Hospital outpatient responses to potential driving impairment due to prescribed medications

Driving and using prescription medicines that have the potential to impair driving is an emerging research area. To date it is characterised by a limited (although growing) number of studies and methodological complexities that make generalisations about impairment due to medications difficult. Consistent evidence has been found for the impairing effects of hypnotics, sedative antidepressants and antihistamines, and narcotic analgesics, although it has been estimated that as many as nine medication classes have the potential to impair driving (Alvarez & del Rio, 2000; Walsh, de Gier, Christopherson, & Verstraete, 2004). There is also evidence for increased negative effects related to concomitant use of other medications and alcohol (Movig et al., 2004; Pringle, Ahern, Heller, Gold, & Brown, 2005). Statistics on the high levels of Australian prescription medication use suggest that consumer awareness of driving impairment due to medicines should be examined. One web-based study has found a low level of awareness, knowledge and risk perceptions among Australian drivers about the impairing effects of various medications on driving (Mallick, Johnston, Goren, & Kennedy, 2007). The lack of awareness and knowledge brings into question the effectiveness of the existing countermeasures. In Australia these consist of the use of ancillary warning labels administered under mandatory regulation and professional guidelines, advice to patients, and the use of Consumer Medicines Information (CMI) with medications that are known to cause impairment. The responsibility for the use of the warnings and related counsel to patients primarily lies with the pharmacist when dispensing relevant medication. A review by the Therapeutic Goods Administration (TGA) noted that in practice, advice to patients may not occur and that CMI is not always available (TGA, 2002). Researchers have also found that patients' recall of verbal counsel is very low (Houts, Bachrach, Witmer, Tringali, Bucher, & Localio, 1998). With healthcare observed as increasingly being provided in outpatient conditions (Davis et al., 2006; Vingilis & MacDonald, 2000), establishing the effectiveness of the warning labels as a countermeasure is especially important. There have been recent international developments in medication categorisation systems and associated medication warning labels. In 2005, France implemented a four-tier medication categorisation and warning system to improve patients' and health professionals' awareness and knowledge of related road safety issues (AFSSAPS, 2005). This warning system uses a pictogram and indicates the level of potential impairment in relation to driving performance through the use of colour and advice on the recommended behaviour to adopt towards driving. The comparable Australian system does not indicate the severity level of potential effects, and does not provide specific guidelines on the attitude or actions that the individual should adopt towards driving. It is reliant upon the patient to be vigilant in self-monitoring effects, to understand the potential ways in which they may be affected and how serious these effects may be, and to adopt the appropriate protective actions. This thesis investigates the responses of a sample of Australian hospital outpatients who receive appropriate labelling and counselling advice about potential driving impairment due to prescribed medicines. It aims to provide baseline data on the understanding and use of relevant medications by a Queensland public hospital outpatient sample recruited through the hospital pharmacy. It includes an exploration and comparison of the effect of the Australian and French medication warning systems on medication user knowledge, attitudes, beliefs and behaviour, and explores whether there are areas in which the Australian system may be improved by including any beneficial elements of the French system. A total of 358 outpatients were surveyed, and a follow-up telephone survey was conducted with a subgroup of consenting participants who were taking at least one medication that required an ancillary warning label about driving impairment. A complementary study of 75 French hospital outpatients was also conducted to further investigate the performance of the warnings. Not surprisingly, medication use among the Australian outpatient sample was high. The ancillary warning labels required to appear on medications that can impair driving were prevalent. A subgroup of participants was identified as being potentially at-risk of driving impaired, based on their reported recent use of medications requiring an ancillary warning label and level of driving activity. The sample reported previous behaviour and held future intentions that were consistent with warning label advice and health protective action. Participants did not express a particular need for being advised by a health professional regarding fitness to drive in relation to their medication. However, it was also apparent from the analysis that the participants would be significantly more likely to follow advice from a doctor than a pharmacist. High levels of knowledge in terms of general principles about effects of alcohol, illicit drugs and combinations of substances, and related health and crash risks were revealed. This may reflect a sample specific effect. Emphasis is placed in the professional guidelines for hospital pharmacists that make it essential that advisory labels are applied to medicines where applicable and that warning advice is given to all patients on medication which may affect driving (SHPA, 2006, p. 221). The research program applied selected theoretical constructs from Schwarzer's (1992) Health Action Process Approach, which has extended constructs from existing health theories such as the Theory of Planned Behavior (Ajzen, 1991) to better account for the intention-behaviour gap often observed when predicting behaviour. This was undertaken to explore the utility of the constructs in understanding and predicting compliance intentions and behaviour with the mandatory medication warning about driving impairment. This investigation revealed that