Pain and u-shaped dose responses: occurrence, mechanisms, and clinical implications

This article assesses pain within the context of the dose response. A substantial number of studies indicate that the dose response for pain-related endpoints is commonly biphasic, being independent of the type of biological model employed, endpoint measured, or agent tested. The quantitative features of the dose response are also remarkably consistent regardless of the receptor pathway that mediates the nociceptive response, indicating a likely downstream message convergence. These findings have important implications for drug discovery, development, and clinical evaluation.     

The effects of pyridostigmine bromide, permethrin, and DEET alone, or in combination, on fixed-ratio and fixed-interval behavior in male and female rats.

Concurrent exposure to pyridostigmine bromide (PB), permethrin (PERM) and/or N,N-diethyl-m-toluamide (DEET) may have contributed to the development of a syndrome that appears to have afflicted military personnel who served during the Gulf War. The present experiment sought to evaluate the behavioral effects of these compounds alone, or in various combinations, in male and female rats. Subjects were exposed to a multiple fixed-ratio (FR) 50, fixed-interval (FI) 2-min schedule of reinforcement. PB dose-dependently decreased FR and FI response rates. FR responding was disrupted by lower doses and there were no differences between the sexes. PERM vehicle administration decreased response rates maintained by both schedules of reinforcement; this was offset by an increase in response rate after the administration of the intermediate dose of PERM. The highest dose of PERM decreased both FR and FI response rates. FR rates in male rats were more disrupted than those in female rats. Only the highest dose of DEET decreased FR and FI response rates in male and female rats. FR rates were more disrupted in female rats than in male rats. Synergistic effects were only observed when FI response rates decreased in male rats upon exposure to half the low dose of PB with half the low dose of PERM or half the low dose of PB with half the low dose of DEET. The results of this experiment thus show that small doses of PB, PERM and DEET disrupt well-established, schedule-controlled behavior in male and female rats in a schedule- and gender-dependent manner; schedule-dependent and gender-dependent synergistic effects were also observed. The mechanism by which the compounds exert these behavioral effects remains to be determined.     

Safety,tolerability, pharmacokinetics,and time course of pharmacologic response of the active metabolite of roxifiban,XV459, a glycoprotein IIb/IIIa antagonist,following oral administration in healthy volunteers

Roxifiban is an esterprodrug that is hydrolyzed, after oral administration, to the active glycoprotein (GP) IIb/IIIa antagonist, XV459. The objectives of the study were to investigate the safety, tolerability, pharmacokinetics, and the time course of the pharmacologic response of XV459 in escalating doses of roxifiban and to assess the effect of age, loading dose of roxifiban, and aspirin pretreatment on XV459 pharmacokinetics, pharmacologic response, and safety profile in a five-part double-blind, placebo-controlled study. Healthy male volunteers (ages 18-46 years) received 7 (0.75-1.5 mg; n = 20) and 10 (0.75-1.0 mg; n = 8) multiple, oral, qd doses of roxifiban or placebo (n = 5). Healthy older male and female volunteers (ages 47-75 years) received roxifiban qd doses (0.5-0.75 mg; n = 8) or placebo (n = 3) for 7 days. Healthy male subjects (ages 18-46 years; n = 16) received a 1.5 or 1.0 mg loading dose either with or without pretreatment of 325 mg aspirin once daily for 3 days followed by single daily doses of 1.0 mg roxifiban for 6 days. Measurable plasma concentrations of XV459 appeared rapidly and were sustained throughout the dosing interval of 24 hours. The pharmacokinetics of XV459 were nonlinear. Systemic exposure of XV459 plateaued at the 1-mg dose level; plasma concentrations approached steady state in 4 to 6 days for doses greater than 1.0 mg. The time course of pharmacologic response as measured by the inhibition of platelet aggregation in response to an ex vivo 10 microM adenosine 5'-diphosphate (ADP) agonist correlated closely to the plasma concentration of XV459. Potent inhibition of ADP-induced platelet aggregation (IPA) persisted over the entire dosing interval. A clear dose response was achieved with roxifiban doses of 0.5 and 1.0 mg. For doses greater than 1.0 mg, a dose-proportional increase in IPA was not observed. Both the pharmacokinetics and pharmacologic response of XV459 exhibited low intraindividual variability (coefficient of variation [CV] < 15%) and higher interindividual variability (CV < 30%). Pretreatment with aspirin and/or a loading dose of 1.5 mg roxifiban had no significant effect on the pharmacokinetics and pharmacologic response of XV459. A dose-related increase in template bleeding time was observed at 1.25- and 1.5-mg doses of roxifiban, as compared to placebo. However, these bleeding time increases in the 1.25- and 1.5-mg dose groups were not significantly different from those at the lower dose groups. Overall, once-daily oral administration of roxifiban was fairly well tolerated and provided sustained systemic drug exposure and pharmacologic response over the entire administration interval.     

