Comparison of the analgesic efficacy of oral ketorolac versus intramuscular tramadol after third molar surgery: A parallel, double-blind, randomized, placebo-controlled clinical trial.

BACKGROUND: Preemptive analgesia is considered an alternative for treating the postsurgical pain of third molar removal. The aim of this study was to evaluate the preemptive analgesic efficacy of oral ketorolac versus intramuscular tramadol after a mandibular third molar surgery. MATERIAL AND METHODS: A parallel, double-blind, randomized, placebo-controlled clinical trial was carried out. Thirty patients were randomized into two treatment groups using a series of random numbers: Group A, oral ketorolac 10 mg plus intramuscular placebo (1 mL saline solution); or Group B, oral placebo (similar tablet to oral ketorolac) plus intramuscular tramadol 50 mg diluted in 1 mL saline solution. These treatments were given 30 min before the surgery. We evaluated the time of first analgesic rescue medication, pain intensity, total analgesic consumption and adverse effects. RESULTS: Patients taking oral ketorolac had longer time of analgesic covering and less postoperative pain when compared with patients receiving intramuscular tramadol. CONCLUSIONS: According to the VAS and UAC results, this study suggests that 10 mg of oral ketorolac had superior analgesic effect than 50 mg of tramadol when administered before a mandibular third molar surgery.

Evidence for a postsynaptic action of the serotonergic anxiolytics: ipsapirone, indorenate and buspirone.

In the present experiment we analyzed whether the antianxiety action of the serotonergic 1A agonists buspirone (5 mg/kg), ipsapirone (5 mg/kg), indorenate (5 mg/kg), and 8-OH-DPAT (0.5 mg/kg) were mediated through the stimulation of pre- or postsynaptic serotonergic receptors. The experimental anxiety values were determined with the burying behavior test, where a reduction in the cumulative time of burying behavior was interpreted as a reduction in anxiety. To that purpose we analyzed the putative anxiolytic action of these drugs in animals with lesion of the serotonergic fibers after the intracerebroventricular (ICV) injection of 5,7-dihydroxytyptamine (5,7-DHT, 10 or 150 micrograms/10 microliters). The neurochemical analysis shows that these treatments produce a statistically significant reduction in 5-HT and 5-HIAA levels in various brain areas. The results of the behavioral experiments reveal that buspirone, ipsapirone, and indorenate produced exactly the same reduction in burying behavior in lesioned animals as compared with control rats. The reduction in burying behavior produced by 8-OH-DPAT was effectively prevented by the lesion with 5,7-DHT. These data suggest that the anxiolytic effect of buspirone, ipsapirone, and indorenate is mediated via the stimulation of postsynaptic receptors, while the somatodendritic receptors are involved in the antianxiety effect of 8-OH-DPAT.

In vitro activity of two phenyl-carbamate derivatives, singly and in combination with albendazole against albendazole-resistant Giardia intestinalis.

Giardia intestinalis is one of the most prevalent parasites in adults and children in Mexico. Benzimidazoles have been proposed as a therapeutic alternative in the treatment of giardiasis. However, high-dose related toxicity and the development of resistance have emerged in clinical trials using this therapy. In the search of alternative drugs, we found that benzimidazole-resistant strains of fungi have shown increased sensitivity to phenyl-carbamates, hence, we developed several substituted phenyl-carbamates, two of which were tested against the protozoan parasite G. intestinalis in susceptible and albendazole-resistant Giardia strains. 4-R-ethyl-phenyl-carbamates IRE-6A and IRE-7B demonstrated antigiardial, albeit modest, activity when compared with albendazole, against susceptible and albendazole-induced resistant Giardia. However, when albendazole 0.38 microg/mL (MIC(50)) was combined with each IRE compound, a significant antigiardial synergism (fractional inhibitory concentration index (FICI < 0.5)) was obtained not only with sensitive cultures but also with resistant Giardia parasites. The results described here suggest a potential role for a combined therapy with phenyl-carbamates and sub-doses of benzimidazoles in the treatment of giardiasis.