the theoretical constructs related to intention and planning to avoid driving if an effect from the medication was noticed were useful. Not all the theoretical model constructs that had been demonstrated to be significant predictors in previous research on different health behaviours were significant in the present analyses. Positive outcome expectancies from avoiding driving were found to be important influences on forming the intention to avoid driving if an effect due to medication was noticed. In turn, intention was found to be a significant predictor of planning. Other selected theoretical constructs failed to predict compliance with the Australian warning label advice. It is possible that the limited predictive power of a number of constructs including risk perceptions is due to the small sample size obtained at follow up on which the evaluation is based. Alternately, it is possible that the theoretical constructs failed to sufficiently account for issues of particular relevance to the driving situation. The responses of the Australian hospital outpatient sample towards the Australian and French medication warning labels, which differed according to visual characteristics and warning message, were examined. In addition, a complementary study with a sample of French hospital outpatients was undertaken in order to allow general comparisons concerning the performance of the warnings. While a large amount of research exists concerning warning effectiveness, there is little research that has specifically investigated medication warnings relating to driving impairment. General established principles concerning factors that have been demonstrated to enhance warning noticeability and behavioural compliance have been extrapolated and investigated in the present study. The extent to which there is a need for education and improved health messages on this issue was a core issue of investigation in this thesis. Among the Australian sample, the size of the warning label and text, and red colour were the most visually important characteristics. The pictogram used in the French labels was also rated highly, and was salient for a large proportion of the sample. According to the study of French hospital outpatients, the pictogram was perceived to be the most important visual characteristic. Overall, the findings suggest that the Australian approach of using a combination of visual characteristics was important for the majority of the sample but that the use of a pictogram could enhance effects. A high rate of warning recall was found overall and a further important finding was that higher warning label recall was associated with increased number of medication classes taken. These results suggest that increased vigilance and care are associated with the number of medications taken and the associated repetition of the warning message. Significantly higher levels of risk perception were found for the French Level 3 (highest severity) label compared with the comparable mandatory Australian ancillary Label 1 warning. Participants' intentions related to the warning labels indicated that they would be more cautious while taking potentially impairing medication displaying the French Level 3 label compared with the Australian Label 1. These are potentially important findings for the Australian context regarding the current driving impairment warnings about displayed on medication. The findings raise other important implications for the Australian labelling context. An underlying factor may be the differences in the wording of the warning messages that appear on the Australian and French labels. The French label explicitly states "do not drive" while the Australian label states "if affected, do not drive", and the difference in responses may reflect that less severity is perceived where the situation involves the consumer's self-assessment of their impairment. The differences in the assignment of responsibility by the Australian (the consumer assesses and decides) and French (the doctor assesses and decides) approaches for the decision to drive while taking medication raises the core question of who is most able to assess driving impairment due to medication: the consumer, or the health professional? There are pros and cons related to knowledge, expertise and practicalities with either option. However, if the safety of the consumer is the primary aim, then the trend towards stronger risk perceptions and more consistent and cautious behavioural intentions in relation to the French label suggests that this approach may be more beneficial for consumer safety. The observations from the follow-up survey, although based on a small sample size and descriptive in nature, revealed that just over half of the sample recalled seeing a warning label about driving impairment on at least one of their medications. The majority of these respondents reported compliance with the warning advice. However, the results indicated variation in responses concerning alcohol intake and modifying the dose of medication or driving habits so that they could continue to drive, which suggests that the warning advice may not be having the desired impact. The findings of this research have implications for current countermeasures in this area. These have included enhancing the role that prescribing doctors have in providing warnings and advice to patients about the impact that their medication can have on driving, increasing consumer perceptions of the authority of pharmacists on this issue, and the reinforcement of the warning message. More broadly, it is suggested that there would be benefit in a wider dissemination of research-based information on increased crash risk and systematic monitoring and publicity about the representation of medications in crashes resulting in injuries and fatalities. Suggestions for future research concern the continued investigation of the effects of medications and interactions with existing medical conditions and other substances on driving skills, effects of variations in warning label design, individual behaviours and characteristics (particularly among those groups who are dependent upon prescription medication) and validation of consumer self-assessment of impairment.

