Appropriateness and surveillance of medication in a cohort of diabetic patients on polypharmacy.

CONTEXT: It is assumed that with increasing polypharmacy, medication surveillance by the General Practitioner (GP) and adherence to the therapy regimen by the patient will both decline. AIM OF THE STUDY: We evaluated clinical and medication records taken from GP documentations in a cohort of 102 diabetic patients (48 f, 54 m, median age 70, range 39 - 81) with 3 or more chronic prescriptions. Patients were asked about their current medication and its tolerability by means of a structured telephone interview. RESULTS: 45% of the patients received up to 6 medications, 36% 7 - 9 and 19% > 10. The main comorbidity was hypertension (93%) and symptomatic CAD (39%). The use of established medications (beta-blockers and ACE inhibitors) for these comorbidities was appropriate. Although 76% were eligible for a statin therapy, only 51% actually took a statin, and 28% had a dose lower than the defined daily dose. 68% of the patients had no prescriptions other than those recorded in the GP documentation, but 8% of the total number of medicines taken by the patients were not recorded in the GP's database. 62% of patients took all the medication prescribed by the GP, while 7% of all medicines recorded in the GP's database were not taken by the patients. In 10% of cases, an incompatible medication (defined in accordance with a consented list) was taken by the patient. 81% of patients regularly (twice per year) had their HbA1c checked, but only 62% had their potassium levels checked, despite the use of ACI and diuretics. Most patients knew the reason for taking at least one medication, but 18% knew this for less than half of their (multiple) medications. 70% of the patients said they had been informed about the possible risks of their medication by the GP, and 7% knew the risks for only one medication. CONCLUSION: In this cohort of patients on polypharmacy and with a high risk profile for adverse drug reactions, we found a mismatch between GPs' documentation of prescriptions and the medication taken by the patient. Patients had no detailed knowledge about indications and almost no knowledge about risks. Although the overall performance of therapy (appropriateness) was deemed sufficient, there would appear to be room for improvement in order to fill information gaps and strive for stricter surveillance.

Electrically evoked release of glutamate in rat hippocampal slices: effects of various drugs and fimbria-fornix lesions.

A model of electrically evoked release of glutamate from rat hippocampus was developed and used to detect possible changes induced by lesions of hippocampal afferences. Neuronal glutamate in hippocampal slices was labelled by preincubation with [3H]glutamine. The slices were then superfused with physiological medium in the presence of the glutamate uptake inhibitor L-transpyrrolidine-2,4-dicarboxylic acid (100 microM or 3 microM) and stimulated twice electrically (S1, S2: 240 pulses, 3 Hz, 2 ms, 26-30 mA); various drugs were added before S2. In order to determine the basal and evoked outflow of [3H]glutamate only, the mixture of 3H-labelled compounds (glutamine, glutamate and GABA) was separated by ion exchange chromatography in superfusate fractions and slices. The electrically evoked overflow of [3H]glutamate was largely Ca2+-dependent and tetrodotoxin-sensitive and hence represented action potential-induced exocytotic release of [3H]glutamate. Evoked [3H]glutamate release was significantly increased by the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 0.1 microM), suggesting the presence of endogenous inhibitory adenosine, and reduced by the A1 receptor agonist N6-cyclopentyladenosine (1 microM, antagonized by DPCPX, 0.1 microM). There was no evidence for a cholinergic, serotonergic, or adrenergic modulation of the evoked release of [3H]glutamate: the corresponding selective agonists (or antagonists) were ineffective. After aspirative lesions of the septohippocampal pathways the hippocampal noradrenaline content was markedly increased, whereas cholinergic and serotonergic markers were reduced. The evoked release of [3H]glutamate in hippocampal slices of lesioned rats was significantly increased by a mechanism which still has to be determined, but which is not related to alterations in A1 receptor function. It is concluded that the present model was able to detect lesion-induced differences in electrically evoked release of [3H]glutamate, but the relationship of these differences to changes of noradrenergic, cholinergic or serotonergic hippocampal innervations remains to be established.

Gabapentin-lactam (8-aza-spiro[5,4]decan-9-on; GBP-L) inhibits oxygen glucose deprivation-induced [3H]glutmate release and is a neuroprotective agent in amodel of acute retinal ischemia.

