Structure of the low-density lipoprotein receptor-related protein (LRP) promoter.

The low-density Lipoprotein receptor-related protein (LRP) is a 4544-amino-acid membrane protein which closely resembles the LDL receptor in its arrangement of cysteine-rich motifs. Binding studies have suggested that one function of the molecule is as a receptor for ligands containing apolipoprotein E. We present here the sequence and structure of the promoter region of the LRP. These data show that the LRP contains no sterol regulatory element, and is not down-regulated by sterols like the LDL receptor. This lends further support to the identity of the LRP as a chylomicron remnant receptor.

Carbamazepine in difficult to control epileptic out-patients.

Twenty-three difficult to control patients with 1 or more seizures per week despite diphenylhydantoin (DPH), phenobarbital and/or primidone in near and toxic doses and blood levels were entered in the study. 3 had grand mal. 8 psychomotor seizures and 12 had both. During a 6 1/2 month study period the patient received active drug and placebo for 3 months each; randomized, double-blind. The dose was to be increased within 4 weeks up to 6 capsules per day equal to 1,200 mg of carbamazepine (C), while the doses or previously taken (basis) anticonvulsants were to remain unchanged. Hematopoetic system and heptic functions were monitored. Complete seizure control attributable to C was not achieved in any, but up to 50% improvement occurred in 12 patients. Questionable improvement was thought to take place in 3 patients, no change occurred in 7, and psychomotor seizures became more frequent in 1 patient. A clear-cut psychotropic effect was not observed. Adverse effects attributable to C were a decline of WBC below 4,000 with relative neutropenia in 3 patients followed by at return to the previous after discontinuation of C. Nystagmus and unsteadiness were seen in about half of the patients, and some headache and drowsiness occurred in one quarter. The highest C blood level was 11.8 mug/ml, the lowest 3.8 mug/ml (average 5.6 mug/ml) during 1,200 mg intake. It seemed, generally, that intoxication occurred with lower blood levels of carbamazepine in those patients whose basis anticonvulsant blood levels were highest.

Plasma 10-hydroxynortriptyline in elderly depressed patients.

Plasma concentrations of nortriptyline (NT) and of unconjugated E-10-hydroxynortriptyline (E-10-OH-NT) were measured under steady-state conditions in elderly (60 yr and older) and young adult (40 yr and younger) patients treated with NT. The two groups received equivalent doses of NT. Plasma NT concentrations of the two groups did not differ, but plasma E-10-OH-NT concentrations were higher in the elderly. The plasma E-10-OH-NT/NT ratios were twice as high in the elderly group. Plasma E-10-OH-NT/NT ratios varied 2000% between individuals in the elderly group but were stable within individuals. Plasma E-10-OH-NT/NT ratios correlated positively but weakly with serum creatinine concentrations.

Plasma 10-hydroxynortriptyline and ECG changes in elderly depressed patients.

Among 18 elderly depressed patients given ECGs before and during nortriptyline treatment, plasma E-10-hydroxynortriptyline and the sum of E-10-hydroxynortriptyline and nortriptyline distinguished the group with conduction/repolarization effects. Plasma nortriptyline, age, drug dose, and baseline cardiovascular status did not.

Heart failure associated with high plasma 10-hydroxynortriptyline levels.

The authors describe a patient who developed congestive heart failure and had a high plasma concentration of 10-hydroxynortriptyline. They discuss the need for further research to define the contribution of antidepressants' active metabolites to toxic and therapeutic effects.

Clinical significance of the relationship between O-methyldopa levels and levodopa intake.

A recent clinical trial of controlled-release carbidopa/levodopa preparation afforded us the opportunity to examine the effects of chronically increasing circulating 3-O-methyldopa (OMD) levels on the clinical response to levodopa. In patients taking standard Sinemet, both mean plasma OMD levels and the area under the plasma concentration-versus-time curve (AUC) obtained during 8-hour periods of blood sampling correlated highly with the total daily intake of levodopa. In patients taking the controlled-release formulation, the mean daily intake of levodopa was doubled. This, in turn, led to a doubling of the mean OMD level and its AUC, whereas the AUC for levodopa was unchanged. Despite the increase in circulating OMD there was no reduction in mobility in either the "on" or "off" conditions. Thus, doubling plasma OMD levels did not seem to interfere with brain uptake of levodopa sufficiently to cause a deterioration in its therapeutic efficacy in these patients.

Sustained enteral administration of levodopa increases and interrupted infusion decreases levodopa dose requirements.

We placed a 60-year-old man with Parkinson's disease and marked therapeutic response fluctuations on a continuous enteral infusion of levodopa. On around-the-clock infusion, motor performance declined, although the infusion rate was progressively increased. We therefore interrupted the infusion each night. The patient could then progressively reduce levodopa intake while remaining continuously "on." Continuous infusion of levodopa downregulates, and interrupted infusion can restore, and even enhance, the sensitivity of striatal dopamine receptors.

