Morgan Feely

Time to stop counting the tablets

We attempted to assess compliance using both a pharmacologic indicator (low‐dose phenobarbital) and a return tablet count in 225 patients who were taking part in three separate studies. There were 216 patients (96%) who kept a follow‐up appointment after 28 days; 161 patients appeared to have good compliance (90% to 109%) by return tablet count. Of these 161 patients, 51 (32%) had plasma phenobarbital concentrations (corrected for dose and weight) that were less than 90% of the lowest value previously found in normal volunteers, which suggested poorer compliance. When compared with the age‐related volunteer values, 77 (48%) had values that were less than 90% of the lowest volunteer value. There were 6 of 10 patients with apparently excessive (≥ 110%) compliance by return tablet count and 4 of 12 who failed to return their container who also had phenobarbital concentrations that were less than 90% of the lowest volunteer value. We concluded that return tablet count grossly overestimates compliance.

Use of a pharmacologic indicator to compare compliance with tablets prescribed to be taken once, twice, or three times daily

By use of an interview, return tablet count, and a pharmacologic indicator (low‐dose phenobarbital), we compared compliance with tablets prescribed to be taken once, twice, or three times daily. One hundred seventy‐nine patients with type II diabetes were randomly allocated to take one 2 mg phenobarbital tablet once, twice, or three times daily for 28 days. Phenobarbital level/dose ratios indicated that compliance was similar with once‐ and twice‐daily regimens, and both were better than thrice‐daily dosing. Mean return tablet counts suggested that compliance was best with the once‐daily regimen; both twice‐ and thrice‐daily regimens were similarly inferior. This difference between the techniques may be explained by the inadequacies of the residual tablet count, which identified only 13% of cases identified by phenobarbital. We conclude that compliance with the once‐daily regimen was best, but that compliance with a twice‐daily regimen was very similar, and both were superior to dosing three times a day.

Tolerance to the anticonvulsant effect of benzodiazepines

Abstract The use of benodiazepines in the long-term treatment of epilepsy is greatly restricted by their capacity to induce tolerance. In the last ten years, this phenomenon has attracted widespread research interest, both as a means of investigating mechanisms of action and in an attempt to discover how such problems might be avoided. Animal models of anticonvulsant tolerance have been developed which correlate well with the clinical observations and also suggest that benodiazepines differ in their intrinsic tolerance-inducing potential. Jeremy Haigh and Morgan Feely discuss how this evidence, coupled with the advent of new benodiazepine receptor ligands and an increasing awareness of the limitations of alternative novel chemical entities, may signal a resurgence of interest in the possible use of particular benodiazepines in the prophylaxis of epilepsy.

Ro 16 6028 a benzodiazepine receptor partial agonist does not exhibit anticonvulsant tolerance in mice

The development of anticonvulsant tolerance with RO 16-6028, a benzodiazepine receptor partial agonist, was assessed in mice using an i.v. infusion of pentylenetetrazol as the convulsive stimulus. In contrast to other benzodiazepines tested previously in this seizure model the anticonvulsant protection afforded by RO 16-6028 did not change significantly during 10 days treatment (2 mg/kg b.i.d.). This result supports the hypothesis that partial agonists at the benzodiazepine receptor may induce less tolerance and/or dependence than full agonists.

Can benzodiazepines be classified by characterising their anticonvulsant tolerance-inducing potential?

The development of anticonvulsant tolerance with three benzodiazepines was assessed in mice using a slow intravenous infusion of pentylenetetrazol as the convulsive stimulus. Chlordiazepoxide (12.5 mg/kg b.d.) and midazolam (0.75 mg/kg b.d.) induced a slowly evolving tolerance over 15 days whereas nitrazepam (0.6 mg/kg b.d.) induced a very marked rapid tolerance which developed no further during 6 days treatment. Tolerance appeared to be incomplete with all three benzodiazepines. Possible explanations for the differences in tolerance profile are discussed and an alternative basis for the classification of benzodiazepines is suggested.

Benzodiazepine cross-tolerance in mice extends to sodium valproate

Slow intravenous infusion of pentylenetetrazol was used to measure the convulsive threshold in mice. The anticonvulsant effects of clobazam, clonazepam, diazepam, lorazepam, sodium phenobarbitone and sodium valproate were assessed in naive animals and compared with the effects of the same compounds in animals which had been pretreated (twice daily for 3 days) with one of the benzodiazepines or sodium valproate. Cross-tolerance was observed between all the benzodiazepines but not between benzodiazepines and sodium phenobarbitone. Animals pretreated with the benzodiazepines were cross-tolerant to valproate, but the converse was not true; nor did sodium valproate induce tolerance to itself.

Lack of anticonvulsant tolerance with RU 32698 and Ro 17-1812

Possible development of anticonvulsant tolerance to three benzodiazepine receptor ligands was assessed in mice using an i.v. infusion of pentylenetetrazol as the convulsive stimulus. Extensive tolerance developed rapidly in the case of diazepam (0.35 mg/kg b.d. or 1.5 mg/kg b.d.). No significant tolerance was seen with the imidazopyrimidine derivative RU 32698 (9 mg/kg b.d.) or the partial agonist benzodiazepine Ro 17-1812 (1 mg/kg b.d.) These results provide further support for the hypothesis that partial agonists at the benzodiazepine receptor induce less tolerance than full agonists.

Undertreatment of patients with Alzheimer's disease in an elderly United States population

The aim of this study was to assess the undertreatment of elderly mild to moderate Alzheimers disease (AD) patients in the United States utilizing baseline data from a community‐based trial that has established comparability to national survey samples on demographic characteristics.