Synergistic effect on reduction in blood pressure with coadministration of the renin inhibitor, CP-80,794, and the angiotensin converting enzyme inhibitor, captopril.

The effects of coadministration of a renin inhibitor, CP-80,794, and an angiotensin converting enzyme inhibitor, captopril, on blood pressure of sodium-depleted guinea pigs was studied. Dose-response curves for CP-80,794 (0.3-3.0 mg/kg i.v.) and captopril (0.03-1.0 mg/kg i.v.) were obtained either alone or in the presence of a submaximal dose of the other inhibitor. The hypotensive response calculated for each compound individually was subtracted from the combined dose response. The results showed that statistically significant synergy with captopril and CP-80,794 occurred when the area rather than the peak drop or duration of change in blood pressure was measured. The degree of the synergy indicated that to achieve the same reduction in blood pressure, the dose of each drug, below the high end of its response range, could be decreased approximately sixfold when administered in combination. It was determined that the plasma pharmacokinetics of CP-80,794 were not altered during coadministration, as plasma concentrations of CP-80,794 were similar in the presence and absence of 0.1 mg/kg i.v. of captopril. These results indicate that by inhibiting sequential enzymes in the renin-angiotensin system, synergistic effects can be produced. The relative safety of each inhibitor could be improved by large reductions in dose when used concurrently.     

Standard and higher dose of olanzapine in patients with schizophrenia or schizoaffective disorder: a randomized, double-blind, fixed-dose study

The objective of this study was to assess the dose-response relationship of standard and higher doses of olanzapine in a randomized, double-blind, 8-week, fixed-dose study comparing olanzapine 10 (n = 199), 20 (n = 200), and 40 mg/d (n = 200) for patients with schizophrenia or schizoaffective disorder and suboptimal response to current treatment. Patients meeting criteria for antipsychotic treatment resistance were excluded. Dose-response relationship was assessed by linear regression analysis with log-transformed dose (independent variable) and Positive and Negative Syndrome Scale (PANSS) total score (dependent variable). There were no significant dose group differences in patients completing the study (overall, 67.8%). All dose groups showed statistically significant improvement in PANSS total scores from baseline to end point without significant dose-response relationship (P = 0.295). Post hoc analysis of response showed significant interaction between baseline PANSS and dose (P = 0.023), indicating better response at higher doses for patients with higher baseline PANSS. There was a significant dose response for mean change in weight (P = 0.003) with significant difference between the 10- and 40-mg-dose groups (P = 0.002; 1.9 [10 mg/d], 2.3 [20 mg/d], and 3.0 kg [40 mg/d]). There was a significant dose response for change in prolactin (P < 0.001) with a significant difference between each group (-10.5 [10 mg/d], -1.7 [20 mg/d], and 4.9 ng/mL [40 mg/d]; P < or = 0.018). Over 8 weeks, non-treatment-resistant patients with schizophrenia or schizoaffective disorder responded to all 3 doses of olanzapine, without a statistically significant dose-response relationship, suggesting that for many patients with schizophrenia or schizoaffective disorder, particularly those who are mildly or moderately ill, 10 mg/d should be the initial dose of choice.     

Different types of combination effects for the induction of micronuclei in mouse lymphoma cells by binary mixtures of the genotoxic agents MMS, MNU, and genistein.

