Effect of everolimus on skin lesions in patients treated for subependymal giant cell astrocytoma and renal angiomyolipoma: final 4-year results from the randomized EXIST-1 and EXIST-2 studies.

BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder associated with tumour growth in various organs, including the brain, kidneys, heart and skin. Cutaneous lesions are prevalent manifestations of TSC, occurring in up to 90% of patients. Oral mammalian target of rapamycin inhibitors, such as everolimus, is believed to be effective for treatment of TSC-associated lesions because they act on the underlying disease pathophysiology. OBJECTIVE: We evaluated the long-term effect of oral everolimus on TSC-associated skin lesions as a secondary objective in the phase III studies EXIST-1 (NCT00789828) and EXIST-2 (NCT00790400) after approximately 4 years of treatment. MATERIALS AND METHODS: Everolimus was dosed 4.5 mg/m2 /day (titrated to trough 5-15 ng/mL) in patients with TSC-associated subependymal giant cell astrocytoma in EXIST-1, and 10 mg/day initially in adult patients with TSC- or sporadic lymphangioleiomyomatosis-associated renal angiomyolipoma in EXIST-2. Following positive results from the core phase, remaining patients were offered open-label everolimus in an extension. Skin lesion response rate was the proportion of patients achieving complete or partial clinical response. RESULTS: A total of 105 patients in EXIST-1 and 107 in EXIST-2 received everolimus and had ≥1 skin lesion at baseline. Skin lesion response rate (95% confidence interval) was 58.1% (48.1-67.7%) in EXIST-1 and 68.2% (58.5-76.9%) in EXIST-2; most were partial responses. At week 192 (EXIST-1: n = 55; EXIST-2: n = 56), 69% and 66% had a response. Most common drug-related adverse event was stomatitis (41-45%). CONCLUSION: Oral everolimus improved TSC-related skin lesions, with responses sustained over 4 years of treatment in EXIST-1 and EXIST-2.

Tuberous sclerosis complex: neurological, renal and pulmonary manifestations.

Tuberous sclerosis complex (TSC) is an important cause of epilepsy and autism, as well as renal and pulmonary disease in adults and children. Affected individuals are subject to hamartomas in various organ systems which result from constitutive activation of the protein kinase mTOR (mammalian target of rapamycin). The clinical course, prognosis and appropriate therapy for TSC patients are often different from that for individuals with epilepsy, renal tumors, or interstitial lung disease, from other causes. Additionally, TSC serves as a model for other conditions in which the mTOR pathways are also up-regulated. This article reviews the molecular pathophysiology and management of neurological, renal and pulmonary manifestations of the disorder. The use of mTOR inhibitors such as rapamycin and everolimus is discussed and recent clinical trials of these drugs in TSC are reviewed.

Dorsal root potentials and ventral root reflexes evoked by nonmyelinated fibers.

Electrical stimulation of C-fibers in the cat superficial peroneal nerve, with the A-fibers either conducting or blocked by cold, evoked dorsal root potentials having the same polarity as those evoked by A-fibers. Ventral root reflexes evoked by A-fibers were facilitated by a pure C-volley in the same or another nerve, but dorsal root potentials evoked by A-fibers were reduced by isolated dorsal root potentials from C-fibers. In the absence of anesthetics, single C-volleys produced brisk and prolonged reflex discharges in ventral roots.

Spinal sympathetic neurons: possible sites of opiate-withdrawal suppression by clonidine.

Morphine, methadone, meperidine, fentanyl, and clonidine rapidly depressed transmission through sympathetic preganglionic neurons in cats with the spinal cord transected. Naloxone promptly antagonized this effect of the opiates but not that of clonidine which was reversed by alpha 2-adrenergic receptor antagonists. The independent depression of preganglionic neurons by clonidine may contribute to the ability of this drug to depress the symptoms of opiate withdrawal that are characterized by sympathetic hyperactivity.

Lithium enhancement of central 5-HT transmission induced by 5-HT precursors.