A pharmacokinetic and pharmacodynamic comparison of Sinemet CR (50/200) and standard Sinemet (25/100).

Seventeen patients with advanced Parkinson's disease who had fluctuations in motor performance while taking standard Sinemet (STD) 25/100 underwent daylong pharmacokinetic and clinical observation studies while taking both STD and Sinemet CR, a new controlled-release formulation containing 50 mg carbidopa and 200 mg levodopa. During treatment with Sinemet CR, there was an increase in the interdose interval, a reduction in the number of medication doses taken each day, an increase in total "on" time, and a reduction in the number of "off" episodes. Total daily levodopa intake was greater with Sinemet CR, although the bioavailability of levodopa and carbidopa from the two preparations was equivalent. The variability in plasma levodopa levels was significantly less with Sinemet CR. The slower release of drug from Sinemet CR was reflected in a prolongation of the Tmax for levodopa and a prolongation of the interval from Tmax to the succeeding trough levodopa level. Clinically, peak antiparkinsonian effect occurred later and lasted longer with the CR preparation.

Controlled-release levodopa/carbidopa. I. Sinemet CR3 treatment of response fluctuations in Parkinson's disease.

Eight Parkinson patients with response fluctuations completed an open-label trial of a controlled-release carbidopa/levodopa preparation (Sinemet CR3). At the end of 6 weeks, percent "on" time and mean interdose interval increased, the number of daily doses and "off" periods was decreased, and the variability of plasma levodopa levels and disability scores was reduced. However, response fluctuations continued to occur, day-to-day consistency was poor, and the bioavailability of levodopa appeared less than that of standard Sinemet. Overall benefit waned over the next 3 to 6 months. Oral controlled-release carbidopa/levodopa is capable of reducing fluctuations in plasma levodopa levels and clinical performance in Parkinson's disease. The response to this particular controlled-release formulation was suboptimal and unsustained.

Controlled-release levodopa/carbidopa. II. Sinemet CR4 treatment of response fluctuations in Parkinson's disease.

Sixteen patients with Parkinson's disease and therapeutic response fluctuations entered an open-label trial of a controlled-release carbidopa/levodopa preparation, Sinemet CR4. Sinemet CR4 behaved as a slow release preparation. At the end of 6 weeks CR4 treatment, there was an increase in percent "on" time and mean interdose interval; the number of daily doses and "off" periods were diminished and a slight reduction in the variability of plasma levodopa levels was observed. Overall benefit waned over the next 6 months, despite addition of standard levodopa or Sinemet to overcome the delayed onset of antiparkinsonian effect of CR4 which resulted from prolongation in the Tmax for levodopa. The major benefits of CR4 were reduction in off time and in the number of daily off periods, with fewer levodopa doses per day and prolongation of the interdose interval.

Seizure disorders and trace metals: manganese tissue levels in treated epileptics.

We determined the concentrations of manganese in whole blood and hair in 52 epileptics, 6 blood relatives, and 24 normal controls. Blood, and possibly hair manganese content, was significantly lower in treated epileptics than in controls (p less than 0.002). Although not all patients showed reduced tissue manganese levels, most of those with frequent seizures had manganese levels falling below the lowest control level, suggesting a relationship between manganese tissue levels and high seizure activity. These differences in manganese levels were not correlated with the type, dose, or plasma levels of anticonvulsant medication. Reduced manganese availability at the neuronal level, where Mn++ stabilizes membrane excitability, may affect epileptogenic lesions to increase the likelihood of seizure activity.

Plasma 10-hydroxynortriptyline and therapeutic response in geriatric depression.

Geriatric inpatients with major depression received nortriptyline for 4 weeks. Plasma E-10-hydroxynortriptyline concentrations were correlated positively with residual Hamilton depression ratings and negatively with changes in ratings.

Drug interactions between antiepileptic drugs and other drugs.

Antiepileptic drugs interact with a variety of other drugs to affect the pharmacokinetic behavior of either drug. Drug interactions may also occur when antiepileptic drugs are given in combination. The possibility of such interactions is not a contraindication to the use of combinations, but it requires that the clinician be aware of the problem and monitor patients given potentially interacting combinations.

3,4-diaminopyridine as a treatment for amyotrophic lateral sclerosis.