Distinction between dose addition and response addition for the analysis of the toxicity of mixtures may allow differentiation of the components regarding similar versus independent mode of action. For nonlinear dose responses for the components, curves of dose addition and response addition differ and embrace an "envelope of additivity." Synergistic or antagonistic interaction may then be postulated only if the mixture effect is outside this surface. This situation was analyzed for the induction of micronuclei in L5178Y mouse lymphoma cells by the two methylating agents methyl methanesulfonate (MMS) and N-methyl-N-nitrosourea (MNU) and the topoisomerase-II inhibitor genistein (GEN). All three chemicals reproducibly generated sublinear (upward convex) dose-response relationships. For the analysis of mixture effects, these genotoxic agents were investigated in the three binary combinations. Statistical testing for dose addition along parallel exponential dose responses was performed by linear regression with interaction based on the logarithm of the number of cells that contain micronuclei. For MMS+MNU, the mixture effect was compatible with dose addition (i.e., significantly larger than calculated for the addition of net responses). For MMS+GEN, the measured effect was larger than for response addition but smaller than for dose addition. For MNU+GEN, the measured effect was below response addition, indicative of true antagonism. In the absence of knowledge on the sublinear dose-response relationships for the individual components, a synergistic effect of MMS on both MNU and GEN would have been postulated erroneously. The observed difference between MMS and MNU when combined with GEN would not have been predicted on the basis of a simplistic interpretation of DNA methylation as the mode of action and may be due to differences in the profile of DNA methylations and/or epigenetic effects. We conclude that knowledge of nonlinearities of the dose-response curves of individual components of a mixture can be crucial to analyze for synergism or antagonism and that an in-depth mechanistic knowledge is useful for a prediction of similarity or independence of action.     

Low‐ and standard‐dose peginterferon alfa‐2a for chronic hepatitis C,genotype 2 or 3: efficacy,tolerability, viral kinetics and cytokine response

Aliment Pharmacol Ther 31 , 1018–1027

Summary

Background Chronic infection with hepatitis C, genotype 2/3, responds better than other genotypes to peginterferon and ribavirin treatment. We hypothesized that a lower dose of peginterferon would be as effective, but less toxic than standard doses. Aim To test the hypothesis that a lower dose of peginterferon would be as effective as, but less toxic than, standard doses. Methods A total of 30 patients were treated with low‐dose peginterferon alfa‐2a (90 μg/week) and 27 patients with standard doses (180 μg/week) for 24 weeks in combination with 800 mg/day of ribavirin. Patients who failed treatment were offered 48 weeks of standard‐dose treatment. Viral and serum inducible protein 10 (IP‐10) levels were measured and early viral kinetic parameters were calculated. Results Sustained virological response was achieved in 68% of the low‐dose and 87% of the standard‐dose patients (per protocol, P = 0.79 for non‐inferiority). Re‐treatment was successful in all patients who tolerated full dose and duration. The standard‐dose group had greater first‐phase declines of viral levels and faster time to negativity. The second‐phase slope was not dose‐dependent. IP‐10 induction was significantly greater with the standard dose. Although fatigue and general feeling during treatment were worse for standard dose, haematological toxicity and depression did not differ between groups. Conclusion A lower dose of peginterferon is associated with some symptomatic benefit, but the response is not equivalent to standard dosing.     

Effects of the NMDA-antagonist,MK-801, on stress-induced alterations of dopamine dependent behavior

The effects of pretreatment with the non-competitive NMDA antagonist (+)MK-801 on the behavioral alterations induced by repeated restraint stress were investigated. Repeatedly stressed (restraint stress 2 h a day × 10 days) mice showed enhanced sensitivity to the inhibitory effects of a low dose of direct dopamine agonist, apomorphine (0.25 mg/kg), on climbing behavior. On the other hand, no changes were observed for the stimulatory effect of the high dose of apomorphine (3 mg/kg) on this behavioral response. Mice pretreated with MK-801 (0.15 mg/kg) before the stressful experience did not show altered response to the low dose of apomorphine (0.25 mg/kg). Finally, ten daily injections with 0.15 mg/kg MK-801 did not affect the behavioral response to the low dose of apomorphine, but enhanced the stimulatory effect of the high dose of the dopaminergic agonist on climbing behavior. Therefore, it is possible that the protective action of MK-801 against stress-induced behavioral alteration is due to changes in sensitivity of postsynaptic receptors.     

