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Biomedical subjects

Anthony W Fox

Publications and source records attributed to Anthony W Fox.

18 recordsLinked to original sources
PubMed2006

Cusums to measure chronic daily headache.

OBJECTIVE: To investigate whether cumulated summed differences (cusums) can be used as a method for detecting effective interventions in chronic daily headache (CDH). If so, then can such interventions be detected sooner than 28 days? BACKGROUND: CDH probably represents the greatest current challenge in the field of headache treatment. Clinical trial methodologies for its study are not standardized but usually use fixed 28-day observation periods. Similarly, 28-day observation periods are common review intervals for stepped-care patient management strategies. METHODS: A theoretical patient was modeled, with daily headache scores that had maximal variation for 28 consecutive daily measures. The cusums for this "norm" or control data set were plotted and correlated with time using a simple spreadsheet. Departure of a postintervention cusum from the 95% confidence interval of the control data set was chosen as an indicator of sensitivity to various model perturbations that had clinical correlates. RESULTS: When 1 to 17 randomly distributed headache-free days were used to perturb the 28-day model, cusums consistently diverged from the norm. If at least 3 headache-free days occurred, then the cusum detected the intervention in less than 28 days of observation. Reanalysis of a previously published study of magnesium oxide suggests that its negative conclusions should be reconsidered. CONCLUSION: Cusums can be useful tools for detecting change in CDH, whether at the level of the clinical trial or when managing patients using stepped-care treatment algorithms.

Clinical Trials as Topic↗
PubMed2005

Resolution of concentration-response differences in onset of effect between subcutaneous and oral sumatriptan.

OBJECTIVE: To investigate whether the concentration-response relationships for onset of effect of oral and subcutaneous (s.c.) sumatriptan differ, and if so, then to explore whether a single model for the onset of effect can nonetheless be found for multiple dose sizes and both routes of administration. METHODS: Active and placebo response rates and mean plasma concentrations were collected from the literature for 0 < or =t < or = 2 hours. Plasma concentration-response relationships were plotted. Logarithmic models for the onset of effect (ie, active response rates), characterized by convexity factor A and location parameter B were constructed from the same data. RESULTS: The concentration-response relationships for s.c. and oral sumatriptan are qualitatively different. A single logarithmic model for the onset of effect provides good estimates of observed response rates during the first 2 hours post-dose for multiple dose sizes after both oral and s.c. routes of administration. The precision of this model resides in both its variables. Location parameters for this model differ for similar absolute doses by the two routes of administration. However, curve convexity (representing rate of onset of effect) is related to absolute dose (and hence plasma concentration) in the same way for sumatriptan tablets and injections. CONCLUSIONS: No simple plasma concentration-response relationship exists that is sufficiently robust to apply to both s.c. and oral sumatriptan. There are separate pharmacokinetic-pharmacodynamic relationships for rate of onset and extent of effect. The design of exploratory clinical trials for new acute therapies for migraine may be more efficient when these factors are considered, and these factors may help to describe the gap between experimental and ordinary clinical environments.

Administration, Oral↗
PubMed2005

Migraine during pregnancy: options for therapy.

Migraine is common during pregnancy, but fortunately this combination of conditions obviously exists for only a finite period. The greatest frequency of migraine attacks occurs during the first trimester. Accurate diagnosis is a sine qua non in this setting as in any headache patient. It is in the first trimester that the fetus is at greatest risk from abortifacient and teratogenic drugs, and when very early pregnancy may be undiagnosed. Ergot alkaloids (including methysergide) should be avoided during pregnancy because of their teratogenicity, and most other drug classes should be used only when unavoidable. The use of prophylactic agents during pregnancy should be the exception, not the rule, and preferably only during the second and third trimesters; propranolol is probably safest in this situation. De novo headache during pregnancy usually requires expert review of the patient. Treatment tactics for uncomplicated migraine in pregnancy depend on the concurrent clinical situation. Paracetamol (acetaminophen) is the mainstay for the patient whose typical attacks continue into the first trimester. If paracetamol is insufficient, then partial agonist opioids may be used if typical migraine attacks persist in the second and third trimesters (which is uncommon). 'Chronic migraine' in pregnancy, i.e. >or=15 headache days per month, is rare, and is the greatest therapeutic challenge. Co-morbidities such as depression or epilepsy require specialised approaches. The complexities associated with these tactics are discussed in this article, and it is emphasised that none has the specific approval of regulatory authorities. Heightened pharmacovigilance will better inform the future pregnant migraineur. However, this type of information is less likely to be available for novel classes of neuropharmacological agents than for existing ones.

