Maximizing the benefit of pharmacotherapy in Parkinson's disease.

Levodopa is one of the principal agents administered to treat patients with Parkinson's disease (PD). Several pharmacologic strategies can limit its side effects and enhance its activity. Although certain exceptions apply, dosage adjustments and drug changes should be instituted slowly.

Effects of lactate on cross-spectral analysis of heart rate, blood pressure, and lung volume in normal volunteers.

Baroreceptor reflex sensitivity, coherence functions, and transfer functions between respiration and heart rate, and between respiration and blood pressure, were studied in nine normal volunteers before and after intravenous sodium lactate infusions. Cross-spectral analysis was used to examine heart rate, finger blood pressure, and respiration obtained with the subjects in a supine posture during spontaneous breathing. Sodium lactate produced a significant decrease of the modulus between respiration and heart rate (beats/min/l).

Effects of isoproterenol infusions on heart rate variability in patients with panic disorder.

Some evidence suggests that patients with panic disorder have a decreased cardiac vagal and a relatively higher sympathetic activity. In this study, spectral analysis of the time series of heart rate before and after isoproterenol infusions was used to study heart rate variability in six panic disorder patients and 11 normal control subjects. These preliminary data reveal a significant increase of sympathovagal ratios only in the patient group after isoproterenol administration.

Sodium lactate increases sympathovagal ratios in normal control subjects: spectral analysis of heart rate, blood pressure, and respiration.

We used spectral analysis of heart rate (HR), blood pressure (BP), and respiration to examine the effects of lactate on cholinergic and adrenergic influences on HR and BP variability, a technique found to be very useful in cardiovascular research. We specifically used high frequency (0.2-0.

Lactate sensitivity and cardiac cholinergic function in panic disorder.

Using spectral analysis of the continuous time series signal before and during lactate and placebo infusions, the authors studied heart rate variability in six patients with panic disorder and nine normal comparison subjects. The decrease in high-frequency (0.20-0.

Lactate-induced anxiety after imipramine and diazepam treatment.

To examine the effect of treatment on lactate-induced anxiety in a controlled study, we infused 44 panic disorder patients with lactate and placebo before and after eight weeks of double-blind treatment with imipramine, diazepam, or placebo. During treatment, both imipramine and diazepam groups improved more than the placebo group. After treatment, patients in both the imipramine and diazepam groups had significantly less anxiety than the placebo patients when reinfused with lactate.

Beta-receptor responsiveness after desipramine treatment.

To examine whether a tricyclic antidepressant affects the functional response to a beta-receptor agonist in man, the response of heart rate, blood pressure, and plasma cAMP to isoproterenol was measured in 14 normal controls taking 75 mg desipramine daily. Desipramine significantly increased the bolus dose of isoproterenol needed to increase heart rate by 25 bpm at 14-30 days but not at 3-8 days. During infusions of isoproterenol, the increase in systolic blood pressure was blunted at both 3-8 days and 14-30 days, while the decrease in diastolic blood pressure was unaffected.

Effects of yohimbine on heart rate variability in panic disorder patients and normal controls: a study of power spectral analysis of heart rate.

We studied the effects of yohimbine on heart rate (HR) variability in 13 normal controls and 13 patients with panic disorder. Yohimbine produced a significant increase in SD of HR in standing posture in both patients (p = 0.01) and normal controls (p = 0.

Diminished mephobarbital anticonvulsant action following diphenhydramine pretreatment.

Diphenhydramine and other antihistamines produce biphasic effects on drug disposition and lower seizure threshold, thereby potentially diminishing the efficacy of anticonvulsants such as mephobarbital. Accordingly, the influence of diphenhydramine (50 mg/kg, IP) pretreatment on the anticonvulsant activity of mephobarbital (50 mg/kg, IP) was determined in adult female Swiss-Webster mice given pentylenetetrazol (SC). Diphenhydramine lowered the pentylenetetrazol convulsive dose (CD50) by 60%.

Effects of clonidine on heart rate variability.

We compared the effects of intravenous infusions of clonidine and placebo on heart rate variability in 10 healthy male controls. Clonidine produced a significant decrease in blood pressure and significantly decreased the heart rate variability during quiet standing.

Monosodium glutamate and tranylcypromine administration in healthy subjects.

The authors administered 400 to 1600 mg of monosodium glutamate and placebo to five healthy males while they were medication-free and again while they were receiving the monoamine oxidase inhibitor tranylcypromine, after having received the drug daily for at least 2 weeks. Monosodium glutamate produced no consistent changes in either blood pressure or heart rate in subjects receiving tranylcypromine. Spontaneous hypertensive episodes were observed in two subjects.

Pharmacokinetic evaluation of erythromycin and caffeine administered with bromocriptine.

A study was performed to determine if the pharmacokinetics of bromocriptine is altered by factors that have been shown to interact with other ergot compounds. The effects on bromocriptine plasma concentrations by bromocriptine coadministration with caffeine and erythromycin were evaluated in five male volunteers. Serial blood samples were obtained during a 12-hour period after a single 5 mg oral dose of bromocriptine (alone and after 4-day treatments of either erythromycin estolate, 250 mg four times/day, or caffeine, 200 mg four times/day).

Somatic and psychological symptoms during isoproterenol-induced panic attacks.

