The actions of calmodulin antagonists W-7 and TFP and of calcium on the gating kinetics of the calcium-activated large conductance potassium channel of the chara protoplasmic drop: a substate-sensitive analysis.

The effects of the calmodulin antagonists W-7 and trifluoperazine have been measured on the Ca2+-activated potassium channel in the membrane surrounding protoplasmic drops expressed from internodal cells of charophyte plants. The large-conductance (170 pS), voltage- and Ca2+-dependent gating, and prominent conductance substrate of this channel shows a strong kinetic resemblance to those of the Maxi-K channel from animal cells. This is the first study of the action of calmodulin antagonists which measures their effects on the most populated substates as well as the closed and main open states of Maxi-K channels. The substate analysis provides new evidence for different modes of action of- and different bindings sites for these calmodulin antagonists. Neither antagonist produces the simple closure of the channel reported previously as its effect on the Maxi-K channel, though both do induce flicker-block, reducing the mean current to near zero at high concentrations following an inverted Michaelis-Menten curve. W-7 reduces residence time in the fully open state, thus raising, in the same proportions, the probabilities of finding the channel in the closed state or a pre-existing substate. Its binding to the channel is voltage- and calcium-dependent. In contrast, trifluoperazine reduces residence in the open state and promotes an apparently new substate which overlaps the closed state at -50 mV but is distinguishable from it at voltages more negative than -100 mV. This substate may represent times that trifluoperazine is bound to the channel. Both antagonists have effects clearly distinguishable from that of withdrawing calcium from the channel, which does not affect open state residence time but increases closed state residence time. Thus neither antagonist reverses the activating effect of Ca2-. This is good kinetic evidence against the view that the channel is activated by Ca2+-calmodulin and that the effect of a calmodulin antagonist is to reverse this process by making Ca2--calmodulin less available.

Psychological morbidity in women referred for treatment of hirsutism.

Sixty-nine pre-menopausal hirsute women were studied to determine the prevalence of psychological morbidity, and to identify factors associated with psychiatric symptoms. Measures used included: GHQ and POMS to assess psychological morbidity; self-esteem; personality (EPQ); and social adjustment, amongst other. About a third of subjects were found to be GHQ cases, one third had never discussed their hirsutism before, and two thirds avoided some social situations. Psychological morbidity was associated with poor social adjustment, higher levels of neuroticism and introversion, and avoidance of some social situations, but not with the severity of hirsutism or testosterone levels. The results suggest that a proportion of women with hirsutism experiences psychological and social difficulties, and that factors other than their dermatological status play an important part in their psychological difficulties.

Cyproterone acetate for severe hirsutism: results of a double-blind dose-ranging study.

OBJECTIVE: The objective was to determine if cyproterone acetate (CPA) therapy for hirsute women demonstrated a dose response. DESIGN: A double-blind dose-ranging study of the effect of 3 doses of cyproterone acetate for a period of 12 months. PATIENTS: Twenty-one hirsute women received the Dianette contraceptive pill (35 micrograms ethinyl oestradiol + 2 mg CPA, Schering Healthcare, UK), 20 received Dianette plus 20 mg CPA and 19 received Dianette plus 100 mg CPA: supplementary CPA was administered on days 1-10 of the birth control pill cycle as described by Hammerstein. MEASUREMENTS: Hair growth was measured using the clinical scale of Ferriman and Gallwey and by direct measurement of hair shaft diameter and linear growth of hair on the face, forearm, abdomen and thigh. RESULTS: Thirty-eight women completed 12 months therapy, eight withdrew due to side-effects and 14 were lost to follow-up. All three dose schedules produced significant reductions in clinical hair growth scores. This reduction was seen after 6 months with Dianette alone (P less than 0.005) and after 3 months with both the higher doses (P less than 0.01). There were no significant differences between the effect of different doses at any of the three-monthly time points. Hair diameter measurements were reduced by all doses after 12 months: face by 27*, 37, 37%*, forearm 5, 10, 8%*, abdomen 22*, 39*, 33%*, thigh 12, 24*, 30%* (median reductions (*P less than 0.01) for Dianette, D + 20 mg CPA and D + 100 mg CPA respectively). There were no significant reductions in daily linear growth rates. A comparison of the percentage reduction in hair shaft diameter at each site demonstrated no significant difference between doses, although the reductions by the three doses on the forearm, abdomen and thigh suggested a trend towards a dose response. CONCLUSIONS: We conclude that cyproterone acetate 2 mg daily appears to be as effective as higher doses in the therapy of hirsute women.

Spironolactone is an effective and well tolerated systemic antiandrogen therapy for Hirsute women.

We treated 22 hirsute women with spironolactone in an open trial to determine whether it caused objective changes in hair growth. Among them, 18 women completed 12 months therapy with 200 mg spironolactone daily. During this period, the mean daily linear growth rates of hair on the face, abdomen, and thigh were reduced to 66% (P less than 0.001), 75% (P less than 0.01), and 72% (P less than 0.001) of their pretreatment values. The mean hair shaft diameters were reduced to 83% (P less than 0.01) on the face, 88% (P less than 0.001) on the arm, 74% (P less than 0.01) on the abdomen, and 80% (P less than 0.001) on the thigh. Daily hair volume production was calculated from the diameter and daily growth rate; it was reduced to 60% (P less than 0.01) on the face, 52% (P less than 0.01) on the arm, 34% (P less than 0.001) on the abdomen, and 48% (P less than 0.001) on the thigh. Six of the 18 women who completed the study developed midcycle vaginal bleeding, and 3 women had previously irregular menstrual cycles regulated. We conclude that spironolactone is effective and well tolerated for hirsute women.