Analgesics↗
PubMed2004

Consequences of transforming measures of efficacy for acute therapies: 5-HT agonists as a worked example.

OBJECTIVES: To examine whether the distributions of active and placebo response rates change after transformation into therapeutic gains, numbers needed to treat, and therapeutic ratios for 51 published clinical trials of 5-HT(1B/1D) agonists in the acute treatment of migraine. BACKGROUND: Acute migraine therapies have been compared using meta-analysis. Before pooling the results of noncontemporaneous clinical trials for meta-analysis, reconciliation of active response rates with concurrent placebo controls is done because of fluctuations in placebo response rates. The 3 common methods of reconciliation are to find for each clinical trial the therapeutic gain, the number needed to treat, or the therapeutic ratio. METHODS: Raw active and placebo response rates were tabulated and displayed as histograms. The distributions of the therapeutic gains, numbers needed to treat, and therapeutic ratios were similarly plotted. These distributions were then compared with normal distributions using chi-squared goodness-of-fit methodology. RESULTS: The distribution of active response rates was consistent with a normal distribution (passing a goodness-of-fit test). Placebo response rates were not normally distributed. The distribution of therapeutic gains failed a test of normality (P=.018), as did the numbers needed to treat (P <.001); the skews of these distributions were toward opposite ends of the scale for relative efficacy. The therapeutic ratios also failed a test for normality, but passed a test for log-normal distribution. CONCLUSIONS: Choice of transformation is a potential source of bias in meta-analysis of acute migraine therapies.

Acute Disease↗
PubMed2004

Onset of effect of 5-HT1B/1D agonists: a model with pharmacokinetic validation.

OBJECTIVE: To quantitate onset of effect of all formulations of sumatriptan, and to investigate whether this is related to rate, not extent, of drug absorption. METHODS: From published literature, for 4 formulations of sumatriptan and matching placebos, response rates were modeled using a simple logarithmic equation, with a being a parameter of curve convexity and B, a location parameter (equal to response rate at 2 hours [the standard regulatory parameter]). The average rate of drug absorption (A) was estimated by dividing the maximal drug concentration by the time needed to achieve it (Cmax/Tmax). Least mean square correlation was then performed between the therapeutic gains and therapeutic ratios of curve convexity and rate of drug absorption. RESULTS: -Models closely fitted observed response rates (2 hours or less). Curve convexity correlated with rate of drug absorption. Sumatriptan response rates (0 to 2 hours) for formulations correlated with rate, not extent, of drug absorption. The range of rates of onset of effect among different routes of administration was greater than that for tablets with 4-fold differences in dose size. CONCLUSION: Onset of effect is related to rate of absorption of sumatriptan. There is greater scope for improving onset of effect using an alternative route of administration than by increasing the oral dose.

Dose-Response Relationship, Drug↗
PubMed2004

Myocardial protection using fructose-1,6-diphosphate during coronary artery bypass graft surgery: a randomized, placebo-controlled clinical trial.