The effects of acute and chronic lithium chloride administration on synaptic transmission between bulbospinal norepinephrine (NE) or 5-hydroxy-tryptamine (5-HT) pathways and sympathetic preganglionic neurons were tested in unanesthetized, spinal cats. Discharges recorded from sympathetic preganglionic white rami were evoked by stimulation of spinal reflex pathways or descending excitatory pathways in the cervical spinal cord. Acute lithium administration (2 meq/kg) produced insignificant depression of the reflex pathway but markedly depressed transmission through the intraspinal pathway, an effect that was prevented by depletion or blockage of 5-HT. These observations and the failure of lithium to alter the typical effects of L-dopa on both pathways indicate that lithium does not affect transmission through the excitatory NE pathway. L-Tryptophan (1,0 mg/kg) alone produced little or no depression of either pathway, but 3--4 hr after lithium, this dose of L-tryptophan gradually depressed transmission through both pathways by about 20%. After chronic lithium pretreatment (1 meq/kg twice a day for 3 days), L-tryptophan rapidly depressed transmission through spinal reflex and intraspinal pathways by 40% and 50% respectively. Chronic lithium pretreatment also more than doubled the depression of transmission through both pathways produced by 30 mg/kg of 5-HTP. The average of plasma lithium levels 8--10 hr after the last chronic dose was 1.5 meq/liter. These results support the proposal that lithium increases the uptake of L-tryptophan and 5-HTP by central 5-HT terminals and thereby enhances 5-HT synthesis which is reflected in increased transmission at central 5-HT synapses.

Topiramate therapy of epilepsy associated with Angelman's syndrome.

Angelman's syndrome, a genetic disorder involving a defect in the DNA coding for subunits of the gamma-aminobutyric acid (GABA) type A receptor, often is associated with intractable epilepsy. Topiramate is a novel anticonvulsant that enhances GABAergic neurotransmission. Five children with Angelman's syndrome and epilepsy were treated with topiramate for clinical indications. The drug was effective and well tolerated, possibly because of its GABAergic properties. Further studies are necessary to confirm and elucidate this observation.

Cardiac complications in pediatric patients on the ketogenic diet.

Cardiac complications of the ketogenic diet, in the absence of selenium deficiency, have not been reported. Twenty patients on the ketogenic diet at one institution were investigated. Prolonged QT interval (QTc) was found in 3 patients (15%). There was a significant correlation between prolonged QTc and both low serum bicarbonate and high beta-hydroxybutyrate. In addition, three patients had evidence of cardiac chamber enlargement. One patient with severe dilated cardiomyopathy and prolonged QTc normalized when the diet was discontinued.

Enhancement of central norepinephrine and 5-hydroxytryptamine transmission by tricyclic antidepressants. A comparison.

The relative abilities of 1--3 mg/kg of desipramine (DES), imipramine (IMIP), amitriptyline (AMI), and chlorimipramine (CI-IMIP) to enhance synaptic transmission mediated by either NE or 5-HT were determined by testing their effects directly on NE or 5-HT transmission to sympathetic preganglionic neurons in unanesthetized, spinal cats. Effects on NE transmission were assessed on intraspinal excitatory pathways which utilize NE as a transmitter. Effects on 5-HT transmission were assessed on 5-HT-mediated depression of spinal sympathetic reflexes produced by 30 mg/kg of 5-HTP. Both DES and IMIP markedly enhanced transmission through the intraspinal excitatory NE pathways whereas AMI and CI-IMIP depressed transmission. However, both AMI and CI-IMIP modestly enhanced transmission in cats depleted of central 5-HT by pretreatment with parachlorophenylalanine. The relative potencies of the four drugs on excitatory NE transmission were DES greater than IMIP greater than AMI greater than CI-IMIP. Each of the four drugs also enhanced the 5-HTP-induced depression of spinal sympathetic reflexes, but their relative potencies on 5-HT transmission were just the opposite to those found on NE transmission. Therefore, all four drugs enhanced transmission by both NE and 5-HT, but their relative selectivities for the two transmitters differed markedly and were complementary. In general, the results support those of previous studies based on less direct methods for assessing inhibition of amine reuptake by tricyclic antidepressants.

Differential sensitivity of four central sympathetic pathways to depression by clonidine.

The dose-response effects of clonidine HCl (2.5-200 micrograms/kg i.v.) on transmission through somatospinal reflex, viscerospinal reflex, intraspinal, and spinal-bulbospinal reflex pathways were determined in spinal or chloralose-anesthetized cats to assess principle sites of drug action. Evoked sympathetic discharges were recorded from upper thoracic preganglionic rami. Clonidine rapidly produced parallel, dose-dependent depression of transmission through each pathway which was rapidly antagonized by tolazoline or yohimbine. The two spinal reflex pathways were least sensitive to depression which was identical and was limited to 60%. In contrast, both descending pathways could be depressed completely. Although the spinal-bulbospinal reflex pathway was more sensitive to depression than its efferent, descending intraspinal pathway alone, analysis of the relative depression of transmission at spinal and at brainstem levels indicates that the spinal site is more sensitive to clonidine that it is generally considered to be.