The modulation of the enhanced release of [3H]glutamate following ischemia-like conditions was studied in rat hippocampal slices using a superfusion system. Ischemia was simulated by a glucose-free medium equilibrated with 95% N2 and 5% CO2. In this model the potential neuroprotective effects of several substances on [3H]glutamate release induced by ischemia-like conditions were investigated. Gabapentin-lactam (8-aza-spiro-5,4-decan-9-on; GBP-L) was synthesised and patented in our laboratory. GBP-L (100 microM) reduced the oxygen glucose deprivation-induced [3H]glutamate release by 42.5%, CI95=[33.4%, 51.5%]. The KATP channel antagonist glibenclamide (1 microM) blocked this effect completely. The high antagonist potency was reflected by an apparent pA2-value of glibenclamide of 8.3, CI95=[6.8, 9.4]. Minoxidil sulfate (10 microM), a KATP channel opener, mimicked the effect of GBP-L (inhibition by 22.8%, CI95=[13.2%, 32.5%]). Similarly to its lactam, also gabapentin (100 microM) reduced the oxygen glucose deprivation-induced [3H]glutamate release by 30.6%, CI95=[15.5%, 45.7%], whereas the "antiglutamatergic" drug riluzole was ineffective. GBP-L and gabapentin were also tested in an in vivo model of acute retinal ischemia in rats. The intraocular pressure was elevated for 1 h above the systolic blood pressure. In the control group, 17.5%, CI95=[13%, 22%], of retinal ganglion cells had survived after 2 weeks. GBP-L doubled the number of surviving ganglion cells up to 35%, CI95=[27%, 43%], while gabapentin had no effect. This difference between gabapentin and its lactam may be due to different pharmacokinetic properties: In contrast to the gamma-amino acid gabapentin, GBP-L is uncharged and therefore might diffuse more easily through biological membranes, e.g. the plasma membrane, to get access to an intracellular locus of action. Thus, the neuroprotective properties in vivo and the diminished oxygen glucose deprivation-induced [3H]glutamate efflux in vitro of the presumed KATP channel agonist GBP-L suggest that this substance might be therapeutically applied in pathological situations induced by a rise in extracellular glutamate and/or neuronal cell death.

Effects of riluzole on electrically evoked neurotransmitter release.

1. The main purpose of the present study was to investigate the effects of the neuroprotective agent riluzole on the electrically evoked release of [(3)H]-glutamate ([(3)H]-Glu) in mouse neocortical slices. The reported selectivity of riluzole for excitatory amino acids was tested in release experiments with further neurotransmitters. Also distinct species, mouse, rat and man were compared. 2. [(3)H]-Glu was formed endogenously during incubation of slices with [(3)H]-glutamine ([(3)H]-Gln). Released [(3)H]-Glu and tissue [(3)H]-Glu was separated by anion exchange chromatography. Electrically evoked [(3)H]-Glu release was strongly diminished by tetrodotoxin (TTX) and Ca(2+)-withdrawal. 3. Riluzole (100 microM) depressed the release of [(3)H]-Glu up to 77% (IC(50)=19.5 microM). Riluzole was also able to inhibit strongly the electrically evoked release of [(3)H]-acetylcholine ([(3)H]-ACh) (at 100 microM by 92%, IC(50)=3.3 microM, and [(3)H]-dopamine ([(3)H]-DA) (at 32 microM by 72%, IC(50)=6.8 microM). However, the release of [(3)H]-serotonin ([(3)H]-5-HT) was less diminished (at 100 microM by 53%, IC(50)=39.8 microM). Riluzole up to 100 microM did not affect [(3)H]-noradrenaline ([(3)H]-NA) release. 4. Between species, i.e. in mouse, rat and human neocortex, no significant differences between the effects of riluzole could be observed. 5. The NMDA-receptor blocker MK-801 (1 microM) and the AMPA/Kainate-receptor blocker NBQX (1 microM) did neither affect the electrically evoked [(3)H]-ACh release nor its inhibition by riluzole, indicating that effects of riluzole on transmitter release were neither due to modulation of ionotropic Glu receptors, nor due to indirect inhibition of Glu release through these receptors. 6. Taken together, riluzole inhibits the release of distinct neurotransmitters differently, but is not selective for the excitatory amino acid Glu.