Ivan S. Login

Tetrabenazine as antichorea therapy in Huntington disease: A randomized controlled trial

BACKGROUND Tetrabenazine (TBZ) selectively depletes central monoamines by reversibly binding to the type 2 vesicular monoamine transporter. Open-label reports indicate TBZ is effective in treating chorea. OBJECTIVE To examine the safety, efficacy, and dose tolerability of TBZ for treating chorea in Huntington disease (HD). METHODS The authors randomized 84 ambulatory patients with HD to receive TBZ (n = 54) or placebo (n = 30) for 12 weeks. TBZ was increased over 7 weeks up to a maximum of 100 mg/day or until the desired antichoreic effect occurred or intolerable adverse effects supervened. The primary outcome was the change from baseline in the chorea score of the Unified Huntingtons Disease Rating Scale (UHDRS) RESULTS: TBZ treatment resulted in a reduction of 5.0 units in chorea severity compared with a reduction of 1.5 units on placebo treatment (adjusted mean effect size = -3.5 +/- 0.8 UHDRS units [mean +/- SE]; 95% CI: -5.2, -1.9; p < 0.0001). There was also a significant benefit on ratings of clinical global improvement. There were five study withdrawals in the TBZ group and five serious adverse events (SAEs) in four subjects (drowning suicide, complicated fall, restlessness/suicidal ideation, and breast cancer) compared with one withdrawal and no SAEs in the placebo group. CONCLUSION Tetrabenazine (TBZ), at adjusted dosages of up to 100 mg/day, effectively lessens chorea in ambulatory patients with Huntington disease. TBZ should be dosed individually based on ongoing assessment of possible adverse side effects.

Prolactin in human and rat serum and cerebrospinal fluid

Rats treated with haloperidol or bearing subcutaneous implants of prolactin-secreting tumors had elevated CSF prolactin levels compared to those observed in control rats. These levels were commensurate with the increased serum level of prolactin, although there appeared to be an upper limit to the CSF prolactin concentration. Patients with prolactin-secreting pituitary adenomas had elevated CSF hormone levels as compared to patients with non-endocrine neurologic disease. This obtained, regardless of whether the tumor was intra- or extrasellar in its growth. The implications for the route of entry of prolactin into CSF under both normal and abnormal conditions, and the potential role for CSF prolactin as part of a feedback regulatory system on pituitary prolactin release are discussed.

DIRECT STIMULATION OF PITUITARY PROLACTIN RELEASE BY GLUTAMATE

The ability of glutamate and other excitatory amino acids to stimulate prolactin secretion when administered to adult animals is hypothesized to depend on a central site of action in the brain, but there are no data to support this position. An alternative hypothesis was tested that glutamate would stimulate prolactin release when applied directly to primary cultures of dispersed adult female rat anterior pituitary cells studied in a perifusion protocol. Glutamate increased the rate of prolactin release within two minutes in a self-limited manner. Glutamate-stimulated prolactin release was augmented about 4-fold by elimination of magnesium from the perfusate and was associated with stimulation of pituitary calcium flux. Ketamine and MK-801 both reduced the basal rate of prolactin release and abolished the effects of glutamate. Pituitary cells of 10-day-old rats responded similarly to glutamate. Exposure to glutamate did not influence subsequent responses to physiological hypothalamic secretagogues, thus the likelihood of toxicity was minimized. These results suggest that the N-methyl-D-aspartate (NMDA) subclass of the glutamate receptor complex is involved. Prolactin secretion may be regulated physiologically through a functional glutamate receptor on pituitary cells.

Nonrhinologic headache in a tertiary rhinology practice

OBJECTIVE: Our goal was to determine the etiology of headache in patients who were referred for sinus evaluation but were found to have no evidence of rhinosinusitis on computed tomography (CT) of the sinuses and on endoscopic examination. METHODS: Data were collected prospectively from 100 patients with headache but with normal sinus CT and endoscopic examination. Headache and 20-Item Sino-Nasal Outcomes Test (SNOT-20) scores of patients with the chief complaint of headache and who requested further neurologic evaluation (group I) were compared with the scores of patients who did not list headache as a significant symptom (group II) and with the scores of patients without headache (group III). RESULTS: The most common neurologic diagnosis for group I patients (n = 36) was migraine headaches (58%). These patients also had higher mean SNOT-20 scores (24 ± 3.3) compared to group II patients with mild headache (14.6 ± 2.3) or group III patients without headache (12.4 ± 2.1). CONCLUSION: Migraine was the most common type of headache in patients with normal sinus CT treated for presumed rhinosinusitis as the cause of the headache. Patients with headache as their chief complaint that required further neurologic evaluation had overall higher SNOT-20 scores than nonheadache patients, indicating greater disability of their overall quality of life index. (Otolaryngol Head Neck Surg 2004;130:449-52.)

