Relative Potency Ratios Research Articles

Guidelines to establish relative potency are not in touch with reality

Garcia-Arieta [1] interprets our data [2] purely from a regulatory perspective with regard to demonstrating equivalence. In this regard, we demonstrated a significant overall dose–response relation from regression analysis of the common slope for shift in methacholine PC20, indicating assay sensitivity for this outcome. However, when one inspects the difference in PC20 shift between the 200 and 800 µg doses, while there was significant dose separation it has to be taken in the context of the biological variability which is of the order of ±1 doubling dilution (i.e. ±2-fold shift). Thus, one needs to distinguish between a statistically significant difference from what may be clinically irrelevant. Pointedly, our patients were selected a priori for being methacholine responsive, with a mean PC20 of 0.66 mg/ml−1, i.e. they had plenty of room for improvement in response to inhaled corticosteroid. When comparing the formulations at each dose level, the confidence limits for the mean difference in PC20 was contained within accepted limits of variability of ±1 doubling dilution, indicating therapeutic equivalence. Our study shows that even using n = 89 patients, while the point estimate for relative potency was close to unity, the 95% confidence interval was well outside of accepted pharmacodynamic equivalence limits. Given that this was performed within a single centre with considerable experience of challenge studies, we are of the firm opinion that it is not feasible to assess relative potency using Finney, and as such this should no longer be recommended in current guidelines for establishing equivalence. Although we also showed significant dose separation for suppression of exhaled nitric oxide, the mean difference between 200 and 800 µg was rather small, amounting to 14% with HFA and 11% with CFC, in comparison to 29 and 20% differences, respectively, for methacholine PC20 shift. We evaluated pharmacokinetic outcomes at steady state to mirror what happens in real-life clinical practice, where patients take their inhaled steroid twice daily and not as single doses, i.e. also to reflect the chronic dosing protocol for our challenge study. In fact, our data for area under the curve showed that the two formulations were equivalent within conventional limits of ±20%, in keeping with the challenge data when comparing the methacholine PC20 shift at each dose. Finally, subtle differences in pharmacokinetic and pharmacodynamic outcomes pointed out by Garcia-Arieta [1] need to be put in their true perspective, because variations in real-life inhaler technique will result in at least 50% differences in dose delivered to the lungs, even within the same individual from day to day. Thus, from a clinical perspective, a 10% difference in delivered dose is rather meaningless for the patient. In the light of our study, we believe that the guidelines are no longer in touch with the reality of performing clinical trials using surrogate inflammatory end-points with inhaled steroids and especially the need to calculate relative potency ratios using Finney.

Effect of sex and pregnancy on the potency of intrathecal bupivacaine: determination of ED50 for motor block with the up–down sequential allocation method

The up-down sequential allocation model has been adapted to estimate the relative potency ratios for analgesia and motor block of the most commonly used epidural and intrathecal local anaesthetics. The aim of this study was to establish the median effective doses (ED50) for motor block with intrathecal bupivacaine and to estimate the ED50 ratios of these in male, female and pregnant patients. In this prospective, double-blind, parallel group, up-down sequential allocation study, we enrolled 30 male patients, 30 female, non-pregnant patients and 30 pregnant patients undergoing elective surgery under combined spinal-epidural anesthesia. The first two groups consisted of male or female patients undergoing elective lower limb surgery and the third group consisted of pregnant women at term (>36 and <41 weeks) with singleton pregnancies undergoing elective caesarean delivery. Patients received intrathecal isobaric bupivacaine 0.5% as part of the spinal-epidural anaesthesia technique. The initial dose was 4 mg and the testing interval was 1 mg with subsequent doses being determined by the outcome in the previous patient in the same group. The end point for efficacy was the occurrence of motor block in the lower limbs within 5 min. There were significant (P < 0.0001) differences in ED50 estimates for motor block with intrathecal bupivacaine: 6.9 mg for men [95% confidence interval (CI), 5.2-8.6), 5.2 mg for women (95% CI, 4.5-5.8) and 3.4 mg for pregnant women (95% CI, 2.9-4.0). We have demonstrated a hierarchy of potencies for motor block with intrathecal bupivacaine for men, women and pregnant women suggesting possible relevant differences owing to the effects of both sex and pregnancy.