Pharmacokinetics of 852A, an imidazoquinoline Toll-like receptor 7-specific agonist, following intravenous, subcutaneous, and oral administrations in humans

852A is an imidazoquinoline Toll-like receptor 7 agonist undergoing evaluation for the systemic treatment of cancer. 852A was administered to 6 healthy subjects as 3 rising subcutaneous doses (0.5 to 1.0 to 2.0 mg), to 6 subjects as 3 oral doses (10.0 to 20.0 to 15.0 mg, the third dose being a de-escalation), and to 6 subjects as a 2.0-mg dose by the subcutaneous, intravenous, and oral routes in crossover fashion. The subcutaneous and intravenous doses were well tolerated. One subject withdrew following the 20.0-mg oral dose because of hypotension. The 2.0-mg subcutaneous dose had 80.5% +/- 12.8% (mean +/- SD) bioavailability and gave serum concentrations comparable to intravenous administration by 30 minutes. Linear kinetics and an interferon-alpha dose response were observed for the 3 subcutaneous doses. Serum concentrations following the 2.0-mg oral dose were always lower than those following the same intravenous dose, and the oral route had a bioavailability of 26.5% +/- 7.84%. Concentrations appeared to increase with oral dose; however, large variabilities in both the rate and extent of absorption were seen between individuals. Approximately 40% of an absorbed dose was excreted unchanged in the urine. Overall, the study suggests that subcutaneous administration may be an acceptable method to deliver 852A for systemic applications.     

Bradykinin B1 and B2 receptors, tumour necrosis factor alpha and inflammatory hyperalgesia

The effects of BK agonists and antagonists, and other hyperalgesic/antihyperalgesic drugs were measured (3 h after injection of hyperalgesic drugs) in a model of mechanical hyperalgesia (the end-point of which was indicated by a brief apnoea, the retraction of the head and forepaws, and muscular tremor). DALBK inhibited responses to carrageenin, bradykinin, DABK, and kallidin. Responses to kallidin and DABK were inhibited by indomethacin or atenolol and abolished by the combination of indomethacin + atenolol. DALBK or HOE 140, given 30 min before, but not 2 h after, carrageenin, BK, DABK and kallidin reduced hyperalgesic responses to these agents. A small dose of DABK+ a small dose of BK evoked a response similar to the response to a much larger dose of DABK or BK, given alone. Responses to BK were antagonized by HOE 140 whereas DALBK antagonized only responses to larger doses of BK. The combination of a small dose of DALBK with a small dose of HOE 140 abolished the response to BK. The hyperalgesic response to LPS (1 microg) was inhibited by DALBK or HOE 140 and abolished by DALBK + HOE 140. The hyperalgesic response to LPS (5 microg) was not antagonized by DALBK + HOE 140. These data suggest: (a) a predominant role for B2 receptors in mediating hyperalgesic responses to BK and to drugs that stimulate BK release, and (b) activation of the hyperalgesic cytokine cascade independently of both B1 and B2 receptors if the hyperalgesic stimulus is of sufficient magnitude.     

Chloroform: exposure estimation,hazard characterization,and exposure-response analysis

Chloroform has been assessed as a Priority Substance under the Canadian Environmental Protection Act. The general population in Canada is exposed to chloroform principally through inhalation of indoor air, particularly during showering, and through ingestion of tap water. Data on concentrations of chloroform in various media were sufficient to serve as the basis for development of deterministic and probabilistic estimates of exposure for the general population in Canada. On the basis of data acquired principally in studies in experimental animals, chloroform causes hepatic and renal tumors in mice and renal tumors in rats. The weight of evidence indicates that chloroform is likely carcinogenic only at concentrations that induce the obligatory precursor lesions of cytotoxicity and proliferative regenerative response. Since this cytotoxicity is primarily related to rates of formation of reactive, oxidative metabolites, dose response has been characterized in the context of rates of formation of reactive metabolites in the target tissue. Results presented here are from a "hybrid" physiologically based pharmacokinetic (PBPK) animal model that was revised to permit its extension to humans. The relevant measure of exposure response, namely, the mean rate of metabolism in humans associated with a 5% increase in tumor risk (TC05), was estimated on the basis of this PBPK model and compared with tissue dose measures resulting from 24-h multimedia exposure scenarios for Canadians based on midpoint and 95th percentiles for concentrations in outdoor air, indoor air, air in the shower compartment, air in the bathroom after showering, tap water, and food. Nonneoplastic effects observed most consistently at lowest concentrations or doses following repeated exposures of rats and mice to chloroform are cytotoxicity and regenerative proliferation. As for cancer, target organs are the liver and kidney. In addition, chloroform has induced nasal lesions in rats and mice exposed by both inhalation and ingestion at lowest concentrations or doses. The mean rate of metabolism associated with a 5% increase in fatty cysts estimated on the basis of the PBPK model was compared with tissue dose measures resulting from the scenarios already described, and lowest concentrations reported to induce cellular proliferation in the nasal cavities of rats and mice were compared directly with midpoint and 95th percentile estimates of concentrations of chloroform in indoor air in Canada. The degree of confidence in the underlying database and uncertainties in estimates of exposure and in characterization of hazard and dose response are delineated.     