Zinc May Have a Physiological Role in Regulating Pituitary Prolactin Secretion

We studied the in vitro influence of physiologically relevant zinc concentrations on the pituitary synthesis and secretion of prolactin (Prl). Zinc in concentrations between 1 and 10 microM reduced Prl secretion and, to a milder extent, synthesis, but not basal or stimulated growth hormone (GH) or LH release. At a supraphysiological concentration of 100 microM, zinc markedly decreased Prl synthesis and secretion, but increased LH secretion. The ability of a physiological zinc concentration to influence Prl secretion suggests that this trace element may have a role in the in vivo regulation of Prl release.

Zinc acutely, selectively and reversibly inhibits pituitary prolactin secretion.

Perifusion of dispersed female rat pituitary cells with medium containing 50 microM zinc acetate caused an acute, sustained and rapidly reversible inhibition of prolactin (Prl) secretion. This treatment had no influence on basal release of thyrotropin stimulating hormone (TSH), luteinizing hormone (LH) or growth hormone (GH). 50 microM Zn2+ also reversibly inhibited prolactin secretion stimulated by either 50 mM K+ or 10 nM TRH, but the secretion of GH, TSH and LH which was stimulated by 50 mM K+ or stimulation of TSH by 10 nM TRH was not inhibited. Thus zinc acts in a dynamic manner to selectively influence pituitary prolactin secretion.

Activation of calcium channels by Maitotoxin

Publisher Summary This chapter describes three techniques that enhance the understanding of the action of maitotoxin by using 45Ca2+ to monitor calcium ion flux. The techniques are not new but are adapted for use with viable dispersed anterior pituitary cells in suspension. Methodology for monitoring 45Ca2+ uptake, fractional 45Ca2+ efflux, and net 45Ca2+ efflux are described with reference to the effects of maitotoxin on these processes. Maitotoxin is a water-soluble material extracted from a marine dinoflagellate and bears the Tahitian name for a species of surgeonfish in which it was also recognized. Maitotoxin is not yet characterized but is extremely lethal when injected into mice; it stimulates a wide variety of physiological processes, all sharing the apparent property of being dependent on extracellular calcium. The spectrum of its activity and the apparent lack of ionophoretic properties suggest that maitotoxin activates calcium channels to exert its biological actions.

Maitotoxin, a Calcium Channel Activator, Increases Prolactin Release from Rat Pituitary Tumor 7315a Cells by a Mechanism That May Involve Leukotriene Production

Arachidonate and its metabolites may play an important role in the release of prolactin. In the present study, the effect of maitotoxin, a calcium channel activator, was measured on the release of arachidonate and its metabolites from the prolactin-secreting 7315a tumor. Maitotoxin increased the release of prolactin, arachidonate, prostaglandins E2 and F2 alpha (PGE2, PGF2 alpha) and leukotriene C4 (LTC4) from 7315a cells prelabeled with [3H]arachidonate. The magnitude of the increase of prolactin and arachidonate release was decreased in low-calcium medium. The release of arachidonate from cellular phospholipids is necessary for the effect of maitotoxin on prolactin release because quinacrine, an inhibitor of arachidonate hydrolysis from phospholipids, blocked the maitotoxin-induced release of prolactin. The ability of maitotoxin to induce prolactin release appears to require metabolic transformation of arachidonate to its metabolites because BW755c, an inhibitor of the conversion of arachidonate, blocked the maitotoxin-induced prolactin release. In particular, LTC4 may be an important component of the prolactin release process because nordihydroguaiaretic acid and nafazatrom, which block the production of leukotrienes and other lipoxygenase-generated products, decreased LTC4 and prolactin release without affecting arachidonate, PGE2 or PGF2 alpha production. In contrast, indomethacin, a prostaglandin synthesis inhibitor, decreased PGE2 and PGF2 alpha production without affecting LTC4 or prolactin release. These data indicate that release of LTC4 and prolactin are closely linked events in 7315a tumor cells.

Failure or opiates to reverse dopamine inhibition of prolactin secretion in vitro

To identify the site of action of opiate-induced prolactin elevation, in vitro rat hemipituitary incubations were performed in the presence of morphine, met-enkephalin, ala2-met5-enkephalinamide and dopamine (DA) and combinations of opiate with the catecholamine. No opiate stimulated prolactin release directly nor did any opiate block the inhibitory effect of DA. We conclude that this opiate endocrine action is not mediated at a pituitary level but may involve interference with hypothalamic DA release.

Maitotoxin activates quantal transmitter release at the neuromuscular junction: evidence for elevated intraterminal Ca2+ in the motor nerve terminal

Maitotoxin (MTX), applied in vitro to the mouse neuromuscular junction, briskly activates the spontaneous release of acetylcholine quanta, manifest as miniature end-plate potentials (MEPPs). This effect requires external Ca2+ and is accompanied by a steady post-junctional depolarization. After the peak activation of the spontaneous release process, the quantal discharge gradually declines with eventual abolishment of MEPPs. In contrast to the striking increase in MEPP frequency, the quantum content of the nerve-evoked end-plate potentials (EPPs) is increased only moderately by MTX. These effects are attributable to the ability of the toxin to elevate the level of free intracellular Ca2+ in the motor nerve terminal. With further characterization of its presynaptic site of action, maitotoxin may become a useful tool in studying synaptic physiology.