Serological biomarker profiles of rapidly progressive osteoarthritis in tanezumab-treated patients.

There is a need for efficacious and safe pain treatments for OA (osteoarthritis). The nerve growth factor (NGF) antibody tanezumab is associated with high efficacy, but when combined with chronic NSAID treatment shows an increased risk of rapidly progressive osteoarthritis (RPOA) in a small group of patients. AIM: The aim of this study was to phenotype with biochemical biomarkers of bone, cartilage, soft tissue, synovial metabolism OA patients who are at risk of developing RPOA type-2, for both limited and chronic NSAIDs users. MATERIAL AND METHODS: The dataset consisted of OA patients participating in tanezumab trials who used NSAIDs <90 days (limited NSAID users) or chronic users (NSAIDs ≥90 days) over an average 10 month period. Biomarker data were available for 47 cases (RPOA type-2) and 92 controls. Non-linear and linear multivariable predictive models were developed. RESULTS: By use of two biomarkers at baseline the receiver operating characteristic (ROC) curve area for RPOA type-2 in limited NSAID users was 71%, [CI] (60-83%). OA subjects with this biomarker phenotype had 8-fold higher confidence interval [CI][(2-33)] relative risk of developing RPOA type-2 as compared to OA patients without this phenotype. The AUC of the model in chronic NSAIDs users based on 5 biomarkers was 78%, [CI](69-88%), with 4-fold [CI (2-6)] relative risk of developing RPOA type-2. CONCLUSION: In this hypothesis generating and exploratory study, we identified combinations of biomarkers associated with OA patients who develop RPOA type-2, which may be related to the pathology of the RPOA type-2 joint.

Identification of serological biomarker profiles associated with total joint replacement in osteoarthritis patients.

OBJECTIVE: Establish a biomarker panel associated with all-cause total joint replacement (TJR) through identification of patients with osteoarthritis (OA) who do or do not progress to TJR and investigate effects of nonsteroidal anti-inflammatory drugs (NSAIDs). DESIGN: Serum samples from patients enrolled in phase III trials of tanezumab who experienced TJR (n = 174) or matched patients who did not (n = 321) were analyzed for bone, cartilage, soft tissue, and inflammation markers. Classification and Regression Tree (CART) analysis was used to identify biomarker phenotypes associated with TJR. RESULTS: At baseline, biomarker combinations for patients who did not use NSAIDs before starting tanezumab and used NSAIDs during tanezumab treatment <90 days ("nonNSAID"), identified 77% (95% confidence interval [CI]: 71-84%) of patients who experienced TJR and 77% (95% CI: 65-86%) who did not over a 6-month study period (on average). These biomarker combinations increased odds of identifying patients to remain free of a TJR by 3.3-fold. In patients who used NSAIDs continuously (during screening and ≥90 days during tanezumab treatment), 64% (95% CI: 54-73%) who had TJR and 75% (95% CI: 68-83%) who did not were identified by biomarker combinations different from nonNSAID patients, with an increase in odds of identifying patients to remain free of a TJR by two-fold. CONCLUSIONS: Although validation on other cohorts is necessary, biomarkers may assist in identifying patients who will need TJR. The profiles suggest NSAID use increases importance of bone metabolism in TJR pathology.

Comparative spinal distribution and clearance kinetics of intrathecally administered morphine, fentanyl, alfentanil, and sufentanil.

