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Pharmacodynamic equivalence study of CFC-free and CFC-containing procaterol hydrochloride metered-dose inhalers.

Equivalence between a CFC-free procaterol hydrochloride metered-dose inhaler using HFA-227 as a propellant (Meptin [HFA]) and a CFC-containing procaterol hydrochloride metered-dose inhaler (Meptin [CFC]) was assessed in 28 patients with bronchial asthma. The study was conducted in a randomized, double-dummy, double-blind crossover manner, using forced expiratory volume in the first second (FEV1) as an index of bronchodilatory effect. In Period I, the patients received 20 microg of either Meptin [HFA] or Meptin [CFC] and then crossed over in Period II after a washout interval of 3-28 days. Pharmacodynamic equivalence was assessed using AUC (FEV1)/h and peak FEV1 as indices, and the data was analyzed by analysis of variance. Factors used for the analysis were the treatment group and/or carryover effect, patients within each group, period, and treatment. The 90% confidence intervals for the differences between the two treatments were -0.0507 to 0.0039 (L) for mean AUC (FEV1)/h and -0.056 to 0.026 (L) for mean peak FEV1, both within the acceptance criteria of -0.15 to 0.15 (L). Meptin [HFA] was therefore assessed as being equivalent to the current Meptin [CFC].

Administration, Inhalation↗

Assessment of the welfare of food restricted male broiler breeder poultry with musculoskeletal disease.

The general and sexual activity of food restricted male broiler breeder poultry was assessed for evidence of behavioural changes associated with musculoskeletal lesions. The activity and fertility of male birds given betamethasone (an anti-inflammatory steroid) or saline were compared in a two-period crossover experiment. Behavioural changes occurred and the birds' mating activity and fertility were decreased when they were given the steroid, but these effects were not associated with the presence of lesions. In a second experiment, there were no differences in sexual motivation between birds either with or without leg disorders. The birds were trained to walk down an alley for their food and the speed of walking was compared in a two-period crossover experiment. Betamethasone decreased their walking speed in period one and the carryover effect was significant in period two. Naloxone decreased the walking speed of birds with lesions more than of those without lesions. This effect was taken as evidence for analgesia by endogenous opioids and may help to explain the lack of response of the birds to the analgesic agent. The evidence that these food restricted male broiler breeder birds experienced pain was equivocal.

Animals↗

Pharmacodynamic study of procaterol hydrochloride dry powder inhaler: evaluation of pharmacodynamic equivalence between procaterol hydrochloride dry powder inhaler and procaterol hydrochloride metered-dose inhaler in asthma patients in a randomized, double-dummy, double-blind crossover manner.

Therapeutic equivalence between procaterol hydrochloride dry powder inhaler (Meptin DPI) and procaterol hydrochloride metered-dose inhaler (Meptin MDI), the currently marketed formulation, was assessed in 16 patients with bronchial asthma. The study was conducted in a randomized, double-dummy, double-blind crossover manner, using forced expiratory volume in the first second (FEV1) as an index of bronchodilatory effect. In Period I, the patients received 20 mcg of either Meptin DPI or Meptin MDI, and then crossed over in Period II after a washout interval of 3--28 days. Pharmacodynamic equivalence was accessed using AUC (FEV1)/h and peak FEV1 as indices, and the data were analyzed by analysis of variance (ANOVA). Factors used for the analysis were the treatment group and/or carryover effect, patients within each group, period, and treatment. The 90% confidence intervals for the differences between the two treatments were --0.0995 to --0.0204 (L) for mean AUC (FEV1)/h and --0.102 to --0.022 (L) for mean peak FEV1, both within the acceptance criteria of --0.15 to 0.15 (L). Meptin DPI was therefore assessed as being equivalent to the current Meptin MDI.

Adrenergic beta-Agonists↗

Underestimation of treatment effect in crossover trials.

In crossover trials each subject serves as his own control. For the study of cardiovascular diseases such as hypertension and angina pectoria, properly designed crossover studies are preferred to parallel studies. There is a considerable between-subject variability of symptoms in some of these conditions. Bias due to this is eliminated by the use of a crossover design. However, a problem is the so-called treatment-by-period interaction. The present study analyzes the potential influences of this on the outcome of the trial. Physical carryover effect, defined as a physical effect of the first treatment period carrying on into the second, tends to minimize differences between two consecutive treatment periods. So does the frustrating experience of an inactive agent in the first treatment period. Outside influences such as the change of the seasons may affect lengthy crossover trials in a similar way. The author concludes that the treatment effect in a crossover trial tends to be underestimated. The current concept that reports of clinical trials are generally biased toward an exaggeration of treatment effects does not seem to apply to crossover trials.