Relative potencies of bupivacaine, levobupivacaine, and ropivacaine for neonatal spinal anaesthesia

Comparing the relative potency of new local anaesthetics such as levobupivacaine and ropivacaine with bupivacaine by the minimum local analgesic concentration model has not been described for neonatal spinal anaesthesia. This information is important to compare agents and to determine the most effective spinal dose. We performed a two-stage study to determine the ED50, the ED95, and the relative analgesic potency of isobaric spinal bupivacaine, levobupivacaine, and ropivacaine in infants. In phase 1, 81 infants were randomized in a Dixon-Massey study to describe the minimum local analgesic dose. In phase 2, a further 70 patients were randomly allocated to receive spinal anaesthesia with doses in the upper dose-response range to define the ED95. The ED50 doses for bupivacaine, levobupivacaine, and ropivacaine were estimated by isotonic regression to be 0.30 mg kg(-1) [95% confidence interval (CI) 0.25-0.43], 0.55 mg kg(-1) (0.50-0.64), and 0.50 mg kg(-1) (0.43-0.64), respectively. The ED(95), respectively, of bupivacaine, levobupivacaine, and ropivacaine were 0.96 mg kg(-1) (95% CI 0.83-0.98), 1.18 mg kg(-1) (1.05-1.22), and 0.99 mg kg(-1) (0.73-1.50). The relative potency ratios at the ED(50) were bupivacaine:levobupivacaine 0.55 (95% CI 0.39-0.88), bupivacaine:ropivacaine 0.61 (0.41-1.00), and levobupivacaine:ropivacaine 1.09 (0.84-1.45). Appropriate doses for infant spinal anaesthesia are 1 mg kg(-1) of isobaric 0.5% bupivacaine and ropivacaine and 1.2 mg kg(-1) of isobaric 0.5% levobupivacaine.

The Median Effective Dose of Bupivacaine, Levobupivacaine, and Ropivacaine After Intrathecal Injection in Lower Limb Surgery

Intrathecal anesthesia is commonly used for lower limb surgery. Bupivacaine, levobupivacaine, and ropivacaine have all been used as intrathecal drugs, but their relative potency in this context has not been fully determined. In this study, we determined the median effective dose (ED(50)) of these three local anesthetics for intrathecal anesthesia in lower limb surgery and hence their relative potencies. Seventy-five patients scheduled for lower limb surgery under combined spinal-epidural anesthesia were randomly allocated to one of three groups receiving intrathecal bupivacaine, levobupivacaine, or ropivacaine. The dose of local anesthetic was varied using up-down sequential allocation technique. The dose for the first patient in each group was 8 mg, and the dosing increment was set at 1 mg. Subsequent doses in each group were determined by the outcome in the previous patient using success or failure of the spinal anesthesia as the primary end point. A success was recorded if a bilateral T12 sensory block to cold was attained within 20 min after intrathecal injection, and the surgery proceeded successfully until at least 50 min after the intrathecal injection without supplementary epidural injection. The ED(50) was calculated using the method of Dixon and Massey. The ED(50)s were 5.50 mg for bupivacaine (95% confidence interval [CI]: 4.90-6.10 mg), 5.68 mg for levobupivacaine (95% CI: 4.92-6.44 mg), and 8.41 mg for ropivacaine (95% CI: 7.15-9.67 mg) in intrathecal anesthesia. The relative anesthetic potency ratios are 0.97 (95% CI: 0.81-1.17) for levobupivacaine/bupivacaine, 0.65 (95% CI: 0.54-0.80) for ropivacaine/bupivacaine, and 0.68 (95% CI: 0.55-0.84) for ropivacaine/levobupivacaine. This study suggests that in intrathecal anesthesia for lower limb surgery, ropivacaine is less potent than levobupivacaine and bupivacaine, whereas the potency is similar between levobupivacaine and bupivacaine.