BACKGROUND: Despite widespread use, little is known about the comparative pharmacokinetics of intrathecally administered opioids. The present study was designed to characterize the rate and extent of opioid distribution within cerebrospinal fluid, spinal cord, epidural space, and systemic circulation after intrathecal injection. METHODS: Equal doses of morphine and alfentanil, fentanyl, or sufentanil were administered intrathecally (L3) to anesthetized pigs. Microdialysis probes were used to sample cerebrospinal fluid at L2, T11, T7, T3, and the epidural space at L2 every 5-10 min for 4 h. At the end of the experiment, spinal cord and epidural fat tissue were sampled, and each probe's recovery was determined in vitro. Using SAAM II pharmacokinetic modeling software (SAAM Institute, University of Washington, Seattle, WA), the data were fit to a 16-compartment model that was divided into four spinal levels, each of which consisted of a caternary arrangement of four compartments representing the spinal cord, cerebrospinal fluid, epidural space, and epidural fat. RESULTS: Model simulations revealed that the integral exposure (area under the curve divided by dose) of the spinal cord (i.e., effect compartment) to the opioids was highest for morphine because of its low spinal cord distribution volume and slow clearance into plasma The integral exposure of the spinal cord to the other opioids was relatively low, but for different reasons: alfentanil has a high clearance from spinal cord into plasma, fentanyl distributes rapidly into the epidural space and fat, and sufentanil has a high spinal cord volume of distribution. CONCLUSIONS: The four opioids studied demonstrate markedly different pharmacokinetic behavior, which correlates well with their pharmacodynamic behavior.

Optimal propofol-alfentanil combinations for supplementing nitrous oxide for outpatient surgery.

BACKGROUND: The combination of propofol and alfentanil with nitrous oxide provides balanced anesthesia with rapid recovery and minimal emetic side effects. The object of this study was to compare recovery parameters at varying proportions of propofol and alfentanil, and to determine the dosing rate and plasma concentration of propofol necessary to supplement nitrous oxide in the presence of varying concentrations of alfentanil METHODS: Forty-eight patients were anesthetized with nitrous oxide, targeted manual infusions of alfentanil (target plasma concentrations of 0, 50, 100, and 150 ng/ml), and propofol at rates that were varied up or down by 25% depending on the response (movement/no movement) of the preceding patient (at the same alfentanil target concentrations) to ulnar-nerve stimulation. The minimum concentrations of propofol and alfentanil required to prevent movement in 50% of patients (EC50) was determined by logistic regression. Speed of emergence and recovery of cognitive function, time to discharge, and incidence of side effects were compared for four different combinations of propofol and alfentanil with nitrous oxide. RESULTS: The EC50 for propofol alone with nitrous oxide was 6.1 microg/ml. AlfentaniL at concentrations of 41+/-17 (SD), 113+/-54, and 130+/-61 ng/mL reduced the EC50 of propofol to 3.3, 2.3, and 2.2 microg/ml, respectively, and decreased emergence time (eye opening) to 8.1, 4.9, and 3.4 min, compared with 24.3 min for propofol alone. Side effects did not differ between groups. CONCLUSIONS: The authors conclude that there is a synergistic effect between propofol and alfentanil, and that combining alfentanil with propofol is associated with faster early recovery.

Cotreatment with racemic fenfluramine inhibits the development of tolerance to morphine analgesia in rats.

As a follow-up study to an earlier report that racemic fenfluramine can acutely potentiate the analgesic effects of morphine in humans, we investigated the effects of fenfluramine on the development of tolerance to morphine analgesia in rats. Antinociceptive effect, as measured by the tail-flick latency, was studied over 8 days in rats that received continuous i.v. infusion of 1) 22 mg/kg/day of morphine, 2) 20 mg/kg/day of fenfluramine, 3) both drugs concomitantly or 4) saline. Infusion with morphine alone resulted in a peak analgesia of 100% maximal possible effect, which declined with time; full tolerance was reached by day 4. Fenfluramine treatment alone had no effect. Fenfluramine coinfusion attenuated the development of tolerance to morphine; >70% maximal possible effect was still present on day 4. The effect of fenfluramine coinfusion occurred in the absence of a significant increase in plasma or brain morphine concentration, or a decrease in the accumulation of morphine's putative antagonistic metabolite, morphine-3-glucuronide. In another set of infusion experiments, rats were challenged with a single i.p. dose of morphine to characterize the morphine dose-response curves at 10 hr following 4-day i.v. infusion of 1) 22 mg/kg/day of morphine, 2) 20 mg/kg/day fenfluramine, 3) morphine plus fenfluramine or 4) saline. An acute i. p. morphine challenge dose response experiment was also conducted in naïve control rats and in rats receiving a concomitant i.p. injection of fenfluramine (2.4 mg/kg). Coinjection of fenfluramine acutely potentiated the antinociceptive potency of morphine. However, potentiation alone does not fully account for the apparent attenuation of tolerance during morphine i.v. infusion. ED50 of morphine was elevated to 7.0 mg/kg in the morphine-infused rats compared to 2.4 mg/kg in saline-infused rats. Coinfusion of fenfluramine increased ED50 to only 3.7 mg/kg. These results demonstrate that fenfluramine significantly attenuates tolerance development to morphine by modulating the pharmacological process responsible for tolerance development to morphine.