Effect of acetylcholine on changes in contractility, heart rate and phosphorylase activity produced by isoprenaline, salbutamol and amino-phylline in the perfused guinea-pig heart.

1. Isolated perfused hearts of guinea-pigs were given graded doses of isoprenaline, salbutamol and aminophylline, both before and during acetylcholine infusion. 2. The three agonists produced increases in contractile force, heart rate and ventricular glycogen phosphorylase activity. 3. Acetylcholine, in the concentration used, had no effect on any of the measured variables but did antagonize the effects of the three agonists on contractility and phosphorylase activity. The positive chronotropic responses were unaltered by acetylcholine infusion. 4. The ratio of the dose required for a standard heart rate response to the dose producing a standard contractile force response was different for each agonist. 5. The selective antagonism of the contractile response to isoprenaline, salbutamol and aminophylline suggest that different mechanisms are involved in the initiation of positive inotropic and chronotropic responses.     

Biologically Based Analysis of Lung Cancer Incidence in a Large Canadian Occupational Cohort with Low-Dose Ionizing Radiation Exposure,and Comparison with Japanese Atomic Bomb Survivors

Lung cancer incidence is analyzed in a large Canadian National Dose Registry (CNDR) cohort with individual annual dosimetry for low-dose occupational exposure to gamma and tritium radiation using the two-stage clonal expansion model (TSCE) and extensions of the model with up to 10 initiation steps. Models with clonal expansion turned off provide very poor fits and are rejected. Characteristic and distinct temporal patterns of excess relative risk (ERR) are found for dose response affecting early, middle, or late stages of carcinogenesis, that is, initiation with one or more stages, clonal expansion, or malignant conversion. Both fixed lag and lag distributions are used to model time from first malignant cell to incidence. Background rates are adjusted for gender and birth cohort. Lacking individual smoking data, surrogate annual smoking doses based on U.S. annual per capita cigarette consumption appear to account for much of the birth cohort effect, leaving radiation dose response relatively unchanged. The mean cumulative exposure for males receiving nonzero cumulative doses of gamma and tritium radiation was 18.2 mSv. The males have a significant dose response with 33 out of a total of 322 lung cancer cases attributable to radiation. There were 78 incident lung cancer among females, (with mean cumulative exposure of 3.8 mSv among females with nonzero exposure). The dose response for females appears smaller than for males but does not differ significantly from zero or from the male dose response. Findings for males include significant dose-response relationships for promotion and malignant conversion, but not initiation, and a protraction effect (sometimes called an inverse-dose-rate effect, where risk increases with protraction of a given dose). The dose response predicted by our analysis appears consistent with the risk for lung cancer incidence in the Japanese atomic bomb survivors cohort, provided that proper adjustments are made for duration of exposure and differences in background rate parameters.     

Toxicity of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD)

In summary, the toxicity of TCDD has been comprehensively examined in multiple acute, subchronic, and chronic studies. Acute toxicity studies have shown marked species differences, with up to a 10,000-fold difference between the single oral LD50 dose for the guinea pig and hamster. TCDD is capable of causing an acnegenic response in man and a similar skin response in certain animals. It is also a potent inducer of microsomal enzymes in some but not all species. A dose-related suppression of cell-mediated immunity has been observed at higher dose levels in laboratory animals but not in humans manifesting TCDD-induced acnegenic response. TCDD causes a dose-related teratogenic response in mice, with the no-adverse-effect level of 0.1 micrograms TCDD/kg/day. In rats, TCDD causes embryo- and fetotoxicity above the no-adverse-effect level of 0.03-0.125 micrograms/kg/day. Dose-related reproductive effects have also been noted in monkeys at doses that elicit maternal toxicity, and additional long-term studies are presently underway. A multigeneration reproduction study as well as a lifetime chronic toxicity study have been completed with TCDD in rats; in both studies, the no-adverse-effect level was found to be 0.001 microgram TCDD/kg/day. Numerous mutagenic studies have been performed using in vitro plant and microbial test systems as well as in vivo tests in mammals and man. A mutagenic response was noted in a few of the vitro test systems, but there are no definitive in vivo correlates of TCDD mutagenicity in higher mammals or man. TCDD has been studied for carcinogenic potential in rats and mice. There is good correlation of the results, with a carcinogenic response noted in both species only after long-term ingestion of higher dose levels that induce toxicity. No carcinogenic response occurred at continuous dose levels of 0.001-0.0014 micrograms/kg/day in rats and 0.001-0.03 micrograms/kg/day in mice. Data presently available are more supportive of a nongenetic (?promotor) rather than a genetic mechanism of carcinogenesis. The most recent research, some of which is still underway, indicates that the biologic uptake and toxicity of TCDD may be significantly decreased if the TCDD is adsorbed onto carbon or soil particles. This information is helpful in hazard assessment of exposure to TCDD.     

