Crossover studies

In 1981, Chinese Restaurant Asthma was reported following capsule administration of MSG to several asthmatics (37). However, the researchers failed to account for other allergens to which the subjects could have been exposed and did not utilize the scientific practice of a "control" substance which would have helped to determine if glutamate triggered this response. In a double-blind crossover study, chronic asthmatics were challenged with MSG or a placebo. No decrease in pulmonary function was observed (39). 

RESPONSE I think this is an area where you would have to do detailed double-blind crossover studies and some fairly extensive testing to map out what the nature of that effect is. 

Finally, trials can follow parallel or crossover study designs. In a parallel trial, patients are assigned to a therapy that they remain on, and they are compared with patients in alternate therapy groups. In a crossover trial, patients switch or change therapy assignments during the course of the trial. 

Additionally, in a crossover study over two 4-week periods that similarly compared boiled coffee with boiled coffee that was paper-filtered, 20 Finnish women and men consumed an average of 8.3 cups of coffee per day. Total cholesterol, LDL-C, and TG levels were all significantly higher during the boiled coffee period (0.36, 0.33, and 0.26 mmol/L [14,13, and 23 mg/dL], respectively). Examination of the paper filters indicated that 80% of the fatty material present in the boiled coffee was trapped by the paper filter.22... 

Finally, a recently published crossover study of coffee oil lipid extracts by Urgert et al.27 compared the effects of 60 mg/day of cafestol with a mixture of 60 mg/day of cafestol plus 50 mg/day of kahweol. These doses were comparable to consuming 10 to 20 cups of boiled Turkish or French-press coffee. In 10 healthy men, 18 days of cafestol alone resulted in significant increases in total cholesterol (0.79 mmol/L [31 mg/dL]), LDL-C (0.57 mmol/L [22 mg/dL]), and TG (0.65 mmol/L [58 mg/dL]), relative to baseline. Compared to cafestol alone, the cafestol/kahweol mixture resulted in additional increases in total cholesterol (0.23 mmol/L [9 mg/dL), LDL-C (0.23 mmol/L [9 mg/dL]), and TG (0.09 mmol/L [8... 

Product bioavailability is mentioned, especially where it is low. Where there are differences between the formulations tested for bioavailability during the development process and the formulation to be marketed, there is considerable discussion of the data provided on the bioequivalence of the different products and/or formulations. This is particularly so where, for example, early clinical studies were undertaken with capsules but the marketed dosage form is to be a tablet. Bioequivalence data and pharmacokinetic data (e.g., in crossover studies) and comparative dissolution studies are usually reported. This is particularly significant where the different strengths of the final products are not achieved by using different quantities of the same granulate formulation. Process optimization may also be addressed in such cases. 

Scheme 20 Crossover studies that document multiple mechanistic pathways...

L Nerbist. Triple crossover study on absorption and excretion of ampicillin, talampicillin, and amoxycillin. Antimicrob Agent Chemother 10 173-175, 1976. 

Kayumov, L., Brown, G., Jindal, R., Buttoo, K. Shapiro, C. M. (2001). A randomized, double-blind, placebo-controlled crossover study of the effect of exogenous melatonin on delayed sleep phase syndrome. Psychosom. Med. 63, 40-8. 

Moss MC, Scholey AB and Wesnes K (1998). Oxygen administration selectively enhances cognitive performance in healthy young adults a placebo-controlled, double blind crossover study. Psychopharmacology, 138, 27-33. 

Schwarz, E. et al., Oral administration of freshly expressed juice of Echinacea purpurea herbs fail to stimulate the nonspecific immune response in healthy young men Results of a double-blind, placebo-controlled crossover study, J Immunother, 25, 413, 2002. 

Because this hypothesis generated considerable anxiety and had broad pubhc health implications, the Nutrition Foundation (formerly affiliated with the International Life Sciences Institute but now defunct) convened a committee to evaluate the scientific evidence relative to the Feingold hypothesis, and if warranted, provide guidelines for further research. The committee, known as the National Advisory Committee on Hyperkinesis and Food Additives (1975), found no conclusive link between diet and behavior, but could not rule out a possible association since no studies appropriate for testing the hypothesis had been carried out. Based on the committee s recommendations, several doubleblind crossover studies were subsequently conducted, but these produced... 

Rostami-Hodjegan A, Shiran MR, Ayesh R, Grattan TJ, Burnett I, Darby-Dowman A, Tucker GT. A new rapidly absorbed paracetamol tablet containing sodium bicarbonate. I. A four way crossover study to compare the concentration-time profile of paracetamol from the new paracetamol/sodium bicarbonate tablet and a conventional paracetamol tablet in fed and fasted volunteers. Drug Dev Ind Pharm 2002 28 523-531. 

The FDA guidance on IVIVC development and validation states that crossover studies are preferred however, parallel studies or cross-study analyses may be acceptable. The advantage of a crossover study is that it avoids bias to any one particular treatment as a result of a period effect. A crossover study also provides the highest probability of successfully validating the IVIVC, since it avoids the variability introduced by cross-study comparisons. 

Cernea S, Kidron M, Wohlgelernter J, and Raz I (2005) Dose-response relationship of an oral insulin spray in six patients with type 1 diabetes A single-center, randomized, single-blind, 5-way crossover study. Clin. Ther. 27 1562-1570. 

Darwish M, Kirby M, Robertson P, Tracewell W, and Jiang JG (2006) Pharmacokinetic properties of fentanyl effervescent buccal tablets A phase I, open-label, crossover study of single dose 100, 200, 400, and 800 micrograms in healthy adult volunteers. Clin. Ther. 28 707-714. 

Davidson, M. H., Dugan, L. D., Burns, J. H., Sugimoto, D., Story, K., and Drennan, K. (1996). A psyllium-enriched cereal for the treatment of hypercholesterolemia in children A controlled, double-blind, crossover study. Am. ]. Clin. Nutr. 63, 96-102. 

Fant RV, Henningfleld JE, Shiffman S, Strahs KR, Reitberg DP (2000) A pharmacokinetic crossover study to compare the absorption characteristics of three transdermal nicotine patches. Pharmacol Biochem Behav 67(3) 479 82... 

In general, bioequivalence is demonstrated if the mean difference between two products is within 20% at the 95% confidence level. This is a statistical requirement, which may require a large number of samples (e.g. volunteers), if the drug exhibits variable absorption and disposition pharmacokinetics. For drugs for which there is a small therapeutic window or low therapeutic index, the 20% limit may be reduced. The preferred test method is an in vivo crossover study and, since this occurs in the development phase, necessitates the emplo)unent of volim-teers. These studies are, therefore, expensive and animal experiments may be substituted, or in vitro experiments if they have been correlated with in vivo studies. 

Table 4.4 Crossover study design with two alternating cohorts of eight subjects and a 6 2 restricted randomisation to active drug (A) or placebo (P) - each subject receives A on three occasions and P on one occasion ...

The AUCs can be obtained by administration of intravenous and oral formulations in a crossover study. It is important to use the exact dose rather... 

Absorption - Because of its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high-fat meal. In a crossover study, 74 healthy adult subjects received a single 80 mg oral dose (two 40 mg capsules) of isotretinoin under fasted and fed conditions. Peak plasma concentration (Cmax)... 

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