Behavioral and Antinociceptive Effects of Alfentanil, Butorphanol, and Flunixin in Horses

To determine the behavioral and antinociceptive effects of narcotic and non-narcotic analgesics administered by intravenous injection in horses, 10 thoroughbred mares weighing between 450 and 550 kg and ranging in age from 8 to 13 years old were analyzed. The effects of alfentanil, butorphanol, flunixin, and saline solution on the general activity of the horses were investigated by measuring spontaneous locomotor activity (SLA) and head height (HH) in two behavior stalls. The antinociceptive effects of alfentanil (0.02 mg kg-1), butorphanol (0.1 mg kg-1), flunixin meglumine (0.5 mg kg-1), and saline were determined by measuring skin twitch reflex latency (STRL) after thermal cutaneous nociceptive stimulation. A paired Student t-test was used to compare SLA and HH between the groups of horses receiving different doses of the same drug at various time points. The Tukey test was used to compare the antinociceptive effect of the treatments. Differences were considered significant when P value was <.05. Horses treated with opioid analgesics demonstrated excitation, as shown by a significant increase in SLA at all doses tested and by neighing and demonstrating attentive attitudes with movement of the ears, stereotypical walking, and ataxia in most of the animals. HH was elevated only in animals treated with alfentanil. Antinociception was observed at 5 and 30 minutes after administration of alfentanil and butorphanol, respectively. Increased SLA was observed at 30 and 90 minutes after administration of alfentanil and butorphanol, respectively. We observed no effect on antinociception in horses given flunixin. In conclusion, this study suggests that alfentanil has a faster onset and a shorter duration than butorphanol; however, both drugs are able to stimulate the central nervous system. © 2013 Elsevier Inc. All rights reserved.

AN ESTIMATION OF IN UTERO DRUG EXPOSURE BY DETERMINANTS OF FREQUENCY AND DISTRIBUTION OF MATERNAL DRUG CONSUMPTION

Data derived from 1,194 gravidas presenting at the observation unit of a city/county hospital between October 11, 1979 through December 7, 1979 were evaluated with respect to the proportion ingesting drugs during pregnancy. The mean age of the mother at the time of the interview was 22.0 years; 43.0 percent were Black; 34.0 percent Latin-American, 21.0 percent White and 2.0 percent other; mean gravida was 2.5 pregnancies; mean parity was 1.0; and mean number of previous abortions was 0.34. Completed interview data was available for 1,119 gravida, corresponding urinalyses for 997 subjects. Ninety and one-tenth percent (90.1 percent) of the subjects reported ingestion of one or more drug preparation(s) (prescription, OTC, or substances used for recreational purposes) during pregnancy with a range of 0 to 11 substances and a mean of 2.7. Dietary supplements (vitamins and minerals) were most frequently reported followed by non-narcotic analgesics. Seventy-six and one tenth percent (76.1 percent) of the population reported consumption of prescription medication, 42.5 percent reported consumption of over-the-counter medications, 45.7 percent reported consumption of a substance for recreational purposes and 4.3 percent reported illicit consumption of a substance. For selected substances, no measurable difference was found between obtaining the information from the interview method or from a urinalysis assay. ^

Sleepiness, sleep-disordered breathing, and accident risk factors in commercial vehicle drivers

Sleep-disordered breathing and excessive sleepiness may be more common in commercial vehicle drivers than in the general population. The relative importance of factors causing excessive sleepiness and accidents in this population remains unclear. We measured the prevalence of excessive sleepiness and sleep-disordered breathing and assessed accident risk factors in 2,342 respondents to a questionnaire distributed to a random sample of 3,268 Australian commercial vehicle drivers and another 161 drivers among 244 invited to undergo polysomnography. More than half (59.6%) of drivers had sleep-disordered breathing and 15.8% had obstructive sleep apnea syndrome. Twenty-four percent of drivers had excessive sleepiness. Increasing sleepiness was related to an increased accident risk. The sleepiest 5% of drivers on the Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire had an in-creased risk of an accident (odds ratio [OR] 1.91, p = 0.02 and OR 2.23, p < 0.01, respectively) and multiple accidents (OR 2.67, p < 0.01 and OR 2.39, p = 0.01), adjusted for established risk factors. There was an increased accident risk with narcotic analgesic use (OR 2.40, p < 0.01) and antihistamine use (OR 3.44, p = 0.04). Chronic excessive sleepiness and sleep-disordered breathing are common in Australian commercial vehicle drivers. Accident risk was related to increasing chronic sleepiness and antihistamine and narcotic analgesic use.