Influence of sex on the pharmacokinetics of tolmetin in the rat.

The purpose of this study was to investigate sex-related differences in the pharmacokinetics of tolmetin, a potent nonsteroidal anti-inflammatory drug, in the rat. Male and female Wistar rats received oral tolmetin at two dose levels, 3.2 and 10 mg/kg. Blood samples were drawn at selected times after drug administration, and tolmetin concentration in whole blood was determined. Tolmetin was rapidly absorbed in all cases. C(max) increased with the dose, but was similar in both sexes. Notwithstanding, tolmetin half-life was significantly prolonged in females compared with males. As a result of the prolonged half-life, area under the curve values were significantly higher in females than in males. Tolmetin clearance was significantly reduced in females. The present results strongly suggest sex-related differences in the pharmacokinetics of tolmetin in the rat. Tolmetin elimination appears to be impaired in females, compared with males. The existence of sex-related differences in tolmetin pharmacokinetics in other species, including humans, requires further investigation.

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.

Pharmacokinetics of oral ranitidine in Mexicans.

The pharmacokinetics of oral ranitidine were studied in 24 Mexican male healthy volunteers. Subjects received a tablet containing 150 mg of ranitidine (Azantac, Glaxo de México, Mexico City) after an overnight fast and blood samples were drawn at several times for a period of 24 h. Ranitidine concentration in plasma was measured by high performance liquid chromatography and pharmacokinetic parameters were determined by non-compartmental analysis. Ranitidine plasma concentration increased with time, reaching a maximum of (mean +/- SEM) 484 +/- 34 ng/ml in 2.7 +/- 0.2 h. Plasma levels then decayed with a terminal half-life of 4.8 +/- 0.3 h. The area under the plasma concentration against time curve was 2440 +/- 126 ngh/ml. Oral ranitidine pharmacokinetic parameters in Mexicans appeared to be similar to those previously reported for Caucasians.

Comparison between Sprague-Dawley and Wistar rats as an experimental model of pharmacokinetic alterations induced by spinal cord injury.

Two strains of rats, Sprague-Dawley and Wistar, were assayed in order to determine which strain is the more suitable experimental model for the study of pharmacokinetic alterations induced by spinal cord injury. Animals were submitted to spinal cord contusion at the T8-T9 level by the weight drop method. A single acetaminophen oral dose (100 mg/ kg) was administered 24 h after injury and blood samples were drawn for a period of 4 h. Acetaminophen concentration in whole blood was determined by high performance liquid chromatography and pharmacokinetic parameters were estimated. For both strains, Cmax and AUC were significantly lower, whereas tmax remained unchanged, in injured animals compared to sham-injured controls. Circulating acetaminophen concentrations were higher; therefore, pharmacokinetic alterations were more easily discerned, in Sprague-Dawley than in Wistar rats. It is concluded that the Sprague-Dawley strain is a more suitable model for the study of pharmacokinetic alterations induced by spinal cord injury.

Analgesic efficacy and bioavailability of ketorolac in postoperative pain: a probability analysis.

BACKGROUND: The analgesic efficacy and bioavailability of 30 mg intramuscular ketorolac was studied in 24 patients with severe or very severe postoperative pain. METHODS: Pain and pain relief were determined by a five-point verbal rating scale and data were submitted to a probability analysis. Ketorolac plasma levels were determined by high-performance liquid chromatography. RESULTS: Two patients chose not to finish the study; 22 patients completed the study achieving at least good pain relief. Of these 22 patients, 13 reached complete pain relief. Ketorolac was rapidly absorbed. Notwithstanding, pain relief increased gradually, showing considerable delay with regard to plasma concentrations. Analysis of the probability-time curves revealed that 25% of the patients obtained moderate pain relief at 7 min after ketorolac administration, 50% at 11 min, 75% at 29 min, and 95% at 60 min. Good pain relief was achieved in 25, 50, and 75% of the patients at 1.1, 1.8, and 2.7 h, respectively. Complete pain relief was achieved in 25% and 50% of the patients at 2.6 h and 3.7 h, respectively. The probability of exhibiting an acceptable pain relief in responsive patients for more than 5 h was 0.97. No serious side effects were detected. CONCLUSIONS: Results show that 30 mg intramuscular ketorolac is an adequate treatment for postoperative pain in the Mexican population. Therefore, the use of higher doses is not justified. Due to gradual installation of analgesia, administration of additional analgesic medication before 1 h is not recommended.

