Sertraline concentrations in pregnant women are steady and the drug transfer to their infants is low.

PURPOSE: Sertraline, a selective serotonin reuptake inhibitor (SSRI), is one of the most commonly used antidepressant during pregnancy. Plasma sertraline concentrations vary markedly between individuals, partly explained by variability in hepatic drug metabolizing cytochrome P450-enzyme activity. Our purpose was to study the variability in the plasma concentrations in pregnant women and the passage to their infants. METHOD: Pregnant women with moderate untreated depression were recruited in 2016-2019 in Stockholm Region and randomized to treatment with sertraline or placebo. All received Internet-based cognitive behavior therapy as non-medical treatment. Sertraline plasma concentrations were measured around pregnancy weeks 21 and 30, at delivery, 1-month postpartum, in cord blood and at 48 h of age in the infant. The clinical course of the infants was followed. RESULTS: Nine mothers and 7 infants were included in the analysis. Median dose-adjusted sertraline concentration in second trimester was 0.15(ng/mL) /(mg/day), in third trimester and at delivery 0.19 and 1-month postpartum 0.25, with a 67% relative difference between second trimester and postpartum. The interindividual variation was 10-fold. Median concentrations in the infants were 33% and 25% of their mothers', measured in cord blood, and infant plasma, respectively. Only mild and transient adverse effects were seen on the infants. CONCLUSION: Placental passage of sertraline to the infant is low. However, the interindividual variation in maternal concentrations during pregnancy is huge, why therapeutic drug monitoring might assist in finding the poor metabolizers at risk for adversity and increase the safety of the treatment. TRIAL REGISTRATION: The trial was registered at clinicaltrials.gov July 9, 2014 with TRN: NCT02185547.

Intracellular free magnesium in synaptosomes measured with entrapped eriochrome blue.

The free Mg2+ concentration within synaptosomes has been measured with an entrapped Mg2+ indicator, eriochrome blue. Ionophores gramicidin and A23187 slowly increased the absorbance of the entrapped dye. Calibration of the dye response in a Na+-based medium gave a value around 0.3 mM for the internal free Mg2+ concentration at 1 mM external Mg2+. The replacement of Na+ by choline increased this value to around 0.65 mM. Depolarisation with a high K+ concentration or depletion of intrasynaptosomal ATP with FCCP and iodoacetate did not affect the level of intracellular free Mg2+ concentration. An elevation of the external Ca2+ concentration significantly reduced internal Mg2+ to about 0.1 mM. Ca2+ had no significant effect when Na+ was replaced by choline. The results indicate that the intrasynaptosomal Mg2+ activity is partially regulated by a Na+-Mg2+ exchange mechanism which does not directly require ATP as an energy source.

Qualitative measurements of cytosolic calcium ion concentration within isolated guinea pig nerve endings using entrapped arsenazo III.

If arsenazo III is present during homogenization of brain this metallochromic indicator is entrapped within subsequently isolated synaptosomes. A large proportion of the entrapped indicator is released upon addition of digitonin to disrupt the synaptosomal plasma membrane. A similar proportion of [3H]sucrose is also trapped within synaptosomes if present in the homogenization medium, suggesting that homogenization causes a transient opening of the nerve ending as it is chopped off from the axon. Addition of the ionophore A23187 or depolarization of the plasma membrane by adding veratridine, gramicidin or increasing external K+ changes the absorbance of the entrapped dye, with peaks of absorbance around 600 and 650 nm, typical of the arsenazo III-Ca2+ complex. The response to veratridine is inhibited by the Ca2+-channel antagonist, verapamil, while that of A23187 is unaffected. The present method provides a sensitive technique for measurements of changes in cytosolic calcium ion concentrations within nerve endings.

Quantitative measurements of the cytosolic Ca2+ activity within isolated guinea pig nerve-endings using entrapped arsenazo III and quin2.

The absorbance changes of intrasynaptosomally entrapped arsenazo III have been converted into values of free Ca2+ concentration by correcting for the nonlinear response of arsenazo III at different concentrations of the dye as well as for changes in internal pH. An average resting value for free Ca2+ concentration around 0.4 microM is obtained. Depolarization with veratridine or gramicidin increases this value to around 3 microM. Measurements of cytosolic free Ca2+ with the quin2 method gives much lower values in similar conditions. The release of prelabelled [14C]noradrenaline from the nerve-endings is maximally activated when the internal free Ca2+ concentration rises as measured with arsenazo III to about 4 microM when titrated with increasing concentrations of ionophore A23187.

Dependence of cytoplasmic calcium transients on the membrane potential in isolated nerve endings of the guinea pig.

The relation of changes in internal, free Ca2+, measured with arsenazo III, to the membrane potential, measured with the cyanine dye di-S-C2(5) or 86Rb+ distribution ratio, was studied in isolated guinea pig cortical nerve endings. Depolarization of the plasma membrane with veratridine or gramicidin as well as addition of ionophore A23187 led to an increase in cytosolic Ca2+. Only the response to veratridine was inhibited by tetrodotoxin. The dependence of the depolarization-induced increase in intraterminal, free Ca2+ on the membrane potential between about -50 to 0 mV was sigmoidal. A maximal increase in cytosolic Ca2+ was reached when the membrane potential was depolarized from the resting level, about -64 mV, to about -40 mV. These results show that in isolated nerve endings the activation of voltage-sensitive Ca2+ channels concomitantly leads to an increase in cytosolic, free Ca2+. Comparison of the results of the present study with the previous electrophysiological observations indicate that Ca2+ channels in synaptosomes, presynaptic nerve terminals of the squid giant synapse and cardiac cells have essentially similar voltage dependency.

