Heterogeneity of Clinical Trials for Antihypertensive Drugs in Japan: Exploratory Analysis of Confirmatory Phase III Trials Used for Marketing Approval.

The results of pivotal trials, which provide a rationale for marketing approval decisions for new drugs, are considered for various comparative purposes in postmarketing analyses. Using meta-regression analysis of 91 randomized controlled trials of 61 approved antihypertensive drugs in Japan, we show that mean baseline blood pressure (BP) of each arm was associated with predetermined entry criteria (EC), age, and trial start year (TSY). BP changes following treatment were associated with EC, subject characteristics (e.g., age, complications, baseline BP), study design (e.g., concomitant drug use), and TSY. Effect sizes were generally larger in trials for the first and second drugs in the same class than in trials for follow-on drugs. Results of pivotal trials may vary depending on many factors, suggesting possible challenges associated with the comparison of these results indirectly. Due to the heterogeneity in pivotal trials, caution should be exercised when comparing approved drugs and conducting meta-analyses retrospectively.

The involvement of volatile infochemicals from spider mites and from food-plants in prey location of the generalist predatory mite Neoseiulus californicus.

We investigated volatile infochemicals possibly involved in location of the generalist predatory mite Neoseiulus californicus to plants infested with spider mites in a Y-tube olfactometer. The predators significantly preferred volatiles from lima bean leaves infested with Tetranychus urticae to uninfested lima bean leaves. Likewise, they were attracted to volatiles from artificially damaged lima bean leaves and those from T. urticae plus their visible products. Significantly more predators chose infested lima bean leaves from which T. urticae plus their visible products had been removed than artificially damaged leaves, T. urticae, and their visible products. These results suggest that N. californicus is capable of exploiting a variety of volatile infochemicals originating from their prey, from the prey-foodplants themselves, and from the complex of the prey and the host plants (e.g., herbivore-induced volatiles). We also investigated predator response to some of the synthetic samples identified as volatile components emitted from T. urticae-infested lima bean leaves and/or artificially damaged lima bean leaves. The predators were attracted to each of the five synthetic volatile components: linalool, methyl salicylate, (Z)-3-hexen-1-ol, (E)-2-hexenal, and (Z)-3-hexenyl acetate. The role of each volatile compound in prey-searching behavior is discussed.

Alleviating effects of plant-derived fragrances on stress-induced hyperthermia in rats.

In the present study, the effects of exposure to plant-derived odors on the autonomic and behavioral responses to novel environment were examined in rats. Male rats (n=42) carrying a telemetry transmitter were individually housed, and on the test day each rat was transferred to a new cage containing bedding that had been sprayed immediately before testing with 200 microl of 0.03% dilution of either lavender essential oil, green leaf odor (a mixture of hexenol and hexenal), alpha-pinene, or solvent (triethyl citrate) as a control. Following the transfer to this novel environment, the body temperature of the rats increased by nearly 1 degrees C, showing a stress-induced hyperthermia. Stress-induced hyperthermia was attenuated by the green odor and the alpha-pinene, but not by the lavender or solvent. There was no clear effect of fragrances on heart rate or behavioral responses. These results suggest that plant-derived fragrances, such as green odor and alpha-pinene, have calming effects on autonomic stress response to novel environments.

Concentration effects of green odor on event-related potential (P300) and pleasantness.

The effects of eight compounds, constituting the so-called "natural green odor", including leaf alcohol, on the event-related potential (P300) were investigated. In experiments with a series of single compounds, each of these eight compounds could be characterized by an overall change consisting predominantly of an increase, a decrease or no change in the amplitude of P300, whereas in experiments with a series of two-component mixtures, noticeable synergism could not be demonstrated, contrary to our expectation. Experiments with leaf alcohol (3Z-hexenol) performed at two concentrations showed a significantly different degree of pleasantness and an increase or decrease in the amplitude of P300 depending on their concentration, suggesting that concentration is important in odorant-presentation studies.