Enantioselective estrogenicity of o,p'‐dichlorodiphenyltrichloroethane in the MCF‐7 human breast carcinoma cell line

Research increasingly suggests that selectivity between enantiomers may exist in acute and chronic toxicological effects of chiral contaminants. In this study, we used the human breast carcinoma MCF-7 cell line to evaluate enantioselectivity of o,p'-dichlorodiphenyltrichloroethane (o,p'-DDT). Baseline separation of o,p'-DDT enantiomers was achieved on the Chiralcel OJ chiral column by high-performance liquid chromatography, and the absolute configuration and optical rotation of the resolved enantiomers were further identified. Significant differences in estrogenic potential were observed between the two enantiomers of o,p'-DDT in the MCF-7 cell proliferation assay (i.e., the E-Screen assay) and the real-time quantitative polymerase chain reaction (PCR). In the E-Screen assay, the relative proliferative effect ratios of R-(-)-o,p'-DDT and S-(+)-o,p'-DDT were 89.4 and 27.9%, respectively, and the relative proliferative potency ratios were 0.1 and 0.001%, respectively. Compared to the solvent control, R-(-)-o,p'-DDT induced the maximal increase of 2.31-fold at a concentration of 10(-6) mol/L, while S-(+)-o,p'-DDT at 10(-5) mol/L induced the maximal increase of 1.65-fold in estrogenic biomarker pS2 mRNA level. The maximal down-regulation of the transcription levels of estrogen receptor alpha (ERa) and ER3 by R-(-)-o,p'-DDT were 49 and 40% at the concentration of 10(-6) mol/L, while those by S-(+)-o,p'-DDT were 24 and 26% at the concentration of 10(-5) mol/L. The cell proliferation, the up-regulation of pS2, and the down-regulation of ERalpha and ERbeta gene expressions induced by the racemate and enantiomers of o,p'-DDT were all reversed by cotreatment with 10(-6) mol/L ICI 182,780. Therefore, the enantioselective estrogenicity of o,p'-DDT was likely through the ERalpha and ERbeta signaling pathways. Results from this study suggest the need for considering enantioselectivity of chiral contaminants in chronic ecological toxicities.

Within-subject comparison of the psychopharmacological profiles of oral hydrocodone and oxycodone combination products in non-drug-abusing volunteers

Background Non-medical use and abuse of prescription opioids is a significant problem in the United States. Little attention has been paid to assessing the relative psychopharmacological profile (including abuse liability-related effects) of specific prescription opioids. The purpose of this study was to directly compare the psychopharmacological profile of two widely prescribed and abused oral opioid combination products within the same subject. Methods Twenty non-drug-abusing volunteers participated in a crossover, randomized, double-blind study in which they received, all p.o.: placebo; 975 mg acetaminophen (ACET); 10 mg oxycodone (OXY)/487 mg ACET; 20 mg OXY/975 mg ACET; 15 mg hydrocodone (HYD)/487 mg ACET; and 30 mg HYD/975 mg ACET. OXY and HYD doses were chosen to equate the drugs on an objective measure of opiate effects: miosis. Dependent measures were subjective, psychomotor/cognitive, reinforcing, and physiological effects, and relative potency estimates. Results In general, the two opioid combination products at equi-miotic doses produced similar prototypic opiate-like effects and psychomotor impairment, and of similar magnitude. The higher dose of OXY/ACET produced slightly more abuse liability-related subjective effects than the higher dose of HYD/OXY, but also produced slightly more negative effects. Neither drug at either dose functioned as a reinforcer, as measured by the Multiple Choice Procedure. Relative potency ratios indicated that OXY/ACET was approximately 1.5 times more potent than HYD/ACET. Conclusions Consistent with a recent study published in this journal using identical doses of HYD and OXY (without ACET) in prescription opioid abusers (Walsh, S.L., Nuzzo, P.A., Lofwall, M.R., Holtman Jr., J.R., 2008. The relative abuse liability of oral oxycodone, hydrocodone and hydromorphone assessed in prescription drug abusers. Drug Alcohol Depend. 198, 191–202), we found little difference in the pharmacodynamic effects of HYD/ACET and OXY/ACET in non-drug-abusing volunteers.