Bioavailability of etoposide after oral administration of the solution marketed for intravenous use: therapeutic and pharmacoeconomic perspectives.

BACKGROUND: Oral etoposide administration is a suitable alternative to the intravenous route; therefore, commercial capsules have been developed. Before these capsules were available in Mexico, we studied drug bioavailability after oral administration of the intravenous etoposide solution (IVES). METHODS: Eight adult cancer patients received a 50-mg oral etoposide dose as IVES and blood samples were collected over a period of 24 h. Plasma etoposide concentration was determined by high-performance liquid chromatography, plasma concentration against time curves were constructed, and bioavailability parameters were calculated. RESULTS: Oral IVES yielded an adequate bioavailability profile because Cmax was 2.38 +/- 0.30 micrograms/mL, AUC was 12.87 +/- 2.02 micrograms/mL and half-life was 6.72 +/- 0.97 h. CONCLUSIONS: Considering that the pharmacokinetic aim is to maintain plasma concentrations between 0.5 and 1.0 microgram/mL for several hours while avoiding high concentrations, i.e., of 10 micrograms/mL or higher, oral administration of 50-mg etoposide as IVES appears to be a suitable dosing option. In addition, oral IVES is considerably less expensive than intravenous administration in terms of both drug presentation and administration.

Usefulness of the pain-induced functional impairment model to relate plasma levels of analgesics to their efficacy in rats.

In this work we show that the pain-induced functional impairment model (PIFIR) can be used with cannulated rats as a useful procedure for pharmacokinetic/pharmacodynamic modelling. This model evaluates analgesia by measuring motor impairment of the right limb after intra-articular administration of uric acid. Time of contact with a rotating cylinder is referred to the control limb. We studied the pharmacokinetic and pharmacodynamics of naproxen after six peroral doses to Wistar rats, and we examined the adjuvant action of caffeine with naproxen. Surgery and blood sampling did not produce any difference on functional impairment either in rats without uric acid or in the dysfunction produced by uric acid. The relation between naproxen plasma concentration and the analgesic effect was obtained with few rats. Caffeine alone did not produce any significant modification in functional impairment but the co-administration significantly increased the effect of naproxen. Plasma levels of naproxen did not change when caffeine was co-administered. The PIFIR model with blood sampling is a suitable method for pharmacokinetic/pharmacodynamic relationship studies and is specially useful to characterize drug-drug interactions.

Analgesic efficacy of lysine clonixinate plus tramadol versus tramadol in multiple doses following impacted third molar surgery.

This study compared the analgesic and anti-inflammatory efficacy, trismus control, and tolerability of the combination of lysine clonixinate and tramadol (LCT) versus tramadol (T) alone after surgical removal of impacted mandibular third molars. This study was a double-blind, randomized clinical trial, including two study groups of 20 patients each, who exhibited acute pain subsequent to surgical extraction of two mandibular third molars. Pain intensity was quantified over a 96-h period using a visual analogue scale and a 5-point verbal rating scale. Secondary indicators of analgesic and anti-inflammatory efficacy, trismus control, and tolerability were determined. Patients administered LCT exhibited better therapeutic effects that those administered T. Fifty percent of patients in the LCT group rated this therapy as 'excellent analgesia' compared with only 10% in the T group. The onset of the analgesic effect of LCT was significantly faster, without any therapeutic failures. There were no significant differences between the groups with regard to anti-inflammatory effect or trismus. The results of this study suggest that the postsurgical analgesic efficacy of LCT in combination (LC 125 mg + T 25 mg) is superior to that obtained with T alone, administered at the standard dose of 50 mg, for up to 96 h after the extraction of both impacted mandibular third molars.

