A Phase I study of LGD1069 in adults with advanced cancer.

LGD1069 [Targretin; 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphtalenyl) propenyl] benzoic acid] is a novel synthetic retinoid X receptor-selective retinoid that has been recently identified. The goals of this study were to determine the safety, toxicity, pharmacokinetics (PKs), and metabolic profile of LGD1069 in advanced cancer patients. Sixty patients received oral LGD1069 at doses ranging from 5-1000 mg/m2/day with PK sampling performed on days 1 and 15. No dose-limiting toxicities (DLTs) were observed up to the 500 mg/m2/day dose level. DLT observed at and above 650 mg/m2/day included skin desquamation, hyperbilirubinemia, transaminase elevation, leukopenia, and diarrhea. Asymptomatic, dose-related alterations in lipid and thyroid metabolism were also observed. DLTs frequently observed with retinoic acid receptor-selective retinoids and pan agonists, including headache, mucocutaneous toxicity, and hypercalcemia, were not dose-limiting with LGD1069. Day 1 LGD1069 Cmax and area under the curve values increased dose-proportionately up to 800 mg/m2/day. Repeat-dose (day 15) area under the curve values varied between 25 and 105% of day 1 values. Although no objective tumor responses were observed, tumor progression may have been substantially arrested or delayed in non-small cell lung cancer (5 of 16) and in head and neck cancer (1 of 5), as well as other tumor types. At the higher dose levels, the molar concentration of LGD1069 was up to 10-fold higher than observed with other retinoids, yet toxicity was minimal. LGD1069 is an retinoid X receptor-selective retinoid agonist with a more favorable PK and toxicity profile than previously studied retinoids and merits further investigation as a chemopreventive and anticancer agent. On the basis of this Phase I trial, the recommended Phase II dose is 500 mg/m2/day.

Why does the central nervous system not regenerate after injury?

Spinal cord injuries in humans and in other mammals are never followed by regrowth. In recent years, considerable progress has been made in analyzing mechanisms that promote and inhibit regeneration. The focus of this review is changes that occur in the transition period in development when the central nervous system (CNS) changes from being able to regenerate to the adult state of failure. In our experiments we have used the neonatal opossum (Monodelphis domestica), which corresponds to a 14-day embryonic rat or mouse. The CNS isolated from an opossum pup and maintained in culture shows dramatic regeneration. Fibers grow through and beyond lesions and reform synaptic connections with their targets. Similarly, anesthetized neonatal pups attached to the mother recover the ability to walk after complete spinal cord transection. Although the CNS isolated from a 9-day-old animal will regenerate in vitro, CNS from a 12-day-old will not. This is the stage at which glial cells in the CNS develop. Present research is devoted toward molecular screening to determine which growth-promoting molecules decrease during development, which inhibitory molecules increase, and which receptors on growing axons become altered. Despite progress in many laboratories, major hurdles must be overcome before patients can hope to be treated. Nevertheless, the picture today is not as discouraging as it was: one can think of strategies for research on spinal cord injury so as to promote regeneration and restore function.

Metabolic and hemodynamic effects of magnesium supplementation in patients with essential hypertension.

The effect of magnesium supplementation on blood pressure, erythrocyte cation metabolism, and serum lipids was evaluated in 13 patients with mild hypertension. After randomization and a 3-wk placebo run-in period, seven patients received 40 mmol Mg aspartate (20 mmol elemental Mg twice daily) and six received placebo for 3 mo. In comparison with placebo treatment, magnesium aspartate therapy had no effect on blood pressure, lipid concentrations, or erythrocyte cation metabolism. These results demonstrate that in magnesium-repleted hypertensive subjects, magnesium supplementation does not affect blood pressure or lipids probably because magnesium has no effect on cellular cation metabolism in magnesium-replete individuals.

A pilot study of magnesium aspartate hydrochloride (Magnesiocard) as a mood stabilizer for rapid cycling bipolar affective disorder patients.

1. Nine severe rapid cycling manic-depressive patients were treated with a magnesium preparation, Magnesiocard 40 mEq/day in an open label study for a period up to 32 weeks. 2. Magnesiocard was found to have clinical results at least equivalent to those of lithium in about 50% of these patients. These results were obtained in an exploratory study and should be interpreted with caution. 3. The possibility that Magnesiocard could replace or improve the efficacy of lithium as a preventive treatment of manic-depressive illness merits further clinical investigation.

Respite care for mentally ill patients and their families.

An inpatient psychiatric unit at a Veterans Administration Medical Center offers regularly scheduled psychiatric respite care, an intervention intended to reduce recidivism among chronic patients who live with a family member and to support the family in their caregiving role. Patients and their families have the option of arranging for respite admissions for two to seven days at six- to eight-week intervals. Preliminary one-year data for 14 patients show that with participation in the respite program, subsequent hospital days are significantly decreased. Subjective data indicate that respite care helps stabilize improvements patients made in the hospital, allows staff to work with family systems in a nonadversarial manner, and gives the family needed relief from difficult behaviors.