UNLABELLED: In vitro and in vivo studies suggest that fructose-1,6-diphosphate (FDP), an intermediary glycolytic pathway metabolite, ameliorates ischemic tissue injury through increased high-energy phosphate levels and may therefore have cardioprotective properties in patients undergoing coronary artery bypass graft (CABG) surgery. We designed a randomized, placebo-controlled, double-blinded, sequential-cohort, dose-ranging safety study to test 5 FDP dosage regimens in patients (n = 120; 60 FDP, 60 control) undergoing CABG surgery. Of these dosage regimens, 3 produced no benefit, 1 produced improved cardiac function, and 1 required adjustment as a result of metabolic acidosis. This suggests that we achieved the intended effect of a dose-ranging study. The expected response was observed in patients treated with 250 mg/kg FDP IV before surgery and 2.5 mM FDP as a cardioplegic additive (n = 15). These patients had lower serum creatine kinase-MB levels 2, 4, and 6 h after reperfusion (P < 0.05), fewer perioperative myocardial infarctions (P < 0.05), and improved postoperative cardiac function, as evidenced by higher left ventricular stroke work index (LVSWI) 6, 12, and 16 h (P < 0.01) and cardiac index (CI) at 12 and 16 h (P < 0.05) after reperfusion. Overall efficacy of FDP was tested across all regimens that included IV FDP (n = 88; 44 FDP, 44 control) using 2 (FDP versus placebo) x 3 (dose size) factorial analyses. Area-under-curve (AUC) analysis demonstrated a significant increase in CI (AUC-16h, P = 0.013) and LVSWI (AUC-16h, P = 0.003) and reduction in CK-MB levels (AUC-16h, P < 0.05) in FDP-treated patients. The internal consistency of this dataset suggests that FDP may provide myocardial protection in CABG surgery and supports previous laboratory and clinical studies of FDP in ischemic heart disease. IMPLICATIONS: Fructose-1,6-diphosphate (FDP) may increase high-energy phosphate levels under anaerobic conditions and therefore ameliorate ischemic injury. A dose-ranging safety study for FDP was conducted in patients undergoing coronary artery surgery. Preischemic provision of FDP significantly improved cardiac function and reduced perioperative ischemic injury. These myocardial protective effects may improve patient outcome after cardiac surgery.

Aged↗
PubMed2002

Evidence-based assessment of pregnancy outcome after sumatriptan exposure.

OBJECTIVE: Assessment of best available evidence for tolerability of sumatriptan after inadvertent exposure during pregnancy. BACKGROUND: Migraine's demography suggests that inadvertent exposure to acute therapies is likely during the earliest undiagnosed stages of pregnancy. The tolerability of such therapies under these conditions is not amenable to clinical trial for ethical reasons. In the United States, sumatriptan is currently labeled pregnancy category C (ie, not recommended for use during pregnancy unless the potential benefit justifies the potential risk to the fetus). METHODS: Three types of adverse events were studied: spontaneous abortion, fetal abnormality, and obstetric complications. Traditional evidence-based criteria were used to assess a search-protocol product of four clinical studies and two case reports. RESULTS: The single positive finding ("preterm delivery" without low birth weight) was in the smallest study; this study was retrospective and the finding was externally inconsistent with the other three larger studies, all of which were prospective. No study followed children for more than 4 years, which is the period needed to identify the maximum number of congenital anomalies. Rigorous teratological technique was generally not employed. Post hoc power calculations were used to provide parameters of the hazard detectable by these studies in aggregate. CONCLUSIONS: Pregnancy categories B and C both seem feasible for sumatriptan. Within the limits of the examined studies, there is no evidence for any specific effect of sumatriptan on pregnancy outcome. Patients inadvertently exposed to sumatriptan during an early stage of pregnancy should be reassured by these data.

Abnormalities, Drug-Induced↗
PubMed2002

Migraine therapy:seamlessness between plant-derived and synthetic drugs.

