Clotrimazole analogues: effective blockers of the slow afterhyperpolarization in cultured rat hippocampal pyramidal neurones.

1. The pharmacology of the slow afterhyperpolarization (sAHP) was studied in cultured rat hippocampal pyramidal neurones. 2. Clotrimazole, its in vivo metabolite, 2-chlorophenyl-bisphenyl-methanol (CBM) and the novel analogues, UCL 1880 and UCL 2027, inhibited the sI(AHP) with similar IC50s (1-2 microM). 3. Clotrimazole and CBM also inhibited the high voltage-activated (HVA) Ca2+ current in pyramidal neurones with IC50s of 4.7 microM and 2.2 microM respectively. UCL 1880 was a less effective Ca2+ channel blocker, reducing the HVA Ca2+ current by 50% at 10 microM. At concentrations up to 10 microM, UCL 2027 had no effect on the Ca2+ current, indicating that its effects on the sI(AHP) were independent of Ca2+ channel block. 4. Clotrimazole also inhibited both the outward holding current (IC50=2.8 microM) present at a potential of -50 mV and the apamin-sensitive medium AHP (mAHP; IC50 approximately amp;10 microM). The other clotrimazole analogues tested had smaller effects on these two currents. The present work also shows that 100 nM UCL 1848, an inhibitor of apamin-sensitive conductances, abolishes the mAHP. 5. Currents were recorded from HEK293 cells transfected with hSK1 and rSK2. The SK currents were very sensitive to inhibition by UCL 1848 but were not significantly reduced by the sI(AHP) inhibitor, UCL 2027 (10 microM). 10 microM UCL 1880 reduced the hSK1 current by 40%. 6. UCL 2027 appears to be the first relatively selective blocker of the sAHP to be described. Furthermore, the ability of UCL 2027 to block the sAHP with minimal effect on SK1 channel activity questions the role of this channel in the sAHP.

Fractures of the femoral neck in the 'young' elderly.

Eighty-six patients, aged under 60 years, who had sustained fractures of the femoral neck, were studied, as well as the circumstances of injury and the long term medication they may have had. They were divided into two groups: 'injured' (38), with an average age of 41 years, and the 'uninjured' (48), with an average age of 55 years. Unlike other series, the male to female ratio was equal. Trochanteric fractures were more common in men involved in high speed accidents and the prognosis was excellent, but subcapital fractures were most frequent in patients with concurrent illness and 77 per cent were taking drugs which could affect bone density. The prognosis in these relatively young patients with subcapital fractures was no different from that in much older patients: 28.5 per cent developed avascular necrosis and 21.4 per cent required prosthetic replacement.