Oral paracetamol bioavailability in rats subjected to experimental spinal cord injury.

The purpose of the present study was to examine the time dependence of oral paracetamol (acetaminophen) bioavailability in an experimental model of spinal cord injury (SCI). Female Sprague-Dawley rats were subjected to spinal cord contusion at the T8-T9 level by the weight drop method producing permanent paraplegia. Oral paracetamol bioavailability after administration of a single 100 mgkg-1 dose was determined 1, 12, and 50 d after SCI. Cmax and AUC were significantly decreased 1 d after SCI compared to sham-injured controls. This reduction, however, was temporary, as there was a recovery of bioavailability parameters which was partial 12 d after SCI, being complete by day 50. The present results confirm the usefulness of animal models for the characterization of the effect of SCI in drug kinetics. Data show that SCI induces significant changes in paracetamol pharmacokinetics. Nonetheless, despite the fact of a permanent loss of functions related to locomotion, pharmacokinetic alterations evolved with time.

Limited sampling model for area-under-the-curve monitoring in pediatric patients receiving either Sandimmune or Neoral cyclosporin A oral formulations.

Several limited sampling equations were tested to predict the area under the curve (AUC) of cyclosporin A (CsA) at steady state in 10 children with end-stage renal disease receiving oral CsA 2.5 mg/kg b.i.d. as two different formulations, namely Sandimmune and Neoral, according to a randomized crossover design with a one-month washout period. AUC was significantly correlated with CsA concentration at 5 h. The equation derived from this single concentration time point was able to adequately predict the AUC for Sandimmune but not for Neoral. The equation derived from CsA concentration data, measured at 2 and 12 h, significantly improved predictive performance in terms of bias and precision, allowing adequate AUC predictions in both formulations. CsA concentration at 2 h was also able to predict Cmax, while the concentration at 12 h corresponded to the trough value in a b.i.d. dosing scheme. Therefore, it is concluded that a limited sampling model including concentration data at 2 and 12 h allows the estimation of AUC, Cmax and trough levels, yielding a complete profile in patients exposed to CsA as Sandimmune or Neoral. Hence, this model can be used for therapeutic monitoring of CsA levels in pediatric patients being switched from one formulation to another.

Determination of diclofenac in micro-whole blood samples by high-performance liquid chromatography with electrochemical detection. Application in a pharmacokinetic study.

A rapid and sensitive method for the determination of diclofenac (CAS 15307-86-5) in whole blood samples by high-performance liquid chromatography with amperometric detection has been developed. This method was then used to study the pharmacokinetics of oral diclofenac sodium in the rat. The method includes a single extraction of acidified whole blood with ethyl acetate. Extracts were analyzed on a reversed-phase column eluted with a mixture of acetonitrile and 0.075 mol/l sodium acetate solution (pH 3.3) and detected amperometrically at + 1.1 V against Ag/AgCl. Retention times for diclofenac and the internal standard (naproxen) were 3.5 and 6 min, respectively. The method was linear in the range of 25 to 2000 ng/ml and the detection limit of the method was 10 ng/ml, using 100 microliters of whole blood sample. Employing this method, the oral pharmacokinetics of diclofenac in the rat was studied. Wistar male rats received an oral dose of 1, 3.2 or 10 mg/kg of diclofenac and blood samples were drawn at selected times during 12 h. After administration of diclofenac, a rapid increase of circulating concentrations was observed reaching a maximum in about 10 min. Then concentration decayed with a half-life of about 15 h. It is concluded that the method here reported is adequate for realization of pharmacokinetic studies of diclofenac in small species.