Biologically based analysis of lung cancer incidence in a large Canadian occupational cohort with low-dose ionizing radiation exposure, and comparison with Japanese atomic bomb survivors

Lung cancer incidence is analyzed in a large Canadian National Dose Registry (CNDR) cohort with individual annual dosimetry for low-dose occupational exposure to gamma and tritium radiation using the two-stage clonal expansion model (TSCE) and extensions of the model with up to 10 initiation steps. Models with clonal expansion turned off provide very poor fits and are rejected. Characteristic and distinct temporal patterns of excess relative risk (ERR) are found for dose response affecting early, middle, or late stages of carcinogenesis, that is, initiation with one or more stages, clonal expansion, or malignant conversion. Both fixed lag and lag distributions are used to model time from first malignant cell to incidence. Background rates are adjusted for gender and birth cohort. Lacking individual smoking data, surrogate annual smoking doses based on U.S. annual per capita cigarette consumption appear to account for much of the birth cohort effect, leaving radiation dose response relatively unchanged. The mean cumulative exposure for males receiving nonzero cumulative doses of gamma and tritium radiation was 18.2 mSv. The males have a significant dose response with 33 out of a total of 322 lung cancer cases attributable to radiation. There were 78 incident lung cancer among females, (with mean cumulative exposure of 3.8 mSv among females with nonzero exposure). The dose response for females appears smaller than for males but does not differ significantly from zero or from the male dose response. Findings for males include significant dose-response relationships for promotion and malignant conversion, but not initiation, and a protraction effect (sometimes called an inverse-dose-rate effect, where risk increases with protraction of a given dose). The dose response predicted by our analysis appears consistent with the risk for lung cancer incidence in the Japanese atomic bomb survivors cohort, provided that proper adjustments are made for duration of exposure and differences in background rate parameters.     

Response rates,duration of response,and dose response effects in phase I studies of antineoplastics

Summary Over a period of 14 years, 7,960 patients were treated in 228 phase I trials. In these patients, there were 75 complete and 432 partial responses for an overall objective response rate of 6%. Complete responses lasted a median of six months (range 1–18), while partial responses lasted a median of three months (range 1–17). Of note is that no drug has made it to the market which has not had a response in phase I trials. Responses were noted in very diverse histologic types of tumors. Although there were responses at doses which were as low as 3–5% of the recommended dose for phase II trials, the majority of responses did occur at 80–120% of the dose recommended for phase II trials. Although the response rate in phase I trials is indeed low, responses do occur. This response rate information should help the clinician provide facts for the patient considering a phase I trial with new anticancer agents. These findings also emphasize that although phase I trials are characteristically dose-finding studies, if no responses are noted in phase I studies, it is unlikely the drug will be used routinely in the clinic.     

The interaction of morphine and meperidine with the analgesic, convulsant, and lethal properties of lidocaine in mice.