Regional differences in the in vitro penetration of hydrocortisone through equine skin

Little is known about the transdermal penetration of hydrocortisone in the horse and, although commercial formulations containing hydrocortisone are registered for topical use in the horse, there have been no studies investigating the movement of this glucocorticoid through different regions of equine skin. Skin was harvested from the thorax, groin and leg (dorsal metacarpal) regions of five Thoroughbred geldings and frozen (-20 degrees C) until required. Defrosted skin was placed in Franz-type diffusion cells and the amount of radiolabelled (H-3) hydrocortisone, in a saturated solution of unlabelled hydrocortisone in 50% ethanol (w/w), which penetrated through and remained within skin samples was measured over 24 h. Significantly higher (P < 0.001) maximum flux (J(max); mol/cm(2)/h) was measured when hydrocortisone was applied to skin from the leg, compared to thorax and groin, although significantly less hydrocortisone (P < 0.001) was retained within skin from the leg at 24 h. Topical application of hydrocortisone in a vehicle containing ethanol would penetrate faster through leg skin from the lower leg when compared with the thorax or groin, which depending on cutaneous blood flow, may result in higher systemic drug concentrations or greater efficiency in treating local inflamed tissue.

Structural studies of analgesics and their interactions. VII. Stereoisomerism and disorder in the structure of oxyphenbutazone monohydrate

Oxyphenbutazone, C19H20N203, a metabolite and perhaps the active form of phenylbutazone, is a widely used non-narcotic analgesic and anti-inflammatory pyrazolidinedione derivative. The monohydrate of the compound crystallizes in the triclinic space group Pi with two molecules in a unit cell of dimensions a -- 9.491 (4), b = 10.261 (5), c = 11.036 (3)A and ¢~ = 72.2 (1), fl = 64.3 (1), 7 = 73.0 (1) °. The structure was solved by direct methods and refined to an R value of 0.107 for 1498 observed reflections. The butyl group in the molecule is disordered. The hydroxyl group occupies two sites with unequal occupancies. On account of the asymmetry at the two N atoms and one of the C atoms in the central five-membered ring, the molecule can exist in eight isomeric states, of which four are sterically unfavourable. The disorder in the position of the hydroxyl group can be readily explained on the basis of the existence, with unequal abundances, of all four sterically favourable isomers.The bond lengths and angles in the molecule are similar to those in phenylbutazone. The crystal structure is stabilized by van der Waals interactions, and O-H... O hydrogen bonds involving the carbonyl and the hydroxyl groups as well as a water molecule.

Structural Studies of Analgesics and Their Interactions. V.* The Crystal and Molecular Structure of Metamizol Monohydrate

Metamizol, Na[Ct3H16N3045], C13H16N304S-Na +, a sulphonyl derivative of amidopyrine, is perhaps the most widely used non-narcotic analgetic and antiinflammatory pyrazolone derivative. The monohydrate of the compound crystallizes in the monoclinic space group P2Jc with eight molecules in a unit cell of dimensions a = 9.143 (3), b = 49.50 (2), c = 7.314 (2)/k and fl = 90.9 (1) °. The structure was solved by direct methods and refined to an R value of 0.080 for 4466 observed reflections. The two crystallographically independent molecules in the structure have similar dimensions. The elongated molecules are hydrophobic at one end and hydrophilic at the other with the middle portion partly hydrophobic and partly hydrophilic. The pyrazolone group in the structure has dimensions similar to those found in uncomplexed antipyrine and amidopyrine. The crystal structure can be described as consisting of double layers of metamizol molecules stacked perpendicular to the b axis. The adjacent double layers are separated by a layer of Naions and water molecules.

Structural studies of analgesics and their interactions .10. A hydrated 1-1 complex between niflumic acid and ethanolamine, c13h8f3n2o-2.c2h8no+.h2o.

