Patch clamp studies on the kinetics and selectivity of N-methyl-d-aspartate receptor antagonism by memantine (1-amino-3,5-dimethyladamantan)

Memantine (1-amino-3,5-dimethyladamantan) was tested as an antagonist of N-methyl-d-aspartate (NMDA) receptors on cultured superior collicular and hippocampal neurones using the patch clamp technique and its actions were compared to those of Mg²⁺ ions, ketamine, dextrorphan, dextromethorphan, phencyclidine and dizocilpine (MK-801). Memantine (2–33 μM) concentration-dependently antagonized responses to NMDA 100 μM with an IC₅₀ of 2.92 ± 0.05 μM. In contrast, current responses to (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (l-AMPA 50–100 μM) and γ-amino butyric acid (GABA 10 μM) were unaffected by Memantine 8 μM. Memantine 8 μM caused a non-parallel shift of the NMDA concentration-response curve to the right in a manner indicative of uncompetitive open channel block. The effects of memantine were similar to ketamine in that both antagonists were weakly use- and strongly voltage-dependent. In contrast, MK-801, phencyclidine and dextrorphan showed much slower kinetics that was reflected in their marked use- and weaker voltage-dependency. The antagonistic effects of memantine were not reversed by increasing concentrations of glycine (0.1–100 μM) ruling out the possibility of an interaction of memantine with the strychnine-insensitive glycine modulatory site associated with the NMDA receptor-channel complex. Memantine (1–100 μM) also selectively antagonized responses to NMDA (40 μM) in the cortical wedge preparation with IC₅₀ of 12.9 ± 1.5 μM.     

Does the health status of chronically ill patients predict their judgements of the quality of general practice care?

Patients' health status as well as patients' judgements of care are used for assessing patients' perspectives, but the relation between those two concepts is unclear. In this study we explored whether health status predicts patients' judgements of the quality of general practice care. Hand-distributed and mailed surveys were performed by 28 general practitioners in The Netherlands. Chronically ill patients were approached when visiting the general practice or drawn from the practice registers. Health status was measured by WONCA/COOP charts, and patients' judgements by the CEP, a previously validated questionnaire. The response rate was 63% (n=762). When controlled for other patient characteristics, a poor overall health predicted less positive judgements of medical care, information, counselling, relation and communication, continuity of care and the organization of appointments (p[lessthan]0.01). Poor mental well-being predicted less positive judgements of the cooperation between care providers and a stronger need for more care (p[lessthan]0.001). The four other aspects of health status did not predict the patients' judgements. Judgements about the premises and the availability for emergencies were not predicted by health status. It can be concluded that a multidimensional approach should be used for interpreting the relations between patients' health status and their judgements of general practice care.     

Genotypic selection of mutated DNA sequences using mismatch cleavage analysis, a possible basis for novel mutation assays

A novel technique for the selection of mutated DNA sequences,termed mismatch cleavage-polymerase chain reaction (MC-PCR),is proposed. The method is based on hybridizing genomic DNAwith a suitable probe, several 100 bp long. Mutated DNA sequenceswill form mismatched heteroduplexes which are cleaved by usingresolvases. Cleaved heteroduplexes are detected by ligationto an oligonucleotide adaptor and then amplified by using PCR.If practical, this technique would have considerable advantagesover the restriction site mutation (RSM) method. Failure toachieve cleavage efficiencies of close to 100% will not compromisesuccess. This is because positive signals (PCR amplification)arise from cleaved mutated sites and not, as in RSM, from DNAsequences resistant to cleavage by restriction endonucleases.Furthermore, the mutational target is much larger than in RSM.It would be possible to screen stretches of DNA several 100bp in length for mutations. Any mutation, independent of itslocation, could be identified. The usefulness of MC-PCR forthe genotypic selection of mutants will depend on the effectivenesswith which a small number of mismatched heteroduplexes can berecognized, cleaved and ligated. ¹To whom correspondence should be addressed     

Practice‐based evidence: benchmarking NHS primary care counselling services at national and local levels

There are a number of problems for evidence‐based practice (EBP) including limited generalizability of efficacy research results, the consequent lack of confidence in the relevance of such research, and the conceptual distance of most practitioners from the research process. The result is that EBP, although sound in principle, often fails to achieve its aim of improving practice. Practice‐based evidence (PBE) provides a complementary bridge for the gap between research and practice to offset some of these problems, promoting collaboration between mental health services and academic institutions. This paper presents the initial results of such a collaboration via three phases: (1) the development of a referential database for primary care counselling services, (2) ‘practitioner‐friendly’ feedback on grouped data to services, and (3) the combination of the two to build an evidence base for work with ethnic minorities—an area in which research trials are not well adapted to provide much evidence. Copyright © 2003 John Wily & Sons, Ltd.     

Academic Achievement of Children with Epilepsy

The academic achievement scores of 122 children with epilepsy were examined in relation to demographic and clinical seizure variables. As a group, these children were making less academic progress than expected for their age and IQ level. Academic deficiencies were greatest in arithmetic, followed by spelling, reading, comprehension, and word recognition. Results of the multiple regression analyses indicated a modest combined predictive significance of the demographic and clinical seizure variables for academic performance. In addition, the magnitude of these relationships varied by academic area. Among the individual variables examined the strongest correlates of academic performance were age of the child, age of seizure onset, lifetime total seizure frequency, and presence of multiple seizures (absence and tonic-clonic). These results are discussed in relation to developing an understanding of the factors which underlie academic vulnerability in children with epilepsy.     

Hydroxyurea potentiation of the antineoplastic activity of cyclophosphamide and 4′-(9-acridinylamino)methanesulfon-M-anisidide (AMSA) in the brown Norway rat myelocytic leukemia model

Summary The activities of hydroxyurea (HU), 4-(9-acridinylamino) methanesulfon-M-anisidide (AMSA) and cyclophosphamide (CY) were examined in the brown Norway rat myelocytic leukemia model in experiments designed to determine the synergy, optimal drug sequencing, and therapeutic index of combinations of these agents. A single dose of CY or four consecutive daily doses of AMSA produced increased survival in leukemic rats, with a positive-slope dose-response curve up to the maximum tolerated dose (MTD). HU at 1/2 MTD produced a minimal antileukemic effect but significantly potentiated the antineoplastic activity of 1/2 MTD of CY or AMSA with no significant toxic death rate. Drug-sequence experiments demonstrated that maximal synergy was achieved when HU was given immediately after CY but immediately before or during AMSA administration. No significant cure rate was seen with any CY/HU or HU/AMSA sequence. The three drugs given in the sequence of CY followed 3 days later by HU and AMSA simultaneously, however, was curative in the majority of rats with advanced leukemia, whereas other sequences were more toxic or less effective. Each of the drugs in these experiments was given at 1/2 of its single-agent MTD. HU significantly potentiates the antineoplastic effect of CY and AMSA in a drug-sequence-dependent manner in this model, apparently with an improved therapeutic index.Supported by the State of Nebraska Cancer and Smoking Disease Research Program Grant #87-10R