reduced the antinociceptive effect of GR46611 (0.3 microg/paw). Interestingly, the effects of BRL54443 and LY344864 (300 microg/paw each) were partially reduced by methiothepin, but not by the highest doses of WAY-100635, SB224289 or BRL15572. The above antagonists did not produce any effect by themselves. These results suggest that peripheral activation of the 5-HT(1A,) 5-HT(1B), 5-HT(1D), 5-HT(1F) and, probably, 5-HT(1E) receptor subtypes leads to antinociception in the rat formalin test. Thus, the use of selective 5-HT(1) receptor agonists could be a therapeutic strategy to reduce inflammatory pain.

Pharmacokinetics of Oral Nifedipine in Different Populations

Nifedipine disposition varies among populations. Reports on oral nifedipine pharmacokinetics show that peak plasma levels and AVC values are higher in Mexican and Japanese than in European and North American subjects. Increased nifedipine bioavailability in the nonwhite populations is likely due to nutritional habits. Certain flavonoids that inhibit the first‐pass metabolism of dihydropyridines are present in the diets of both Mexican and Japanese. Differences in phenotypes may play a role in interethnic variability.

Characterization of the Analgesic Effects of Paracetamol and Caffeine Combinations in the Pain-induced Functional Impairment Model in the Rat

Abstract— The analgesic activities of paracetamol (100, 178, 316 and 562 mg kg−1), caffeine (10,18, 32 and 56 mg kg−1) and combinations of these doses were tested on a pain‐induced functional impairment model in the rat. Dysfunction of the right hind limb was induced by an intra‐articular injection of 30% uric acid in the knee. Drugs were given orally and the recovery of functionality over time was considered as an expression of analgesia. Paracetamol alone induced a dose‐dependent analgesic effect whereas caffeine alone did not show any activity at the assayed doses. Combinations of 316 mg kg−1 paracetamol with either 10, 18, 32 or 56 mg kg−1 caffeine yielded analgesic effects significantly greater than that of paracetamol alone. The highest potentiation was observed with a paracetamol‐caffeine mixture of 316–32 mg kg−1. Caffeine coadministration, however, did not significantly change paracetamol plasma levels. No potentiation was obtained with other combinations. Paracetamol plasma levels and analgesic effect observed with administration of 316 mg kg−1 paracetamol alone or 316–32 mg kg−1 of paracetamol‐caffeine were fitted to the sigmoidal Emax model according to the Hill equation. The curves obtained were parallel, but that of the combination was shifted to the left. It is concluded that caffeine is able to potentiate the analgesic effect of paracetamol by a pharmacodynamic mechanism, but this only occurs at certain dose combinations.

Relationship Between Paracetamol Plasma Levels and its Analgesic Effect in the Rat

Abstract— The relationship between plasma levels of paracetamol and its analgesic effect was studied in the rat using a model of pain‐induced functional impairment (PIFI). Female Wistar rats received an intraarticular injection of 30% uric acid in the knee of the right hind limb, inducing its dysfunction. Animals then received oral paracetamol at doses of 178, 316 or 562 mg kg−1and the recovery of functionality over time was considered as an expression of analgesia. Paracetamol plasma levels were determined by HPLC. Results showed that there is a direct relationship between paracetamol plasma levels and its analgesic effect that follows a sigmoidal model according to the Hill equation. The PIFI model appears to be a useful tool to establish pharmacokinetic/pharmacodynamic relationships for non‐narcotic analgesics.

Effect of caffeine coadministration and of nitric oxide synthesis inhibition on the antinociceptive action of ketorolac

The effects of caffeine and nitric oxide synthesis inhibition on the antinociceptive action of ketorolac were assessed using the pain-induced functional impairment model in the rat. Nociception was induced by the intra-articular injection of uric acid. Ketorolac, but not caffeine, produced an antinociceptive effect which was reduced by NG nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthesis. Caffeine coadministration potentiated the ketorolac effect. L-NAME induced a dose-dependent reduction of this potentiation. The results suggest the participation of the L-arginine-nitric oxide-cyclic GMP pathway in the caffeine potentiation of ketorolac-induced antinociception.