Pharmacokinetic/pharmacodynamic relationship of benzodiazepines in the direct cortical stimulation model of anticonvulsant effect.

The in vivo concentration-anticonvulsant effect relationships of six benzodiazepines, midazolam, clonazepam, oxazepam, flunitrazepam, diazepam and clobazam were quantified in individual rats and correlated with the affinity to the GABAA-benzodiazepine receptor complex. Furthermore the interaction between midazolam and the benzodiazepine antagonist flumazenil was characterized. All benzodiazepines exhibited a nonlinear relationship between concentration and anticonvulsant effect without ceiling of the effect at higher concentration. The potency of most benzodiazepines was similar with values of the EC250, between 0.067 +/- 0.01 mg. l-1 for midazolam and 0.21 +/- 0.03 mg. l-1 for diazepam. The EC250,u of clobazam was 2.8 +/- 0.9 mg. l-1. These values were considerably larger than the Ki for binding at the GABAA-benzodiazepine receptor complex. No correlation was observed between EC250,u and Ki. Antagonism of the anticonvulsant effect of midazolam by flumazenil was associated with a remarkable change in the concentration-anticonvulsant effect relationship. Analysis of these data on basis of a composite model provided evidence for two separate effects of which only one is antagonized by flumazenil. The anticonvulsant effect at low midazolam concentration was characterized on basis of the sigmoid E maximal effect pharmacodynamic model. The value of the EC50,u was 0.0086 +/- 0.0013 mg. l-1 which is similar to the Ki for binding at the GABAA-benzodiazepine receptor complex. The second more pronounced anticonvulsant effect occurred at higher concentration and was described by an exponential function. The findings of this study indicate that the effect of benzodiazepines against seizures induced by cortical stimulation in vivo cannot be fully accounted for by an interaction at the GABAA-benzodiazepine receptor complex.

Stereoselective pharmacokinetics of stiripentol: an explanation for the development of tolerance to anticonvulsant effect.

An earlier pharmacodynamic study of the chiral antiepileptic drug stiripentol in an intravenous pentylenetetrazol-induced seizure model in the rat showed the development of a significant degree of tolerance to the anticonvulsant and neurotoxic effects following subacute treatment with the racemic compound. A more recent study with the pure enantiomers of stiripentol indicated that the (+)-enantiomer is 2.4 times more potent than the (-)-enantiomer, based on a comparison of brain EC50 values for the anticonvulsant effect. Moreover, (-)-stiripentol has a much longer elimination half-life than (+)-stiripentol. We have re-analyzed the brain and blood samples from the first pharmacodynamic study using a newly developed chiral HPLC assay to investigate whether the tolerance phenomenon with racemic stiripentol was due to a shift in the enantiomeric composition of stiripentol in brain tissue during repetitive administration of racemic drug. A large increase, as much as 5-6-fold, in the (-)/(+) ratio in brain concentration of stiripentol was observed after subacute administration, as compared with that after a single dose of the racemic drug. The enrichment in the less potent enantiomers during repetitive drug administration explains the previous observation of an apparent development of tolerance when the pharmacologic effects were related to total [(-)+(+)] brain concentrations of stiripentol as measured by a non-stereoselective assay. The results of this study highlight the importance of stereoselective pharmacokinetics in investigating the pharmacodynamics of the racemic mixture of a chiral anticonvulsant.