Bias↗

Erosive effect of a new sports drink on dental enamel during exercise.

PURPOSE: To compare the potential erosive effect of a prototype carbohydrate-electrolyte drink (PCE) with a neutral control (water) and a commercially available carbohydrate-electrolyte drink (CCE) during exercise. METHODS: : Nineteen healthy adults (male, N = 16; female, N = 3) took part in this single blind, three-way crossover study. Subjects were given each of the three drinks according to a randomization schedule, approximately balanced for first-order carryover effects. At the beginning of each of the three study periods, the volunteers were fitted with an intraoral appliance containing two human enamel blocks. During each study period, volunteers exercised for 75 min.d(-1) (5 repetitions of 15 min of exercise, with 5-min rests between exercise repetitions), 5 d.wk(-1) for 3 wk. Each day, drink aliquots of 200 mL were consumed during a 5-min period before exercise and after every 15-min bout of exercise, followed by a final 400-mL aliquot ingested over a 10-min period: a total of 1400 mL per study day. Dental erosion was measured as tissue loss from the enamel blocks by profilometry at the end of each study period. RESULTS: Water, PCE, and CCE produced 0.138 microm (SD 0.090 microm), 0.138 microm (SD 0.038 microm), and 4.238 microm (SD 3.872 microm) of enamel loss, respectively. A Wilcoxon t statistic showed a significant statistical difference between the PCE and CCE drinks (P < 0.001), whereas no significant difference could be detected between the PCE drink and water (P = 0.740). CONCLUSION: The PCE solution showed minimal erosion compared with the commercially available drink, and was statistically indistinguishable from water under the conditions of this study. Use of CE solutions formulated to minimize erosion during exercise may provide significant dental benefits.

Adult↗

Alternating treatments design: one strategy for comparing the effects of two treatments in a single subject.

A little used and often confused design, capable of comparing two treatments within a single subject, has been termed, variously, a multielement baseline design, a multiple schedule design, and a randomization design. The background of these terms is reviewed, and a new, more descriptive term, Alternating Treatments Design, is proposed. Critical differences between this design and a Simultaneous Treatment Design are outlined, and experimental questions answerable by each design are noted. Potential problems with multiple treatment interference in this procedure are divided into sequential confounding, carryover effects, and alternation effects and the importance of these issues vis-a-vis other single-case experimental designs is considered. Methods of minimizing multiple treatment interference as well as methods of studying these effects are outlined. Finally, appropriate uses of Alternating Treatments Designs are described and discussed in the context of recent examples.

Behavior Therapy↗

Acupuncture has no immediate treatment effect on the neutrophil respiratory burst: a randomized single-blinded two-period crossover study.

Little is known about the influence of acupuncture treatment on the immune system. The respiratory burst (RB) of polymorphonuclear leukocytes (PMN) is a recognized measure of their cytotoxicity, an important component of the immune system. The present trial was therefore performed to examine whether a single-acupuncture treatment has an immediate effect on the RB of neutrophil PMNs. Sixteen volunteers were enrolled in the study. After randomization, eight volunteers were treated bilaterally with standard needles at acupoint LI11 and eight volunteers with placebo needles at the same acupoint, each for 30 min. The RB was determined before and 30 min after treatment. After two weeks, each group received the alternative treatment. There was a drop-out of two volunteers. No period or carryover effects were found in the remaining fourteen volunteers. No effect of acupuncture on the neutrophil RB was observed.

Acupuncture↗

The effect of an ibuprofen-codeine combination for the treatment of patients with pain after removal of lower third molars.