Migraine has been endemic for many centuries. Seamlessness between plant-derived and synthetic migraine therapies is evident in three major aspects: (A) The latter are molecular adaptations of the former, (B) Combinations of herbal and non-herbal migraine therapies (e.g., one for prophylaxis and the other for acute therapy) are used by many patients, and (C) All migraine treatments, whether plant-derived or not, are capable of clinical trial using the same endpoints. At least two, newly discovered plant-derived migraine therapies are currently under research using standard clinical trial methodology. Suggestions are provided for more flexible clinical trial designs that might particularly suit research into herbal remedies. The future of migraine therapy is likely to continue to exhibit an intimate, symbiotic relationship between plant-derived and synthetic drugs.

Journal Article↗
PubMedDate not supplied

Comparison of therapeutic gain with therapeutic ratio for the assessment of selective 5HT(1B/1D) agonist efficacy in migraine.

OBJECTIVE: Comparison of use of therapeutic gain (TG) and therapeutic ratio (TR) for relative assessments of selective 5HT(1B/1D) agonist efficacy in the acute treatment of migraine. BACKGROUND: Comparison of selective 5HT(1B/1D) agonist efficacy in the acute treatment of migraine is complicated by the impracticality of conducting high-quality head-to-head active comparator trials for all permutations of drug, dose, and route of administration; the clinical trials that are available are usually noncontemporaneous, and have fluctuating active and placebo response rates (ARR and PRR, respectively) for the necessarily subjective endpoints. The standard primary endpoint is conversion of headache score 2 (moderate pain) or score 3 (severe pain) into score 0 (no pain) or score 1 (mild pain) at a single timepoint (usually 2 or 4 hours postdose). Two principal methods have been used for comparison of ARR between studies: TG = ARR - PRR and TR = ARR/PRR. Secondary endpoints can be treated in the same way, although the 24-hour remedication rate is the only secondary endpoint that is subject to regulatory authority standardization. Does either TG or TR have an advantage over the other? METHODS: Efficacy data were collected from published sources and included pain score conversion at 2- and 4-hour, as well as 24-hour remedication rates. TG and TR were calculated for each endpoint, as shown above. The ranges of these variables were found from all observed measures. Correlations between TG and TR were found using least squares methods. The 95% confidence intervals (CI) for TG and TR were then found for all clinical trials, and for the whole range of observed PRR. RESULTS: Values for TR and TG generally were well correlated for pain score conversion at 2 hours postdose (n = 51 clinical trials). Deviations from this correlation were greatest for drugs that were evidently very efficacious. When standardized for the observed ranges of PRR and ARR, the 95% CI for TR were narrower than for TG. A subset of these studies also reported 4-hour data (n = 23 clinical trials), but the correlation between TR and TG was again good, with narrower 95% CI for TR than TG. For the 24-hour remedication data (n = 18 trials), PRR was less variable; TR and TG again correlated well, but there was little difference in their relative 95% CI. CONCLUSIONS: For comparison of drugs in noncontemporaneous studies, when PRR fluctuates, relative ranges for TR are narrower than for TG. For assessing single clinical trial results (ie, point estimates of efficacy) TR will generally be relatively nearer to its mean than TG. For both these reasons, TR is a more robust statistic than TG.

Acute Disease↗
PubMedDate not supplied

Time-series data and the "migraine generator".

OBJECTIVE: To examine circadian and menstrual patterns of migraine frequency in order to identify properties of the putative migraine generator. METHODS: Analysis of circadian and menstrual migraine attack frequency distributions, using between-interval differences as estimates, at each time point, of the derivative of the equation that would, theoretically, model the observed oscillating functions. RESULTS: Circadian and menstrual analyses exhibit many similarities that are consistent with a single migraine generator in the final common pathway for expression of the phenotype. These analyses are inconsistent with a role for cortisol or ACTH to be activators of the putative migraine generator, could be consistent with visual stimulation as a deactivator of the generator, and may also be consistent with a low threshold concentration of estradiol and/or progestagens as inactivators of the migraine generator. CONCLUSIONS: Analysis of time-series data using differentials uncovers some previously unidentified chronobiological properties of migraine, helps select amongst various candidate provocative factors, and suggests some properties of a putative migraine generator.

Adult↗