Practice patterns of neurologists regarding bone and mineral effects of antiepileptic drug therapy.

BACKGROUND: Antiepileptic drug (AED) therapy has been linked to bone disease that can be treated and prevented with calcium and vitamin D. However, because there have been no definitive studies on this subject, many physicians might not be aware of this association. OBJECTIVE: To determine the approaches of neurologists to skeletal disorders in patients taking AEDs. DESIGN: A self-administered mail survey. PARTICIPANTS: United States board-certified or board-eligible pediatric (n = 404) and adult (n = 624) neurologists. MAIN OUTCOME MEASURES: Practice patterns of neurologists regarding methods of screening for bone disorders and recommendations for treatment and prophylaxis. RESULTS: Few pediatric (41%) and adult (28%) neurologists routinely evaluate AED-treated patients for bone and mineral disease. Of physicians who detect bone disease through diagnostic testing, 40% of pediatric and 37% of adult neurologists prescribe calcium or vitamin D, and about half (54% of pediatric and 57% of adult neurologists) refer patients to specialists. Few neurologists (9% of pediatric and 7% of adult neurologists) prescribe prophylactic calcium or vitamin D for patients taking AEDs. CONCLUSIONS: There is a lack of consensus among neurologists concerning the impact of AED therapy on bone. Because considerable evidence suggests that much of the bone pathology caused by AED therapy can be treated or prevented by administration of calcium and vitamin D, raising physician awareness of this problem could significantly improve the skeletal health of AED-treated individuals.

Calcitonin and the treatment of osteoporosis.

Calcitonin, a potent inhibitor of bone resorption, is an important agent for the treatment of osteoporosis. An analgesic effect of salmon calcitonin has also been reported. The recent development of calcitonin nasal spray should eliminate the need for injections.

Follicular and Hürthle cell carcinoma of the thyroid.

Follicular and Hürthle cell thyroid cancers account for about one fifth of thyroid cancers in the United States. Diagnosis can be difficult, despite the use of fine needle biopsy, and surgery is often necessary to make a definitive diagnosis. Total thyroidectomy is the treatment of choice, and in the case of follicular cancer, radioiodine ablation is usually performed. Distant metastatic disease can also be treated with radioiodine. For Hürthle cell tumors, radioiodine therapy is unlikely to be beneficial.

Stimulation of human fat cell adenylate cyclase by GDP and guanosine 5'-O-(2-thiodiphosphate).

GDP regulation of basal and receptor-mediated catecholamine-sensitive human fat cell adenylate cyclase was studied using purified plasma membrane preparations and assay conditions selected to minimize conversion of GDP to GTP. Under ordinary assay conditions (low NaCl concentration) and with App(NH)p as substrate to prevent GDP conversion to GTP, basal enzyme activity was stimulated up to 2-fold by GDP (0.1 mM) while addition of epinephrine (0.1 mM) eliminated stimulation by GDP and reduced basal adenylate cyclase activity. With ATP as substrate, the enzyme was not responsive to hormone in the absence of guanyl nucleotides and GDP augmentation of basal activity was small (0-1.5-fold) while stimulatory effects of epinephrine and isoproterenol were minimally but definitely exhibited (1.5-fold over basal). Guanosine 5'-O-(2-thiodiphosphate) (GDP beta S), a GDP analog resistant to phosphorylation and hydrolysis and an antagonist of GTP, stimulated enzyme activity more than did GDP but did not promote epinephrine action. Rather, inhibition of GDP beta S-stimulated adenylate cyclase activity was seen with both epinephrine and isoproterenol and also with GTP. In the presence of NaCl (200 mM), which alone produced 2-3-fold increase in basal enzyme activity, GDP (0.1 mM) and GDP beta S (50 microM) produced 8- and 15-fold increases of activity, respectively. Addition of UDP, to prevent possible conversion of GDP to GTP, had no effect on NaCl-enhanced activation by GDP. The results indicate that the human fat cell adenylate cyclase system is unique in responding to GDP and its analog GDP beta S by stimulation in the absence of hormone but suggest that as in other systems catecholamine-mediated stimulation is normally dependent on GTP. Salts (Na+) appear to stimulate the enzyme by facilitating the interaction of the guanyl nucleotide regulatory protein (N8) with the catalytic unit.

Mechanism of action of forskolin on adenylate cyclase: effect on bovine sperm complemented with erythrocyte membranes.

The mechanism of action of forskolin stimulation of adenylate cyclase was investigated by examining its effects on the enzyme's Mg2+ activated catalytic unit (C) from bovine sperm, both preceding and following complementation with human erythrocyte membranes as a source of guanine nucleotide regulatory protein (N). Prior to complementation, sperm C was not activated by either NaF (10 mM) or 5'-guanylyl-beta-gamma-imidodiphosphate (Gpp(NH)p, 10 microM), suggesting that functional N was not present in this preparation. Forskolin (100 microM) was also without effect on C. Following complementation of the sperm membranes with those of erythrocytes, Mg2+-dependent sensitivity to forskolin, NaF, and Gpp(NH)p was imparted to C. Our findings are incompatible with the current hypothesis that forskolin stimulates adenylate cyclase by direct activation of C. Rather, the data suggest that the activation process occurs through an effect on N or by augmentation of the interaction between the components of the adenylate cyclase complex.

Salts promote activation of fat cell adenylate cyclase by GTP: special role for sodium ion.

The effects of GTP on adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] of human and rat fat cell membranes ("ghosts" and purified membranes) were examined in the absence and presence of added inorganic salts. With human ghosts GTP alone (0.1 mM) inhibited enzyme activity by 40% at 30 degrees C and had no significant effect at 37 degrees C. At both temperatures Na+ salts of Cl-, N3-, and SO2-(4) stimulated activity (up to 4-fold basal activity for 200 mM NaN3), with maximal effects at salt concentrations of 100-200 mM. Over the same concentration range these salts also allowed temperature-dependent stimulation by GTP. GTP increased the maximal activity produced by salt alone by about 2-fold at 30 degrees C and about 4-fold at 37 degrees C. Na+ (added as Cl-) was much more effective than other alkali metal cations in promoting activation by GTP. Na+ salts allowed activation of the human enzyme by the GTP analog 5'-guanylyl imidodiphosphate and also promoted stimulation of rat fat cell adenylate cyclase by both nucleotides. In time course studies of human and rat fat cell ghosts, GTP appeared to sustain an initial high rate of salt-stimulated activity, which in the absence of nucleotide subsequently fell to a lower rate, suggesting that salts might activate adenylate cyclase by promoting the stimulatory effect of endogenous membrane-bound GTP. However, with purified human fat cell membranes and a GTP-free system, salts were still stimulatory and promoted activation by added GTP. These results differ from those of previous reports in other systems in which Na+ has promoted only inhibitory effects in GTP regulation of adenylate cyclase.