Evidence for inhibition of sympathetic preganglionic neurons by bulbospinal epinephrine pathways.

Two selective inhibitors of central epinephrine synthesis, LY 134046 and SKF 64139 (20 mg/kg, i.v.), gradually but markedly enhanced descending intraspinal transmission to sympathetic preganglionic neurons in spinal cats. Enhancement increased linearly to maximum values of 200% and 250%, respectively, at 4.5-5.5 h. Spinal sympathetic reflexes were not enhanced by either drug. The results support the proposal that bulbospinal epinephrine pathways depress the excitability of sympathetic preganglionic neurons by activating postsynaptic alpha 2-adrenergic receptors.

Clonidine prevents enhancement of spinal sympathetic transmission by phosphodiesterase inhibitors.

Preganglionic sympathetic discharges, evoked by cervical stimulation in spinal cats, were rapidly and markedly enhanced for 1-2 h by aminophylline or isobutylmethylxanthine. Clonidine depressed intraspinal transmission and prevented enhancement by the xanthines; alpha 2-receptor antagonists blocked the effect of clonidine and not only restored but also markedly prolonged the enhancement by the xanthines. The results suggest that the excitability of sympathetic preganglionic neurons is regulated by cyclic AMP through activation of different subtypes of adrenergic receptors that are either positively or negatively coupled to adenylate cyclase.

Diagnosis and management of tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal-dominant neurocutaneous disorder with a high spontaneous mutation rate. Understanding of this disorder has greatly increased in recent years. Two chromosomal loci can produce the TSC phenotype: 9q34 and 16p13. These appear to code for proteins that have a tumor suppressor function. TSC results in hamartomas that affect various organ systems, most commonly brain, skin, heart, and kidney. Previously thought to consist of intractable seizures, facial angiofibromas, and dementia, increasing numbers of persons with less severe involvement have been identified. Diagnostic criteria, various types of lesions, and medical management are reviewed.

Metachromatic leukodystrophy and nonverbal learning disability: neuropsychological and neuroradiological findings in heterozygous carriers.

Metachromatic leukodystrophy (MLD) is an autosomal recessive neurodegenerative disorder due to deficiency of the enzyme arylsulfatase A that leads to progressive, diffuse demyelination. The syndrome of nonverbal learning disability has been attributed to white matter abnormality and has been reported in children with this disorder and in some healthy family member carriers of gene. We examined the neuropsychologic profiles and MRIs of eight members of the family of a 7-year-old girl with this disease, all of whom were heterozygous carriers of the mutation and five of whom were also carriers of the MLD pseudodeficiency gene. All had low normal levels of arylsulfatase A, and seven of the eight had average or better profiles across all assessed neuropsychological domains. The patient's younger sister had a profile with features of the syndrome of nonverbal learning disability despite a normal MRI, whereas two members with minor white matter findings did not. This family does not provide evidence for the syndrome of nonverbal learning disability in heterozygous carriers of the gene for MLD, even when associated with the MLD pseudodeficiency gene.

L-dopa-induced hypotension: depression of spinal sympathetic neurons by release of 5-hydroxytryptamine.

In studies designed to determine the respective functional roles of two bulbospinal monoaminergic pathways to sympathetic preganglionic neurons, both L-dopa and precursors of 5-HT depressed transmission through excitatory spinal reflex and bulbospinal sympathetic pathways. Transmission through spinal reflex pathways was secondarily enhanced after L-dopa. Pharmacological tests indicated mediation of these affects by monoamines. After antagonism or depletion of central 5-HT, L-dopa only enhanced transmission through both pathways. The results indicate that hypotension and other sympathoinhibitory effects of L-dopa are produced at the spinal level by release of 5-HT from terminals of bulbospinal 5-HT pathways that are inhibitory to sympathetic preganglionic neurons. The excitatory effects of L-dopa are apparently mediated by release of catecholamines from bulbospinal noradrenergic pathways that are excitatory.