The slow potassium channel blocker 3,4-diaminopyridine (DAP) enhances acetylcholine release from the nerve terminal and improves conduction in unmyelinated nerve. In this open label pilot study, we examined the effect of DAP combined with inpatient rehabilitation in seven patients with motor weakness due to amyotrophic lateral sclerosis (ALS). A single daily 20 mg oral dose of DAP was gradually increased to the maximum tolerated dose, and serum DAP concentrations were measured. Videotaped motor examination (for subsequent "blinded" review and assignment of a quantitative motor score), Functional Independence Measure (FIM) assessment, nerve conduction studies and neuropsychological evaluations were performed on admission, 1 h after maximum DAP dose, and post-treatment. DAP was tolerated in all patients, though dose was limited by gastrointestinal side effects in five patients. The mean peak serum level was 128 (+/- 50) ng/ml, occurring 1.0 (+/- 0.50) h after dose. A modest but statistically significant (p = 0.045) peak in motor score occurred on DAP. A significant (p = 0.045) improvement from baseline in FIM performance was apparent with DAP. Nerve conduction studies showed small increases in evoked response amplitudes and conduction velocities on DAP, but they did not reach statistical significance. No cognitive or affective changes were apparent. This unblinded pilot study shows that DAP is tolerated in ALS patients, and may be associated with functional and electrophysiologic improvement.

Controlled-release levodopa/carbidopa. III: Sinemet CR5 treatment of response fluctuations in Parkinson's disease.

Five patients with advanced Parkinson's disease and fluctuations in therapeutic response to levodopa participated in, and four completed, an open label study of the efficacy of Sinemet CR5. Reductions in the number of daily doses and "off" periods as well as the increase in interdose interval and percent "on" time versus standard Sinemet were comparable to those achieved with Sinemet CR4 in these same patients. As compared with Sinemet CR4, there was a greater delay in the occurrence of peak plasma levodopa concentrations, and relative bioavailability was reduced. Sinemet CR5 appears to offer no advantages over Sinemet CR4 in the treatment of response fluctuations in Parkinson's disease.

L-deprenyl, levodopa pharmacokinetics, and response fluctuations in Parkinson's disease.

Six patients with Parkinson's disease (PD) and therapeutic response fluctuations (RF) on levodopa treatment participated in an open-label trial of L-deprenyl (Eldepryl) in conjunction with Sinemet. Deprenyl (10 mg/day) allowed a slight but not statistically significant 22% reduction of total daily levodopa intake after 4 weeks of treatment, with a significant but unsustained reduction in the number of daily "off" periods and an increase in the portion of waking day spent "on." Pharmacokinetic studies revealed no effect of deprenyl on the plasma levodopa concentration vs. time curve, or the coefficient of variation (C.V.) of plasma levodopa levels measured over an 8-h period. Plasma DOPAC levels were unaffected, suggesting that the majority of peripheral DOPAC is generated by action of MAO-A. For most patients, benefit was not maintained. Two patients have continued taking the drug, and both have enjoyed significant reductions in total levodopa dose. Both have mild end-of-dose failure and little dyskinesia. Since no changes in peripheral pharmacokinetics of levodopa could be demonstrated, any therapeutic action of deprenyl in PD would appear to be due to prolongation of dopaminergic activity within the CNS.

Effect of supplemental carbidopa on bioavailability of L-dopa.

The effect of doubling carbidopa intake on single dose bioavailability of L-Dopa was examined in five parkinsonian patients. Increasing carbidopa from a mean of 145 to 290 mg/day caused a mean increase in peak plasma Dopa concentrations from 1,893 +/- 476 to 2,733 +/- 607 ng/ml and area under the Dopa plasma concentration versus time curve of 24.6 +/- 10.0%, as well as a decrease in the time to peak plasma concentration to 0.7 +/- 0.2 versus 1.2 +/- 0.3 h. Increasing the within-dose ratio of carbidopa to L-Dopa, even in patients receiving "maximally effective" doses of carbidopa, further increases bioavailability of L-Dopa, presumably by inhibiting "first pass' metabolism in the gut.

Feasibility and pharmacokinetics of carbamazepine oral loading doses.

The pharmacokinetics and adverse effects of an oral loading dose of carbamazepine administered in tablet or suspension form were studied. Patients on a hospital epilepsy unit who were to receive carbamazepine as a discharge medication were randomly assigned to receive either an oral 8-mg/kg loading dose of the tablet formulation or the same dose of the suspension on an empty stomach. Blood samples were drawn before and at intervals up to 12 hours after the loading dose. Adverse effects were evaluated subjectively and objectively. Total and free serum carbamazepine and carbamazepine-10, 11-epoxide (CBZE) concentrations were determined by high-performance liquid chromatography. Six adult patients were enrolled in and completed the study. All the patients achieved therapeutic total carbamazepine levels; the suspension group did so within two hours and the tablet group within five hours. Maximum serum carbamazepine concentrations ranged from 7.10 to 9.92 mg/L, area under the concentration-versus-time curve from 54.85 to 82.23 micrograms.hr/L, and terminal elimination half-life from 14.05 to 15.71 hours. Adverse effects were mild, few, and short-lived; none of the patients developed gastrointestinal toxicity. Adverse effects were not associated with total or free carbamazepine and CBZE concentrations or with total or free CBZE:carbamazepine ratios. An oral loading dose of carbamazepine 8 mg/kg achieved therapeutic levels within two hours when given as a suspension and within five hours when given as tablets and was well tolerated in all patients.