A double-blind randomized crossover analgesic trial was carried out on 70 patients undergoing surgical removal of one lower third molar at each visit. The analgesic efficacy of a two-dose regimen of the combination ibuprofen-codeine, 400 to 60 mg, was compared with ibuprofen, 400 mg. Each of the two doses was taken when the patient needed pain relief and the pain intensity was measured on a visual analog scale during the 10-hour period after the first medication. Because of carryover effects between periods 1 and 2, the analysis was carried out only for period 1 according to a parallel group design. Of the 60 patients who were evaluated for analgesic effect, the mean pain reduction of dose 1 was 63% for the 29 patients given ibuprofen-codeine and 50% for the 31 patients given ibuprofen; the mean duration of effect was 7.5 and 6.3 hours, respectively. The difference in pain reduction index (pain reduction X duration of effect) between the two treatments was significant in favor of the combination, whereas the separate variables of pain reduction and duration of effect were not significantly different. The mean pain reduction was 67% after doses 1 and 2 for patients on ibuprofen-codeine and 52% for those on ibuprofen; the mean duration of effect was 9.4 and 9.2 hours, respectively. For doses 1 and 2, the difference in pain reduction index per dose between the two treatments was significant but not the difference for the separate variables, pain reduction, and duration of effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

Randomized, double-blind, cross-over trial comparing safety and efficacy of oral controlled-release oxycodone with controlled-release morphine in patients with cancer pain.

PURPOSE: Use of oxycodone for chronic cancer pain has been hampered by its short elimination half-life. This study was designed to compare the efficacy and safety of controlled-release formulations of oxycodone and morphine for cancer pain. PATIENTS AND METHODS: Thirty-two adult patients with cancer pain and a > or = 3-day history of stable analgesia with oral opioids provided written informed consent and were randomized to controlled-release oxycodone or controlled-release morphine for 7 days. To blind the study using available tablet strengths, the dose ratio of oxycodone to morphine was set at 1:1.5. On day 8, patients were crossed over to the alternate drug for 7 days. Pain intensity was assessed using a visual analog scale (VAS 0 to 100 mm) and a categorical scale (CAT 0 to 4). Side effects were assessed using a checklist (four-point categorical severity) and a nondirected questionnaire. Patients and investigators made blinded global ratings of efficacy and treatment preference. RESULTS: Twenty-three patients completed the study (10 men, 13 women). The VAS and CAT scores were (mean+/-SD) 23+/-21 and 1.2+/-0.8 on controlled-release oxycodone, and 24+/-20 (P=.43) and 1.3+/-0.7 (P=.36) on controlled-release morphine. No period or carryover effect was detected. There were no significant differences in adverse effects (P=.40) or ratings of efficacy and preference. The median oxycodone/morphine dose ratio was 1.5 and the maximum was 2.3. CONCLUSION: Controlled-release oxycodone is as safe and effective as controlled-release morphine in the treatment of cancer pain.

Administration, Oral↗

Dynamic vs. static-stretching warm up: the effect on power and agility performance.

The purpose of this study was to compare the effect of a dynamic warm up (DWU) with a static-stretching warm up (SWU) on selected measures of power and agility. Thirty cadets at the United States Military Academy completed the study (14 women and 16 men, ages 18-24 years). On 3 consecutive days, subjects performed 1 of the 2 warm up routines (DWU or SWU) or performed no warm up (NWU). The 3 warm up protocols lasted 10 minutes each and were counterbalanced to avoid carryover effects. After 1-2 minutes of recovery, subjects performed 3 tests of power or agility. The order of the performance tests (T-shuttle run, underhand medicine ball throw for distance, and 5-step jump) also was counterbalanced. Repeated measures analysis of variance revealed better performance scores after the DWU for all 3 performance tests (p < 0.01), relative to the SWU and NWU. There were no significant differences between the SWU and NWU for the medicine ball throw and the T-shuttle run, but the SWU was associated with better scores on the 5-step jump (p < 0.01). Because the results of this study indicate a relative performance enhancement with the DWU, the utility of warm up routines that use static stretching as a stand-alone activity should be reassessed.

Adolescent↗

Clinical evaluation of a quaternary ammonium-containing mouthrinse.

This was a double-blind, radomized, crossover study of adult subjects to evaluate the effect of a test mouthrinse (Cepacol) on plaque accumulation. The study was divided into two parts, four weeks each, one in which only a mouthwash was used (part I) and the other in which a mouthwash and toothbrushing were used (part II). 1. The test mouthrinse produced a satistically significant reduction in dental plaque when compared to a placebo rinse. 2. The GI averaged approximately 1.0 throughout the study regardless of which mouthrinse was used. 3. A possible carryover effect of the test mouthrinse was noted. 4. A lower plaque score was seen in 67 to 75% of all patients during the period in which the test mouthrinse was used as compared to the placebo. 5. Ten subjects reported a burning sensation of the tongue with the test mouthrinse. No objective adverse effects were seen.