Estimation of the minimum motor blocking potency ratio for intrathecal bupivacaine and lidocaine

Background The up-down sequential allocation model has been adapted to investigate a variety of clinical and pharmacological issues in neuraxial anaesthesia including the estimation of relative potency ratios for analgesia and motor block of the most commonly used epidural and intrathecal local anaesthetics. The aim of this study was to establish the median effective doses (ED50) for motor block with intrathecal lidocaine and bupivacaine and to define the relative motor blocking potency ratio. Methods In this prospective, randomised, double blind, parallel group, up-down sequential allocation study, we enrolled 71 parturients undergoing elective caesarean section under combined spinal-epidural anaesthesia. The women received either intrathecal lidocaine 2% w/v or bupivacaine 0.5% w/v. The initial dose was 4 mg for bupivacaine and 12 mg for lidocaine. Subsequent doses were determined by the outcome in the previous parturient, according to the up-down sequential allocation technique. The end point was the occurrence of any motor block in either lower limb within 5 min. Results The intrathecal ED50 for motor block was 13.7 mg for lidocaine (95% CI, 13.1 to 14.4) and 3.4 mg for bupivacaine (95% CI, 2.6 to 4.1) ( P < 0.0001) and the relative motor blocking potency ratio was 4.1 (95% CI 3.3 to 5.2). Conclusions Intrathecal bupivacaine was 4.1 times more potent than lidocaine for motor block.

Motor Blocking Minimum Local Anesthetic Concentrations of Bupivacaine, Levobupivacaine, and Ropivacaine in Labor

Obstetric Anesthesia Digest: March 2008 - Volume 28 - Issue 1 - p 38-39 doi: 10.1097/01.aoa.0000308321.61682.3e

Within-subject comparison of the psychopharmacological profiles of oral oxycodone and oral morphine in non-drug-abusing volunteers

Nonmedical use and abuse of prescription opioids is a significant problem in the USA. Little attention has been paid to assessing the relative psychopharmacological profile (including abuse liability-related effects) of specific prescription opioids. The aim of this study is to directly compare the psychopharmacological profile of two oral opioids within the same subject. A randomized, placebo-controlled, crossover study was done in which 20 non-drug-abusing volunteers ingested 10 and 20 mg of oxycodone, 30 and 60 mg of morphine, and placebo in separate sessions. Drug doses were equated on an objective measure of opiate effects: miosis. Subjective, psychomotor, reinforcing, and physiological effects of the opioids were assessed. In general, the two opioids at equimiotic doses produced similar prototypic opiate-like effects and psychomotor impairment of similar magnitude. However, several effects were found only with 20 mg oxycodone. Both drugs produced abuse liability-related subjective effects but also dysphoric effects, particularly with 60 mg morphine. Neither drug at either dose functioned as a reinforcer, as measured by the Multiple Choice Procedure. Relative potency ratios indicated an average oxycodone/morphine [corrected] ratio of 1:3 [corrected] The psychopharmacological profile of oxycodone and morphine at equimiotic doses had many similarities; however, differences were found in producing abuse liability-related and dysphoric effects. In the medical community, it is commonly accepted that oral oxycodone is 1.5 to 2 times as potent as oral morphine in producing analgesia; using this ratio, although patients may experience similar degrees of pain relief, those receiving oxycodone may be experiencing stronger and potentially different psychopharmacological effects.