Because of increased intravenous use of lidocaine in medicine, a study was undertaken to evaluate the interaction of the commonly used narcotics, morphine and meperidine, with the analgesic, convulsant, and lethal properties of lidocaine in male Swiss-Webster mice. An analgesic response (Eddy hot plate test) was defined as a reaction time that was at least twice the control time. Equipotent doses of morphine and meperidine were determined by measuring the analgesic response 30 min after ip administration. The dose that produced analgesia in 25% of the mice (AD25) for morphine was 3.9 mg/kg and for meperidine was 24 mg/kg. Thereafter the mice were evaluated with three drug combinations: lidocaine and saline, lidocaine p;us the AD25 of morphine, and lidocaine plus the AD25 of meperidine. The morphine-lidocaine and meperidine-lidocaine combinations were equally effective in increasing the analgesic properties of lidocaine. However, only the meperidine-lidocaine drug combination significantly decreased the median convulsive dose (CD50) and the median lethal dose (LD50) of lidocaine alone. By comparing the ratios of the CD50/AD50 and the LD50/AD50 for the morphine-lidocaine and meperidine-lidocaine drug combinations, it can be concluded that the meperidine-lidocaine interaction, because of its increased toxicity, is a less favourable combination.     

Effects of caffeine, cocaine and their combination on fixed-interval behavior in rats

The effects of the central nervous system stimulants, caffeine and cocaine, on schedule-controlled behavior were determined in rats trained to perform a fixed-interval (FI) 5-minute task. When given alone caffeine produced a doubling of FI response rate at a dose of 10 mg/kg and reduced responding at a dose of 32 mg/kg. Cocaine, which was also expected to increase FI responding, did not increase response rate at doses of 3.2 or 10 mg/kg and decreased the rate of responding at a dose of 32 mg/kg. Caffeine had minimal effects on quarter life and appeared to increase local rates of responding across the interval. Cocaine decreased quarter life dramatically at a dose that had no effect on overall response rate. Local rates of responding were increased early in the interval and decreased in the later segments. The effects of both drugs were found to be rate-dependent. When these compounds were given in combination the results obtained appeared to be related to the rate of responding that caffeine alone would produce.     

A meta-analysis of evidence for hormesis in animal radiation carcinogenesis, including a discussion of potential pitfalls in statistical analyses to detect hormesis

A database containing 800 datasets on the incidence of specific tumor types from 262 radiation carcinogenicity experiments identified in a comprehensive literature search through September 2000 was analyzed for evidence of hormesis. This database includes lifetime studies of tumorigenic responses in mice, rats, and dogs to exposures to alpha, beta, gamma, neutron, or x-ray radiation. A J-shaped dose response, in the form of a significant decreased response at some low dose followed by a significant increased response at a higher dose, was found in only four datasets from three experiments. Three of these datasets involved the same control animals and two also shared dosed animals; the J shape in the fourth dataset appeared to be the result of an outlier within an otherwise monotonic dose response. A meta-analysis was conducted to determine whether there was an excess of dose groups with decreases in tumor response below that in controls at doses below no-observed-effect levels (NOELs) in individual datasets. Because the probability of a decreased response is generally not equal to the probability of an increased response even in the null case, the meta-analysis focused on comparing the number of statistically significant diminished responses to the number expected, assuming no dose effect below the NOEL. Only 54 dose groups out of the total of 2579 in the database had doses below the dataset-specific NOEL and that satisfied an a priori criterion for sufficient power to detect a reduced response. Among these 54, a liberal criterion for defining a significant decreases identified 15 such decreases, versus 54 × 0.2 = 10.8 expected. The excess in significant reductions was accounted for almost entirely by the excess from neutron experiments (10 observed, 6.2 expected). Nine of these 10 dose groups involved only 2 distinct control groups, and 2 pairs from the 10 even shared dosed animals. Given this high degree of overlap, this small excess did not appear remarkable, although the overlap prevented a formal statistical analysis. A comprehensive post hoc evaluation using a range of NOEL definitions and alternative ways of restricting the data entering the analysis did not produce materially different results. A second meta-analysis found that, in every possible low dose range ([0, d] for every dose, d) of each of the radiation types, the number of dose groups with significantly increased tumorigenic responses was either close to or exceeded the number showing significantly reduced responses. This meta-analysis was considered to be the more definitive one. Not only did it take dose into account by looking for consistent evidence of hormesis throughout defined low-dose ranges, it was also potentially less susceptible to limitations in experimental protocols that would cause individual animals to respond in a non-independent fashion. Overall, this study found little evidence in a comprehensive animal radiation database to support the hormesis hypothesis. However, the ability of the database to detect a hormetic effect was limited both by the small number of dose groups with doses below the range where positive effects have been found in epidemiological studies (≤ 0.1 Gy) and by the limited power of many of these dose groups for detecting a decrease in response.