Adult↗

Strategies to reduce feedlot cattle heat stress: effects on tympanic temperature.

Three experiments were conducted to evaluate the effect of different management strategies on body temperature of feedlot steers finished in the summer months. In Exp. 1, 24 crossbred steers were chosen to assess the effect of altered feed intake and feeding time on tympanic temperature (TT) response. Managed feeding (MF) treatments were applied for 22 d only and provided 1) ad libitum access to feed at 0800 (ADLIB), 2) feed at 1600 with amount adjusted so that no feed was available at 0800 (BKMGT), 3) feed at 1600 at 85% of predicted ad libitum levels (LIMFD). During heat stress conditions on d 20 to 22 of MF, LIMFD and BKMGT had lower (P < 0.05) TT than ADLIB from 2100 through 2400. A carryover effect of limit-feeding was evident during a severe heat episode (d 36 to 38) with LIMFD steers having lower (P < 0.05) TT than ADLIB. In Exp. 2, TT were obtained from 24 crossbred steers assigned to three treatments, consisting of no water application (CON), water applied to feedlot mound surfaces from 1000 to 1200 (AM) or 1400 to 1600 (PM). From 2200 to 0900 and 1200 to 1400, steers assigned to morning sprinkling treatment had lower (P < 0.05) TT than steers assigned to afternoon sprinkling treatment. In Exp. 3, 24 steers were utilized in a 2 x 2 factorial arrangement of treatments with factors of feeding time [0800 (AMF) and 1400 (PMF)] and sprinkling (WET and DRY). Tympanic temperatures were monitored under hot environmental conditions on d 30 to 32 and 61 to 62. A feeding time x sprinkling interaction (P < 0.001) was evident on d 30 to 32, although AMF/DRY steers had the highest (P < 0.05) TT. On d 61 to 62, TT of PMF steers was higher (P < 0.05) than AMF between 1500 to 1800. Use of sprinklers can effectively reduce TT of feedlot cattle, whereas shifting to an afternoon vs morning feeding time was most beneficial when bunks were empty several hours prior to feeding.

Animal Feed↗

Reproductive performance in the subsequent lactation of dairy cows previously treated for failure to be detected in oestrus.