Mr= 361.3, triclinic, P1, a = 6-239 (2), b=11.280(2), c=12-451(2)A, a=101.2 (1), B= 92.3 (1), 7=99.9(1)°, V=844.123 A3, Z=2, Dx= 1.42, D m = 1.42 (1) Mg m -3, n(Cu Ka) = 1.5418 ,A., g = 1-102 mm -1, F(000) = 376, T= 293 K. Final R = 0.064 for 2150 observed reflections. The niflumic acid anions consist essentially of three planar groupings, namely, two six-membered rings and a carboxylate group attached to one of them. The invariant common structural features observed in the crystal structures of fenamates, namely, the coplanarity of the carboxyl group and the six-membered ring bearing it, and the internal hydrogen bond between the carboxyl group and the imino N atom that bridges the two sixmembered rings, are retained in the complex. The amino N atom is gauche with respect to the terminal hydroxyl group in the ethanolamine cation. The complexation between the two molecules is achieved through ionic and hydrogen-bonded interactions involving the carboxylate group in niflumic acid.

Structural Studies of Analgesics and Their Interactions. VIII.* Rotational Isomerism and Disorder in the Crystal Structure of Meelofenamie Acid

Meclofenamic acid, C I4HIICI2NO2, probably the most potent among analgesic fenamates, crystallizes in the triclinic space group P1, with a = 8.569 (5), b = 8.954(8), c -- 9.371 (4) A, ct = 103.0 (2), fl -- 103.5 (2), y = 92.4 (2) ° , Z = 2, D m = 1.43 (4), D c = 1.41 Mg m -3. The structure was solved by direct methods and refined to R = 0.135 for 1062 observed reflections. The anthranilic acid moiety in the molecule is nearly planar and is nearly perpendicular to the 2,6-dichloro-3-methylphenyl group. The molecules, which exist as hydrogen-bonded dimers, have an internal hydrogen bond involving the imino and the carboxyl groups. The methyl group is disordered and occupies two positions with unequal occupancies. The disorder can be satisfactorily explained in terms of the rotational isomerism of the 2,6-dichloro-3-methylphenyl group about the bond which connects it to the anthranilic acid moiety and the observed occupancies on the basis of packing considerations.

Structural studies of analgesics and their interactions. II. The crystal structure of a 1:1 complex between antipyrine and salicyclic acid (salipyrine)

The complex crystallizes in the space group P21/c with four formula units in a unit cell of dimensions a= 12.747, b= 7.416, c= 17.894 A and/3= 90.2 °. The structure has been solved by the symbolic addition procedure using three-dimensional photographic data and refined to an R value of 0.079 for 2019 observed reflexions. The pyramidal nature of the two hetero nitrogen atoms in the antipyrine molecule is inter:nediate between that observed in free antipyrine and in some of its metal complexes. The molecule is more polar than that in crystals of free antipyrine but less so compared with that in metal complexes. In the salicylic acid molecule, the hydroxyl group forms an internal hydrogen bond with one of the oxygen atoms in the carboxyl group. The association between the salicylic acid and the antipyrine molecules is achieved through an intermolecular hydrogen bond with the other carboxyl oxygen atom in the salicylic acid molecule as the proton donor and the carboxyl oxygen atom of the antipyrine molecule as the acceptor.

Structural studies of analgesics and their interactions. III. The crystal and molecular structure of amidopyrine

Amidopyrine (1-phenyl-2,3-dimethyl-4-dimethylaminopyrazolone), C13HzvN30, a dimethylamino derivative of antipyrine and an important analgesic and antipyretic agent, crystallizes in the triclinic space group P1 with four molecules in a unit cell of dimensions a= 7.458 (5), b = 10.744 (5), c= 17.486 (15)/~,, e=98.6 (2),/~= 85.6 (3), y= 108-6 (2) . The structure was solved by direct methods and refined to an R value of 0.055 for 3706 photographically observed reflexions. The dimensions of the two crystallographically independent molecules are very nearly the same. The pyrazolone moiety in the molecule has dimensions comparable to those in antipyrine. Unlike antipyrine, the molecular dimensions of amidopyrine in the free state (the present structure) are close to those found in some of its hydrogenbonded complexes. Thus it appears that the presence of the dimethylamino group makes the molecule more resistant to changes in its dimensions resulting from molecular association. An attempt has also been made to correlate the polar nature of the pyrazolone moiety and the hybridization state of the hetero nitrogen atoms in antipyrine, amidopyrine and their complexes.

