Pharmacokinetic and pharmacodynamic implications of P-glycoprotein modulation.

P-glycoprotein (P-gp) is a cell membrane-associated protein that transports a variety of drug substrates. Although P-gp has been studied extensively as a mediator of multidrug resistance in cancer, only recently has the role of P-gp expressed in normal tissues as a determinant of drug pharmacokinetics and pharmacodynamics been examined. P-glycoprotein is present in organ systems that influence drug absorption (intestine), distribution to site of action (central nervous system and leukocytes), and elimination (liver and kidney), as well as several other tissues. Many marketed drugs inhibit P-gp function, and several compounds are under development as P-gp inhibitors. Similarly, numerous drugs can induce P-gp expression. While P-gp induction does not have a therapeutic role, P-gp inhibition is an attractive therapeutic approach to reverse multidrug resistance. Clinicians should recognize that P-gp induction or inhibition may have a substantial effect on the pharmacokinetics and pharmacodynamics of concomitantly administered drugs that are substrates for this transporter.

Characteristics of general aviation crashes involving mature male and female pilots.

BACKGROUND: General aviation crashes in the United States were analyzed to identify differences between male and female pilots in the circumstances of their crashes and the types of pilot errors involved. METHODS: All 144 female pilots who were born between 1933 and 1942 and who were involved in general aviation crashes between 1983 and 1997 were matched 1:2 with 287 male pilots by age within 2 yr, medical certificate and pilot certificate, state or region of crash, and year of crash. RESULTS: Mechanical failure, gear up landings, improper IFR approaches, and collisions with wires or poles were more common in crashes of male pilots. Loss of control on landing/takeoff was more common in crashes of female pilots. Mishandling aircraft kinetics was the most common error of pilots of both genders and was noted more often in female pilots' crashes (81% vs. 48%) (p < 0.001). Males' crashes were more likely to involve flawed decisions (29% vs. 19% of females' crashes) (p = 0.027) or inattention (32% vs. 19%) (p = 0.004). Older pilots made fewer errors: among males age 55-63, 26% of crashes were without obvious pilot error compared with only 7% at age 40-49 (p = 0.003). CONCLUSION: There are large gender differences in the types of pilot error involved in general aviation crashes. Mishandling aircraft kinetics, poor decision making, and inattention are the most common pilot errors and merit increased attention in pilot training.

Crashes of instructional flights.

BACKGROUND: A pilot's basic flight training influences his or her entire flying career. Instructional flights are involved in more than 300 crashes annually and in 36% of all midair collisions. Research was undertaken to identify the circumstances of crashes of instructional flights and to describe related factors. METHODS: We analyzed NTSB data types and 2-page descriptive briefs for 638 crashes that occurred during 1989 and 1991 and that involved a student pilot or a flight for instructional purposes. RESULTS: Loss of control on landing characterized 36% of all crashes, and crosswinds contributed to 28%. Stalls occurred in 15% of the series and 46% of all fatal crashes. Trainees on solo comprised 56% of the series; 193 of the 360 students who crashed on solo did so due to loss of control on landing or takeoff. Touch-and-go landings accounted for 22% of all crashes on solo. Among the 84 crashes on cross-country solos, 26 (31%) were due to running out of fuel. Instructors were present in 50% of crashes from stalls and 32% of crashes from fuel starvation. Simulated emergencies ended in 49 crashes. The NTSB identified instructor factors as contributory to one-third of cases. CONCLUSIONS: Greater emphasis during flight training needs to be placed on avoiding stalls and midair collisions, managing crosswinds, and understanding the dynamics of takeoffs and landings prior to solo touch-and-go practice. Instructors contribute to crashes both directly during dual instruction and indirectly through failure to successfully monitor their students and convey the elements necessary for safe and proficient flight.

Pilots involved in multiple crashes: "accident proneness" revisited.

Analysis of crashes of air taxi and commuter flights explored the controversial issue of "accident proneness." There were 20 pilots who had 2 or more crashes during 1983-88. These pilots (repeaters) and their 42 crashes were compared with 534 pilots who were each involved in a single air taxi or commuter crash during the same period (nonrepeaters). Unexpectedly, repeaters were more experienced pilots with a mean total flight time of 7016 h vs. 5321 for nonrepeaters. Repeaters did not differ from nonrepeaters in the overall proportion of crashes in which pilot performance appeared to be a major factor. Repeaters differed significantly from nonrepeaters as to flight hours during the past 90 d (mean 215 vs. 183 h) and the proportion of their crashes that occurred in Alaska (48% vs. 24%). Alaska repeaters differed from non-Alaska repeaters with regard to the proportion of crashes on takeoff (40% vs 14%) and airport conditions as a factor (50% vs. 18%). The high proportion of repeaters involved in crashes in Alaska, where environmental conditions make flying more hazardous, and the substantially greater recent flight time suggest that the intensity and amount of occupational exposure are major determinants of pilot involvement in more than one crash.

Human factors in crashes of commuter airplanes.

Pilots and frequent travelers on commuter aircraft are exposed to higher risks of death or injury than those on major air carriers. To provide a better understanding of the circumstances of crashes of scheduled commuter airplanes, National Transportation Safety Board data were analyzed for all cases of death, serious injury, or major damage involving commuter airplanes during 1983-88, when 172 people were killed and 207 injured in 118 events. Three-fourths of cases involved inadequate pilot performance, notably poor handling of emergencies and improper instrument flying procedures. Pilot errors occurred disproportionately in bad weather, which played a role in 30% of crashes. Aircraft malfunctions were involved in 42% of crashes. Certain airplanes were overinvolved in gear-up landings or in crashes due to fuel mismanagement. Greater priority should be given to applying known preventive measures to the problem of commuter crashes.

Hazards of mountain flying: crashes in the Colorado Rockies.

Between 1964 and 1987, 232 airplanes crashed within 50 nautical miles of Aspen, CO; 90% were general aviation crashes. A total of 202 people died and 69 were seriously injured. The societal cost averaged more than $4 million annually. Most pilots were experienced and many were flight instructors, but 44% had flown less than 100 hours in the type of plane in which they crashed. Forty-one percent of the pilots were out-of-state residents. Crashes in the study area were more likely to be fatal than in the rest of Colorado. Airplanes with three or four occupants and low-powered four-seater aircraft were over-represented among crashes involving failure to outclimb rising terrain. In a subset of crashes examined for restraint use, 50% of the front seat occupants using only lap belts were killed, compared to 13% of those who also wore shoulder restraints. Preventive recommendations include shoulder restraint use and better training in mountain flying, with incentives provided by the FAA and insurance companies.