AIM: To describe the effect of treatment of cows not detected in oestrus (NDO) with progesterone (P4) and oestradiol benzoate (ODB) in one lactation, on the reproductive and productive performance in the subsequent lactation. METHODS: Cows (n=770 from nine herds) which were NDO 10 days before the planned start of the seasonal breeding programme (PSM) were blocked by herd, age (2 or >2 years old) and ovarian status (i.e. with or without a palpable corpus luteum; CL), and treated either with an intravaginal progesterone-releasing device and ODB and resynchrony, or were left as untreated controls. In the following lactation, data were collected on the occurrence of endometritis, NDO, breeding dates, pregnancy test results and milk production. The effect of treatment and ovarian status in the previous lactation on the incidence of disease, and the proportions submitted for service, conceived and pregnant in the subsequent lactation were analysed. Calving dates and intervals from start of breeding to first insemination and conception were analysed using Kaplan Meier survival analysis. Additional multivariate analyses were undertaken to include known confounders such as age, breed, herd, calving date and milk production, as well as the cyclic status (i.e. previously cycling, NDO, or "late-calving") in the previous lactation, to examine the potential "carryover" effects of previous status on the reproductive performance in the subsequent lactation. RESULTS: Treatment of NDO cows resulted in an earlier calving date (Julian calving date 214, 95% CI=207-221, vs 224, 95% CI=220-228; p=0.005), more female calves reared (31.4% vs 23.3%; p=0.01), and reduced risk of being NDO (33.9% vs 46.1%; p=0.002) in the subsequent lactation compared with controls. There were no differences in the incidence of peripartum disease, or the proportion of cows submitted, conceived or pregnant between the Treatment and Control groups in the subsequent lactation (p>0.2). Previously CL-positive (+ve) NDO cows were less likely to produce a female calf that was reared (19.0% vs 29.9%; p=0.005), more likely to be treated as NDO (26.4% vs 18.6%; p=0.02), less likely to conceive by the end of the subsequent lactation's breeding programme (82.2% vs 87.8%; p=0.09), and took longer to conceive (41 vs 33 days from the PSM to conception) than cows that were NDO-CL-negative (-ve) in the previous lactation. There was no interaction between ovarian status and treatment for any of the outcome variables (p>0.05). Cows that were NDO or late-calving in the previous lactation were more likely to be NDO (p<0.005), treated as NDO (p<0.005), and have longer PSM to conception intervals (p<0.005) in the subsequent lactation than cycling herdmates, despite inclusion of factors known to confound reproductive performance in analyses. CONCLUSIONS: Treatment of NDO cows resulted in more female calves reared, earlier calving and a reduced risk of being NDO in the subsequent lactation. Status (i.e. NDO-CL+ve or NDO-CL-ve) affected some reproductive measures in the subsequent lactation, and the effect of treatment in the subsequent lactation differed between the two groups for some measures. Reproductive performance in the subsequent lactation was not improved despite the earlier calving date and longer calving to PSM intervals. Additionally, the previous season's status was still important in the subsequent season's reproductive performance, despite adjusting for known confounders of fertility. CLINICAL RELEVANCE: The economic benefits from treatment of NDO cows are likely limited to effects of an earlier calving date and potential for longer lactation and increased milk yield, increased number of calves derived from artificial insemination and from a reduced number of NDO cows in the subsequent lactation. Effects of improved reproductive performance in the subsequent lactation were not demonstrated and hence should not be included in any economic analysis of therapy of NDO cows.

Age Factors↗

Crossover design to test antihypertensive drugs with self-recorded blood pressure.

In a double-blind, within-patient study, blood pressure was measured at regular intervals at the clinic by the physician and each day at home by the patient. Both methods of blood pressure measurement demonstrated an antihypertensive effect of the diuretics chlorthalidone (25 mg) and triamterene (50 mg) and the beta-blocker oxprenolol (160 mg) and the greater efficacy of the combination of the two therapies. During placebo, as well as during active treatment, blood pressure values were higher at the clinic than at home, except when the patients were taking the beta-blocker, which minimized the arousal response during blood pressure measurements in the clinic. With 2-week treatment periods, separated by 2 weeks of placebo administration, blood pressure returned toward its initial level after each of the three treatments and none of the carryover effects was significant at the 5% level. This methodology was intended to make it possible to demonstrate in 27 patients at the clinic and in 20 patients with measurements made at home, at the usual statistical risks (alpha = 5%, beta = 10%), a fall of 5 mm Hg in diastolic blood pressure in comparison with a placebo. Moreover, at the end of this 3-month follow-up, each patient could continue to receive the treatment that was the most effective and the best tolerated. In conclusion, the use of a within-patient trial design, with a 15-day washout period between active treatments and careful recording of blood pressure values, can minimize the number of patients included in hypertension trials and offer to each patient the possibility of individualization of treatment.

Antihypertensive Agents↗

Dose-related effects of triazolam and flurazepam on a circadian rhythm insomnia.

Forty-eight normal subjects had sleep recordings and multiple sleep latency tests (an EEG measure of sleepiness) before and after a 12-hour shift of sleep-wake schedule. After 2 baseline days, subjects postponed sleep until 12:00 noon, then for three 24-hour periods were in bed from 12:00 noon until 8:00 PM. Treatment in parallel groups were administered before shifted sleeps. Sleep disturbance was greatest in the last quarter of shifted nights (6.5 to 8.5 hours after medication). Subjects taking placebo showed significant sleep loss on shifted nights and increased sleepiness the next day. Triazolam, 0.5 mg, reversed the sleep loss and consequent daytime sleepiness associated with the shifted sleep schedule. Triazolam, 0.25 mg, was not significantly better than placebo. In a dose-related manner, flurazepam mitigated the insomnia, but carryover effects left both dose groups more sleepy than were the placebo control subjects. Whether these laboratory results are applicable to clinically occurring forms of transient insomnia remains to be seen.