Enantioselectivity in Estrogenic Potential and Uptake of Bifenthrin

Despite the fact that the biological processes of chiral compounds are enantioselective, the endocrine disruption activity and uptake of chiral contaminants with respect to enantioselectivity has so far received limited research. In this study, the estrogenic potential and uptake of the enantiomers of a newer pyrethroid insecticide, bifenthrin (BF), were investigated. Significant differences in estrogenic potential were observed between the two enantiomers in the in vitro human breast carcinoma MCF-7 cell proliferation assay (i.e., the E-SCREEN assay) and the in vivo aquatic vertebrate vitellogenin enzyme-linked immunosorbent assay (ELISA). In the E-SCREEN assay, the relative proliferative effect ratios of 1S-cis-BF and 1R-cis-BF were 74.2% and 20.9%, respectively, and the relative proliferative potency ratios were 10% and 1%, respectively. The cell proliferation induced by the two BF enantiomers may be through the classical estrogen response pathway via the estrogen receptor (ER), as the proliferation induced by the enantiomers could be completely blocked when combined with 10-6 mol/L of the ER antagonist ICI 182,780. Measurement of vitellogenin induction in Japanese medaka (Oryzias latipes) showed that, at an exposure level of 10 ng/mL, the response to 1S-cis-BF was about 123 times greater than thattothe Renantiomer. Significant selectivity also occurred in the uptake of BF enantiomers in the liver and other tissues of J. medaka. These results together suggest that assessment of the environmental safety of chiral insecticides should consider enantioselectivity in acute and chronic ecotoxicities such as endocrine disruption.

Motor Blocking Minimum Local Anesthetic Concentrations of Bupivacaine, Levobupivacaine, and Ropivacaine in Labor

Adequate comparison of blocking capabilities of local anesthetics should be done with some knowledge of their relative potencies. The objective of this clinical trial was to simultaneously determine the motor blocking minimum local anesthetic concentrations (MMLAC) and the relative potency ratios for racemic bupivacaine, levobupivacaine, and ropivacaine during labor. We studied parturients with singleton term pregnancies in vertex presentation. Each patient received a 20 mL epidural bolus of bupivacaine, levobupivacaine, or ropivacaine determined by the MMLAC model. Baseline and 30 min after injection, measurements of pain and muscle strength were performed, with assessment of motor strength in the legs at 30 min being the primary outcome measure. There were no differences in demographic, hemodynamic, or obstetric characteristics between the patients receiving the three local anesthetics. The estimated MMLAC with the 95% confidence intervals (CI) were: Bupivacaine: 0.26% wt/vol (0.22-0.30); Levobupivacaine: 0.30% wt/vol (0.25-0.36); Ropivacaine: 0.34% wt/vol (0.29-0.38). ANOVA of MMLAC estimates was significant (F = 3.32, P = .046), and when ranked by analgesic potencies, a significant linear trend (P = .014) to increasing motor blocking potencies from ropivacaine to levobupivacaine to bupivacaine was also found. This study confirms a motor blocking hierarchy for the three pipecoloxylidines.

Effect of sufentanil on minimum local analgesic concentrations of epidural bupivacaine, ropivacaine and levobupivacaine in nullipara in early labour

The aim was to assess the effect of epidural sufentanil on relative analgesic potencies of epidural bupivacaine, ropivacaine and levobupivacaine by determining the minimum local analgesic concentrations during labour. In a randomised, double-blind study, 171 parturients were allocated to one of six groups receiving a 10-mL bolus of bupivacaine, ropivacaine or levobupivacaine alone or with sufentanil 0.75 microg/mL. The concentration of local anaesthetic was determined by the response of the previous parturient using up-down sequential allocation starting at a concentration of 0.13% wt/vol with a testing interval of 0.01%. Effective analgesia was defined as a visual analogue pain score < or = 15/100 mm within 30 min and lasting for 30 min. Median effective concentrations were estimated and two-sided P < 0.05 was significant. Local anaesthetic concentration, use of sufentanil and local anaesthetic drug were independent significant predictors of effective and ineffective analgesia. Bupivacaine was significantly more potent than levobupivacaine and ropivacaine. The relative potency ratios without sufentanil of 0.77:0.83:1.00 were reduced to 0.36:0.38:1.00 by the addition of sufentanil. The major factor influencing local anaesthetic requirements was the addition of sufentanil, which reduced overall requirements by a factor of 4.2 (95% CI 3.6-4.8); this effect was proportionately more enhanced for bupivacaine. Local anaesthetic requirements for bupivacaine, levobupivacaine and ropivacaine follow an analgesic potency hierarchy. Any potency differences are small when compared to the effect of sufentanil, which resulted in a four-fold reduction in local anaesthetic requirements. Sufentanil may also enhance the potency differences between bupivacaine and the two S-enantiomer agents.