To determine which symptoms characterized isoproterenol-induced panic attacks, we analyzed the presence of panic attacks in 54 panic disorder patients who panicked, 24 patients who did not panic, and 37 controls who did not panic during isoproterenol infusions. The increases over the baseline of the symptoms shortness of breath and fear of going crazy were highly associated with panicking patients when compared to nonpanicking patients and nonpanicking controls. The increases of the symptoms trembling and shaking, generally nervous, and fear of going crazy were highly associated with patients when compared to controls.

Pharmacodynamic modeling of concentration-effect relationships after controlled-release carbidopa/levodopa (Sinemet CR4) in Parkinson's disease.

Eight parkinsonian patients participated in a pharmacokinetic pharmacodynamic study of sequential doses of controlled-release carbidopa (CD)/levodopa (LD) at 4-hour intervals, with serial blood samples obtained before and after each dose. Effect measurements obtained with each blood sample included tapping and walking speed as well as a global assessment of motor function. Analysis of the data by extended least squares regression for linear, Emax, and sigmoid Emax pharmacodynamic models revealed that linear relationships do not provide the best fit between LD plasma concentrations and clinical effects after controlled-release CD/LD.

Controlled-release carbidopa/levodopa (Sinemet 50/200 CR4): clinical and pharmacokinetic studies.

Several controlled-release carbidopa/levodopa preparations have been formulated to achieve a more stable and extended antiparkinsonian action. The most effective is Sinemet CR (Sinemet CR4), with an erodible polymer matrix that retards release of levodopa. In 19 parkinsonians with prominent dose-by-dose fluctuations, double-blind crossover trials comparing 8-week regimens of standard carbidopa/levodopa (25/100) to Sinemet CR (50/200) showed comparable clinical outcomes, with mean daily dosing for optimal control reduced from 10.

Pharmacokinetic and pharmacodynamic modeling of L-dopa plasma concentrations and clinical effects in Parkinson's disease after Sinemet.

Eleven parkinsonian patients participated in a pharmacokinetic/pharmacodynamic study in an attempt to model levodopa (L-DOPA) plasma concentrations to clinical effect. Carbidopa 25 mg/L-DOPA 100 mg (Sinemet 25/100) was given orally, and blood samples were obtained before and serially for 4 hours after the dose. Effect measurements were obtained with each blood sample and included tapping score, timed walking, and global assessment of motor function.

Isoproterenol-induced panic attacks.

Eighty-six panic disorder patients and 45 nonpsychiatric controls were infused with isoproterenol at a rate of 1 microgram/min for up to 20 min in a placebo-controlled, double-blind study. Sixty-six percent of panic disorder patients experienced panic attacks during isoproterenol infusions, compared to 16% during placebo infusions. Nine percent of control subjects panicked with isoproterenol, but none panicked with placebo.

Sodium lactate infusions after treatment with tricyclic antidepressants: behavioral and physiological findings.

Fourteen patients with panic disorder were infused with sodium lactate both before and after treatment with tricyclic antidepressants. All patients had panic attacks before treatment, and only five after treatment. There was a significant decrease in measures of anxiety prior to and during infusions after treatment.

Preinfusion anxiety and laboratory-induced panic attacks in panic disorder patients.

Seventy panic disorder patients participated in a double-blind, placebo-controlled, randomized infusion study in which sodium lactate and isoproterenol were used to induce panic anxiety. Patients who panicked during lactate, isoproterenol, and placebo infusions generally had higher preinfusion anxiety scores. These findings held true irrespective of the order the infusions were given.

Effects of laboratory-induced panic-anxiety on subsequent provocative infusions.

The effects of infusion-induced panic-anxiety on subsequent pre-infusion anxiety ratings and infusion-induced panic attacks were studied in 64 panic disorder patients, in a double-blind randomized study using sodium lactate, isoproterenol, and placebo infusions. While there was a decrease of preinfusion anxiety from one infusion to the next infusion both for panickers and nonpanickers, there was no evidence of either a significant decrease or an increase in the frequency of subsequent panic attacks. These results suggest that there is neither a desensitizing nor a sensitizing effect of pharmacologically induced panic attacks on subsequent infusions in a serial three-infusion design.

Follow-up study of control subjects with lactate- and isoproterenol-induced panic attacks.

Eleven of 45 normal control subjects experienced panic attacks during lactate and/or isoproterenol infusions. Ten of the 11 subjects were followed up for a mean period of 32.5 months.

A laboratory procedure for the induction of flashbacks.

The authors administered infusions of lactate intravenously to seven patients with a DSM-III diagnosis of posttraumatic stress disorder, six of whom also met DSM-III criteria for panic disorder. The lactate infusions resulted in flashbacks in all seven patients and panic attacks in six patients. The authors conclude that with further development intravenous lactate infusion may be used to study flashbacks and other dissociative phenomena and to determine the relationship between flashbacks and panic anxiety.

The effect of tricyclic antidepressants on stress-induced heart rate changes in panic disorder patients.

Eight panic disorder patients participated in a double-blind placebo-controlled infusion study designed to induce panic-anxiety in the laboratory both before and after treatment with tricyclic antidepressants. Pre-infusion heart rates for the first infusion were significantly higher than baseline both before and after treatment. The delta increase in pre-infusion heart rates from baseline and the ratios of pre-infusion heart rates to baseline values were not significantly different between before and after treatment conditions indicating similar levels of arousal during the two pre-infusion periods, while the pre-infusion anxiety ratings after treatment were significantly lower.