Adult↗

Estimating equivalency values of microbial phytase for amino acids in growing and finishing pigs fitted with steered ileo-cecal valve cannulas.

Ten crossbred barrows (48.3 +/- 2.3 kg of initial BW) fitted with steered ileo-cecal valve cannulas were used to investigate the effects of supplemental microbial phytase on the apparent ileal digestibilities (AID) of AA, Ca, P, N, and DM, and the apparent total tract digestibilities of Ca, P, N, and DM. All diets were corn-soybean meal-based, and contained 0.44% Ca and 0.40% total P. Diets 1, 2, and 3 contained 12.0, 11.1, and 10.2% CP, respectively. Diets 4 and 5 had the same ingredient composition as diet 3, plus 250 and 500 U/kg phytase (Natuphos), respectively. Pigs were randomly allotted to 1 of 5 dietary treatments in a paired 5 x 5 Latin square with an extra period to test for carryover effects. Each 14-d period consisted of a 7-d adjustment followed by a 3-d total collection, a 12-h ileal digesta collection, a 3-d readjustment, and a second 12-h ileal digesta collection. Pigs were housed individually in metabolism pens (1.2 x 1.2 m). Water was supplied ad libitum, and feed was supplied at a level of 9% of the metabolic BW (BW(0.75)) per day in 2 equal daily feedings. As the dietary CP concentration increased, the AID of CP and all AA measured increased linearly (P < 0.05) with the exception of proline. In addition, the apparent total tract digestibilities (grams per day) and retention of N (grams per day) increased linearly (P < 0.01) with increasing CP levels. Supplementing diets with phytase increased the AID of Ca (P < 0.01), P (P < 0.001), CP (P = 0.07), and the AA (P < 0.10) Gly, Ala, Val, Ile, Thr, TSAA, Asp, Glu, Phe, Lys, and Arg. Protein and phytase response equations were generated for those AA affected (P < 0.10) by both CP level and phytase supplementation. Based on these equations, 500 U/kg of phytase can replace 0.52 percentage units of the dietary CP, which includes a 0.03 percentage unit improvement in Lys AID. The results of this study show that supplementing pig diets with microbial phytase improves CP and AA digestibilities in addition to Ca and P digestibilities.

6-Phytase↗

Body sodium level in hypertensive and normotensive rats: effects of dietary sodium levels and sodium loads.

Rats of the genetically hypertensive (GH) strain do not have an increased body sodium content or increased natriuresis of hypertension. Spontaneously hypertensive rats (SHR), on the other hand, have an increased body sodium content and an increased rate of excretion of a sodium load. They also have an increased appetite for salt. In a study on three groups of normotensive rats with high normal, low normal, and very low sodium intakes, respectively, body sodium content was highest with the highest intake and lowest with the lowest intake. At the age of 22 weeks, after being on these intakes for 6 weeks, all three groups were put on a low sodium intake. Body sodium content of the two groups with the previous higher intakes failed to fall to the level of the group with the previous lowest intake. Thus there may be a prolonged carryover effect of salt intake in rats. The results are discussed in terms of the set point theory for sodium homeostasis.

Animals↗

Methodologic aspects of a population pharmacodynamic model for cognitive effects in Alzheimer patients treated with tacrine.

Tacrine is a cholinesterase inhibitor with activity in the central nervous system originally marketed for the reversal of competitive neuromuscular blockade. Because a marked reduction in cholinergic neurons is a hallmark of brain changes in Alzheimer disease, tacrine has been studied in two placebo-controlled clinical trials of patients with probable Alzheimer disease. Standard analysis of variance (ANOVA) and analysis of covariance (ANCOVA) have shown a difference between the tacrine group and the placebo group in terms of the cognitive component of the Alzheimer disease assessment scale at the end of the placebo-controlled phase. Due to limitations of ANOVA and ANCOVA, only a selected group of patients could be analyzed by those methods. A population pharmacodynamic model has been developed that allows the use of all observations from one or more trials to be combined. It can incorporate any sequence of active or placebo treatments and account for carryover effects of both placebo and active drug. The time courses of active or placebo treatment response and the development of tolerance to active drug or placebo can be defined. The model describes disease progression without treatment, the placebo effect, and the effect of tacrine as a function of daily dose. Placebo effect and active drug effects are modeled by effect site concentration components.

Algorithms↗