Relative Potencies for Acute Effects of Pyrethroids on Motor Function in Rats

The prevalence of pyrethroids in insecticide formulations has increased in the last decade. A common mode-of-action has been proposed for pyrethroids based on in vitro studies, which includes alterations in sodium channel dynamics in nervous system tissues, consequent disturbance of membrane polarization, and abnormal discharge in targeted neurons. The objective of this work was to characterize individual dose-response curves for in vivo motor function and calculate relative potencies for eleven commonly used pyrethroids. Acute oral dose-response functions were determined in adult male Long Evans rats for five Type I (bifenthrin, S-bioallethrin, permethrin, resmethrin, tefluthrin), five Type II (beta-cyfluthrin, lambda-cyhalothrin, cypermethrin, deltamethrin, esfenvalerate) and one mixed Type I/II (fenpropathrin) pyrethroids (n = 8-18 per dose; 6-11 dose levels per chemical, vehicle = corn oil, at 1 ml/kg). Motor function was measured using figure-8 mazes. Animals were tested for 1 h during the period of peak effects. All pyrethroids, regardless of structural class, produced dose-dependent decreases in motor activity. Relative potencies were calculated based on the computed ED30s. Deltamethrin, with an ED30 of 2.51 mg/kg, was chosen as the index chemical. Relative potency ratios ranged from 0.009 (resmethrin) to 2.092 (esfenvalerate). Additional work with environmentally-based mixtures is needed to test the hypothesis of dose-additivity of pyrethroids.

Minimum Local Analgesic Doses of Ropivacaine, Levobupivacaine, and Bupivacaine for Intrathecal Labor Analgesia

Doses for intrathecal opioid-local anesthetic mixtures have been arbitrarily chosen. The aim of this study was to compare the analgesic efficacies of intrathecal ropivacaine, levobupivacaine, and bupivacaine for labor analgesia and to determine the analgesic potency ratios for these three drugs. For this purpose, the authors used the up-down sequential allocation model, which estimates the minimum local analgesic dose for intrathecal local anesthetic. Ninety-seven nulliparous term parturients in spontaneous labor, requesting combined spinal-epidural analgesia, were randomly allocated to one of three groups to receive 0.25% spinal ropivacaine, levobupivacaine, or bupivacaine. The initial dose of the local anesthetic drug was chosen to be 2.5 mg, and the testing interval was set at 0.25 mg. The subsequent doses were determined by the response of the previous parturient. Efficacy was accepted if the visual analog pain score decreased to 10 mm or less on a 100-mm scale within 30 min. The minimum local analgesic dose was calculated using the method of Dixon and Massey. The intrathecal minimum local analgesic dose was 3.64 mg (95% confidence interval, 3.33-3.96 mg) for ropivacaine, 2.94 (2.73-3.16) mg for levobupivacaine, and 2.37 (2.17-2.58) mg for bupivacaine. The relative analgesic potency ratios were 0.65 (0.56-0.76) for ropivacaine:bupivacaine, 0.80 (0.70-0.92) for ropivacaine:levobupivacaine, and 0.81 (0.69-0.94) for levobupivacaine:bupivacaine. There were significant trends (P </= 0.021) for greater motor block with bupivacaine and levobupivacaine. This study suggests a potency hierarchy of spinal bupivacaine > levobupivacaine > ropivacaine.

Dose‐response to salbutamol via a novel palm sized nebuliser (Aerodose® Inhaler), conventional nebuliser (Pari LC Plus) and metered dose inhaler (Ventolin™ Evohaler™) in moderate to severe asthmatics