Structural studies of analgesics and their interactions. Part 4. Crystal structures of phenylbutazone and a 2 : 1 complex between phenylbutazone and piperazine

The X-ray crystal structures of 4-butyl-1,2-diphenylpyrazolidine-3,5-dione (phenylbutazone)(I). and its 2 : 1 complex (II) with piperazine have been determined by direct methods and the structures refined to R 0.096 (2 300 observed reflections measured by diffractometer) and 0.074 (2 494 observed reflections visuallyestimated). Crystals are monoclinic, space group P21/c; for (I)a= 21.695(4), b= 5.823(2), c= 27.881(4)Å, = 108.06 (10)°, Z= 8, and for (II)a= 8.048(4), b= 15.081(4), c= 15.583(7)Å, = 95.9(3)°, Z= 2. The two crystallographically independant molecules in the structure of (I) are similar except for the conformation of the butyl group, which is disordered in one of the molecules. In the pyrazolidinedione group, the two C–C bonds are single and the two C–O bonds double. The two nitrogen atoms in the five-membered ring are pyramidal with the attached phenyl groups lying on the opposite sides of the mean plane of the ring. The phenylbutazone molecule in (II) exists as a negative ion owing to deprotonation of C-4. C-4 is therefore trigonal and the orientation of the Bu group with respect to the pyrazolidinedione group is considerably different from that in (I); there is also considerable electron delocalization along the C–O and C–C bonds. These changes in geometry and electronic structure may relate to biological activity. The doubly charged cationic piperazine molecule exists in the chair form with the nitrogen atoms at the apices. The crystal structure of (II) is stabilized by ionic interactions and N–H O hydrogen bonds.

Structural Studies Of Analgesics And Their Interactions .1. Crystal And Molecular-Structure Of Antipyrine

The complex crystallizes in the space group P21/c with four formula units in a unit cell of dimensionsa= 12.747, b= 7.416, c= 17.894 A and/3= 90.2 °. The structure has been solved by the symbolic addition procedure using three dimensional photographic data and refined to an R value of 0.079 for 2019 observed reflexions. The pyramidal nature of the two hetero nitrogen atoms in the antipyrine molecule is inter:nediate between that observed in free antipyrine and in some of its metal complexes. The molecule is more polar than that in crystals of free antipyrine but less so compared with that in metal complexes. In the salicylic acid molecule, the hydroxyl group forms an internal hydrogen bond with one of the oxygen atoms in the carboxyl group. The association between the salicylic acid and the antipyrine molecules is achieved through an intermolecular hydrogen bond with the other carboxyl oxygen atom in the salicylic acid molecule as the proton donor and the carboxyl oxygen atom of the antipyrine molecule as the acceptor

Structural studies of analgesics and their interactions. XII. Structure and interactions of anti-inflammatory fenamates. A concerted crystallographic and theoretical conformational study

A theoretical conformational analysis of fenamates, which are N-arylated derivatives of anthranilic acid or 2-aminonicotinic acid with different substituents on the aryl (phenyl) group, is reported. The analysis of these analgesics, which are believed to act through the inhibition of prostaglandin biosynthesis, was carried out using semi-empirical potential functions. The results and available crystallographic observations have been critically examined in terms of their relevance to drug action. Crystallographic studies of these drugs and their complexes have revealed that the fenamate molecules share a striking invariant feature, namely, the sixmembered ring bearing the carboxyl group is coplanar with the carboxyl group and the bridging imino group,the coplanarity being stabilized by resonance interactions and an internal hydrogen bond between the imino and carboxyl groups. The results of the theoretical analysis provide a conformational rationale for the observed invariant coplanarity. The second sixmembered ring, which provides hydrophobicity in a substantial part of the molecule, has limited conformational flexibility in meclofenamic, mefenamic and flufenamic acids. Comparison of the conformational energy maps of these acids shows that they could all assume the same conformation when bound to the relevant enzyme. The present study provides a structural explanation for the difference in the activity of niflumic acid, which can assume a conformation in which the whole molecule is nearly planar. The main role of the carboxyl group appears to be to provide a site for intermolecular interactions in addition to helping in stabilizing the invariant coplanar feature and providing hydrophilicity at one end of the molecule. The fenamates thus provide a good example of conformation- dependent molecular asymmetry.