Bioavailability of Oral Cyclosporine in Healthy Mexican Volunteers: Evidence for Interethnic Variability

The existence of population variations in cyclosporine pharmacokinetics could be expected, as this drug, similar to nifedipine, is biotransformed by cytochrome P‐450 subfamily 3A4, and the existence of interethnic variability in nifedipine disposition has been demonstrated previously. The bioavailability of oral cyclosporine was studied in 23 healthy Mexican volunteers receiving 7.5‐mg/kg doses of cyclosporine. Blood samples were drawn over 24 hours, and concentration of cyclosporine in whole blood was determined by a radioimmunoassay using monoclonal antibodies specific for the unchanged drug. The bioavailability of cyclosporine exhibited wide interindividual variability. Maximum concentration (Cmax) ranged from 528 ng/mL to 2,689 ng/mL, area under the concentration—time curve (AUC) ranged from 6,550 ng · hr/mL to 18,562 ng · hr/mL, and time to reach Cmax (tmax) ranged from 1 to 8 hours. Half‐life (t1/2) exhibited less important variations, ranging from 4.4 to 9.1 hours. The bioavailability of oral cyclosporine in Mexicans was higher than that reported for white populations under similar conditions. The present results suggest the existence of interethnic variability in the pharmacokinetics of cyclosporine, as is the case with nifedipine.

PHARMACOKINETICS OF MIDAZOLAM IN MEXICANS: EVIDENCE FOR INTERETHNIC VARIABILITY

AbstractObjective: To determine midazolam pharmacokinetics in healthy Mexican volunteers and to compare them with the pharmacokinetics reported for other populations. Patients and Methods: Eleven healthy Mexican (mestizo) males received a single midazolam dose intravenously (7.5mg) and orally (15mg) with a washout period of at least 7 days. Midazolam plasma concentration was determined by high performance liquid chromatography. Pharmacokinetic parameters were obtained and compared with historical controls reported for other populations. Results: Midazolam pharmacokinetic parameters in Mexicans determined after intravenous administration were (mean ± SEM): clearance 2.54 ± 0.43 ml/min/kg, volume of distribution 0.52 ±0.1 L/kg and half-life 2.61 ± 0.42 hours. After oral administration the area under the plasma concentration-time curve (AUC) was 941 μg/L· h and the maximum concentration was 271 μg/L. There was a significant correlation between AUC values observed after oral midazolam and clearance (r = −0.71, p < 0.02). Systemic midazolam clearance observed in Mexicans was lower, while oral bioavailability was higher, compared with the values reported in the literature for healthy Caucasian volunteers under similar conditions. Conclusion: Midazolam bioavailability in Mexicans is higher than that reported for Caucasians. This appears to be because of a reduced systemic clearance. Since midazolam is mainly eliminated via biotransformation by CYP3A4, our data suggest the existence of interethnic variations in the activity of this enzymatic system. Increased midazolam bioavailability may lead to an increased incidence of adverse effects. Therefore, administration of midazolam should not be blindly extrapolated from one population to another. Midazolam doses in Mexicans should be reduced in relation to those used in Caucasians.

Pharmacokinetic-Pharmacodynamic Modeling of Tolmetin Antinociceptive Effect in the Rat Using an Indirect Response Model: A Population Approach

The relationship between the pharmacokinetics and the antinociceptive effect of tolmetin was characterized by an indirect model using a population approach. Animals received an intra-articular injection of uric acid in the right hindlimb to induce its dysfunction. Once dysfunction was complete, rats received an oral tolmetin dose of 1, 3.2, 10, 31.6, 56.2, or 100mg/kg and antinociceptive effect and blood tolmetin concentration were simultaneously evaluated. Tolmetin produced a dose-dependent recovery of functionality, which was not directly related to blood concentration. An inhibitory indirect response model was used based on these response patterns and the fact that tolmetin reduced nociception by inhibiting prostaglandin synthesis. Pharmacokinetic (PK) and pharmacodynamic (PD) data were simultaneously fitted using nonlinear mixed effects modeling (NONMEM) to the one-compartment model and indirect response model. The individual time courses of the response were described using Bayesian analysis with population parameters as a priori estimates. There was good agreement between the predicted and observed data. Population analysis yielded a maximal inhibition of the nociceptive response of 76% and an IC50of 9.22 μg/ml. This IC50is similar to that for tolmetin-induced prostaglandin synthesis inhibition in vitro (3.0 μg/ml). The present results demonstrate that mechanism-based PK-PD analysis using a population approach is useful for quantitating individual responses as well as reflecting the actual mechanism of action of a given drug in vivo.