The Aerodose inhaler is a novel, palm-sized, breath actuated device which requires little patient coordination. This study compared the dose-response of salbutamol delivered by the Aerodose Inhaler (Aerogen Inc., Mountain View, USA) vs Pari LC Plus jet nebulizer (Pari LC Plus; Pari GmbH, Starnberg, Germany) and Ventolin Evohaler HFA pMDI (Evohaler; Allen & Hanburys [GlaxoSmithkline], Uxbridge, UK). Twenty-two moderate to severe asthmatic patients, mean (s.d.) age: 44.7 (9.4), FEV(1): 58.1 (12.0), received 4 cumulative doubling doses of salbutamol in a randomised, investigator blind, balanced crossover design. Spirometry and systemic safety variables (heart rate, blood pressure, T wave amplitude, QTc interval and potassium) were measured at baseline and after each dose. Parallel regression analysis revealed that microgram relative potency ratios for the Aerodose Inhaler to be five times more efficient for FEV(1) than either the Pari LC Plus (0.202, 90% CI: 0.189-0.216) or the Evohaler (0.202, 90% CI: 0.189-0.216), while there was no difference between Pari LC Plus vs Evohaler. Similarly, Aerodose Inhaler vs. Pari LC Plus showed approximately five-fold greater potency for all systemic parameters, except blood pressure. As compared to the Evohaler, Aerodose Inhaler had equivalent potency for plasma potassium and T wave amplitude, but demonstrated greater potency for heart rate and QT(c) interval. This study has indicated therefore, that Aerodose Inhaler is approximately five times as efficient as the Pari LC Plus and Evohaler in relative lung delivery of salbutamol in moderate to severe asthmatics.

Dose-ranging study of oxycodone for chronic pain in advanced cancer.

We assessed the analgesic efficacy and safety of single-entity oxycodone solution at doses greater than 10 mg orally every 4 hours in 24 patients with chronic cancer pain not controlled by weaker analgesics. Twenty of 24 patients completed the study. Pain relief was obtained with doses up to 60 mg every 4 hours. When oxycodone was taken for long periods, further dose increments could be made safely. The side effects of oxycodone are mild, and common to all opioids, with sedation and constipation most frequent. Nausea was more common in females in all age groups and in patients of either sex less than 50 years of age. Episodes of serious toxicity were rare, and responded to dose reduction. Patients older than 65 years required lower doses, suggesting pharmacokinetic similarities between oxycodone and morphine. Patients changed from oral oxycodone to morphine remained pain-free when relative milligram potency ratios of 1:1 to oral morphine and 3:1 to intravenous morphine were used. Oxycodone has been shown for the first time to be as versatile and flexible as oral morphine in the management of chronic pain in patients with advanced cancer.

Contribution of the C-terminal dipeptide of transforming growth factor-α to its activity: biochemical and pharmacologic profiles

We have used a matrix of biological (two distinct guinea-pig stomach contractile smooth muscle preparations) and biochemical (human placental membrane receptor binding and phosphorylation) assays to evaluate the activity profiles of epidermal growth factor-urogastrone (EGF-URO, mouse and human), transforming growth factor-α (TGF-α, human) and the TGF-α derivative lacking the C-terminal dipeptide, Leu 49-Ala 50, TGF-α-(1–48). In the longitudinal muscle (LM) bioassay, the relative potencies of the peptides were: EGF-URO > TGF-α > TGF-α-(1–48), with relative activity ratios (EC 50s) of approximately 1:3:16. In the LM assay system, TGF-α-(1–48) was a partial agonist. In the cicular muscle (CM) bioassay, the relative order of potencies was: TGF-α > EGF-URO > TGF-α-(1–48), with EC 50s of about 1:2:7. In the CM assay, all three peptides were full agonists, even though EGF-URO caused an intense desensitization of the tissue whereas TGF-α and TGF-α-(1–48) did not. The relative affinities of the peptides in the placenta membrane binding assay, EGF-URO > TGF-α > TGF-α-(1–48), were in good qualitative and quantitative agreement with the LM (but not the CM) bioassay, with relative K Ds in the proportions of about 1:3:17. In the phosphorylation assay, using either the phosphorylated EGF-URO receptor or calpactin-II as an index of receptor kinase activation, the relative potencies of the peptides, EGF-URO > TGF-α > TGF-α-(1–48), were also qualitatively in accord with the relative potencies measured in the LM and ligand binding assays (but not in the CM preparation); however, quantitatively, the relative potency ratios (EC 50s) observed in the phosphorylation assay (1:2:3) were somewhat out of keeping with the relative values observed in the LM and ligand binding assays. All three peptides were full agonists in the phosphorylation assay. Our data point to the importance of the C-terminal dipeptide, Leu 49-Ala 50 of TGF-α in terms of the binding affinity and intrinsic activity of this polypeptide; and our work provides further evidence for the distinct nature of the EGF-URO/TGF-α receptor system present in the CM bioassay preparation. The biological/biochemical activity profiles documented for the three polypeptides can serve as a basis for the further evaluation of other synthetic and naturally occurring members of the EGF-URO/TGF-α family of polypeptides.

Insulin-like growth factor binding to the atypical insulin receptors of a human lymphoid-derived cell line (IM-9)

The cells of the IM-9 human lymphocyte-derived line contain a sub-population of insulin-binding sites whose immunological and hormone-binding characteristics closely resemble those of the atypical insulin-binding sites of human placenta. These binding sites, which have moderately high affinity for multiplication-stimulating activity [MSA, the rat homologue of insulin-like growth factor (IGF) II] and IGF-I, are identified on IM-9 cells by 125I-MSA binding. They account for approximately 30% of the total insulin-receptor population, and do not react with a monoclonal antibody to the type I IGF receptor (alpha IR-3). The relative concentrations of unlabelled insulin, MSA and IGF-I required to displace 50% of 125I-MSA from these binding sites (1:4.7:29 respectively) are maintained for cells, particulate membranes, Triton-solubilized membranes precipitated either by poly(ethylene glycol) or a polyclonal antibody (B-10) to the insulin receptor, and receptors purified by insulin affinity chromatography. Because the atypical insulin/MSA-binding sites outnumber the type I IGF receptors in IM-9 cells by approximately 10-fold, they also compete with the latter receptors for 125I-IGF-I binding. Thus 125I-IGF-I binding to IM-9 cells is inhibited by moderately low concentrations of insulin (relative potency ratios for insulin compared with IGF-I are approx. 1/14 to 1/4) and is partially displaced (65-80%) by alpha IR-3. When type I IGF receptors are blocked by alpha IR-3 or removed by B-10 immunoprecipitation or insulin affinity chromatography, the hormone-displacement patterns for 125I-IGF-I binding resemble those of the atypical insulin/MSA-binding sites.

Interleukin-1 induces analgesia in mice by a central action

The effect of interleukin-1 together with lipopolysaccharide, tumor necrosis factor and interferon on a pain-like response was investigated with the phenylquinone-induced writhing test in mice. Recombinant human interleukin-1α (rHu-IL-1α) inhibited writhing dose relatedly at doses of 0.25–5 μg/kg i.v., and its potency was about 1000 times that of morphine on a molar basis. Potent anti-writhing activity was also seen after an i.v. dose of recombinant human tumor necrosis factor (rHu-TNF) and mouse α-interferon (mIFNα). Lipopolysaccharide, unlike rHu-IL-1α, needed a lag time of about 1 h to develop its anti-writhing action. The relative potency ratios of intracisternal to i.v. and i.p. to i.v. administration of rHu-IL-1α were about 38 and 0.1, respectively. The activity of rHu-IL-1α and rHu-TNF, unlike mIFNα, was not naloxone-reversible. rHu-IL-1α did not produce an increase in writhes counts even if injected directly into the peritoneal cavity. These results suggest that rHu-IL-1α, as well as lipopolysaccharide, rHu-TNF and mIFNα, had potent anti-writhing activity when given i.v. and its action is due to a central mechanism but is not naloxone-reversible, and that rHu-IL-1α is not algesic under the experimental conditions used.

Characterization of a κ-agonist-like antinociceptive action of tifluadom

The novel benzodiazepine tifluadom was compared with a selection of proposed μ- and k-opiate agonists using a combined heat/ pressure nociceptive paradigm. Calculation of the relative potency ratios to the nociceptive stimuli revealed a distinction between μ-and k-agonists. The potency ratio yielded by tifluadom coincided with that displayed by the k-agonists and this finding is discussed in relation to morphine withdrawal and radioligand binding studies.