A review of the pharmacology of selegiline.

Selegiline (1-deprenyl) is an irreversible inhibitor of monoamine oxidase (MAO) type B. Because in the human brain, dopamine is metabolised mainly by MAO-B, selegiline increases dopamine content in the central nervous system. Besides the inhibition of MAO-B, selegiline also inhibits the uptake of dopamine and noradrenaline into presynaptic nerve and increases the turnover of dopamine. Thanks to these properties, selegiline significantly potentiates the pharmacological effects of levodopa. These favourable characteristics have been applied in the treatment of Parkinson's disease using selegiline both with levodopa and alone. Unlike earlier MAO-inhibitors, selegiline does not potentiate the hypertensive effects of tyramine. This is due to the selectivity to MAO-B, leaving intestinal MAO-A intact, and also due to the fact that selegiline inhibits the uptake of tyramine into neurons. Selegiline can prevent the parkinsonism caused by MPTP in animals; similar findings have been reported with other toxins like 6-OHDA and DSP-4, that destroys noradrenergic nuclei. Furthermore, selegiline reduces oxidative stress caused by degradation of dopamine and increases free radical elimination by enhancing superoxide dismutase and catalase activity. These findings may be important when considering the possible neuroprotective effects of selegiline. Besides the basic pharmacology also the interactions and pharmacokinetics of selegiline are reviewed in this article.

Selegiline in the treatment of Parkinson's disease.

Selegiline is a selective, irreversible inhibitor of monoamine oxidase type B (MAO-B). It also inhibits the reuptake of catecholamines into the presynaptic nerve and enhances the synthesis of dopamine by blocking the presynaptic dopamine autoreceptors. Thanks to these properties it potentiates and prolongs the duration of action of levodopa. Several clinical trials have shown its efficacy as an adjuvant to levodopa therapy. Improvement in parkinsonian disability and reduction of fluctuations in disability can be achieved by adding selegiline to the prevailing levodopa therapy. End-of-dose type fluctuations, in particular, react favourably to selegiline. Side-effects of the therapy can be managed by reducing the dose of levodopa. According to preliminary studies selegiline may also have some benefit as monotherapy in de novo parkinsonian patients. High doses of selegiline have been found to have some antidepressant efficacy, especially in patients with nonendogenous depression. It may also have an effect on bradyphrenia and some symptoms of cognitive dysfunction and dementia. In animal models selegiline has been shown to prevent parkinsonism caused by MPTP and also to increase the life span of rats. Whether selegiline slows down the progression of Parkinson's disease needs further examination.

Selegiline in the treatment of daily fluctuations in disability of parkinsonian patients with long-term levodopa treatment.

In order to evaluate in a double-blind manner the therapeutic efficacy of selegiline in the treatment of late-phase Parkinson's disease, 19 patients with end-of-dose type fluctuations were randomized for a double-blind cross-over trial receiving either selegiline 10 mg or placebo. Each period lasted 12 weeks. During a two week prestudy period the dose of levodopa was titrated to optimal levels. The disability was evaluated using the Columbia University Disability Scale (CUDS). The patients kept a daily diary to monitor closely the frequency and severity of their fluctuations and the side-effects of treatment. Their parkinsonian disability and all main symptoms improved significantly during selegiline treatment. The mean duration of action of a levodopa dose was significantly longer and there was significantly less daily end-of-dose and early morning akinesia during selegiline treatment. The side-effects were similar in both treatments. This double-blind study confirms the findings of earlier open studies that selegiline potentiates and prolongs the therapeutic effects of levodopa and thus its use is particularly beneficial in patients with end-of-dose type fluctuations in disability.

Selegiline as primary treatment in early phase Parkinson's disease--an interim report.

We are carrying out a double-blind parallel trial comparing the effect of selegiline monotherapy and placebo in de novo parkinsonian patients. Fifty-six patients (28 in both groups) are included in the trial. This interim analysis reports the results of the first 52 evaluable patients who have had at least one follow-up visit after entering the trial. The efficacy of treatment was assessed using the Columbia University Rating Scale, the North-Western University Disability Scale and the Webster Rating Scale and followed until the addition of levodopa therapy became necessary. The data were analysed at follow-up times of up to twelve months (34 patients evaluable at the end of the period). The overall disability scores of all the rating scales used were significantly smaller in the selegiline group than in the placebo group. Levodopa treatment had become necessary in 12 patients (46%) in the selegiline group and in 14 patients (54%) in the placebo group. The side-effects were mild and similar in both treatment groups. According to the present results selegiline monotherapy seems to have therapeutic efficacy in the early phase of Parkinson's disease. Whether selegiline is able to slow down the progression of Parkinson's disease needs further clarification.

Optoelectronic movement analysis in Parkinson's disease: effect of selegiline on the disability in de novo parkinsonian patients--a pilot study.

New opto-electronic camera systems permit easy quantification of the motor performance during natural acts in freely moving humans. We used a simple test movement (PLM test) to quantify the disturbance in the postural (P), locomotor (L) and manual (M) part of the body movement and the coordination of the different movement phases into a smooth motor act. The test movement time was used to quantify the overall performance. With this technique we have measured the effects of selegiline on the degree of parkinsonism in a double-blind, placebo-controlled pilot study of 5 de novo patients with Parkinson's disease. There was a clear trend that selegiline was superior to placebo in reducing the test movement time.

Selegiline as a primary treatment of Parkinson's disease.

In order to investigate the efficacy of selegiline as a primary treatment in Parkinson's disease (PD), we carried out a placebo controlled, double-blind prospective trial. Fifty-four de novo patients with PD were randomized to receive either selegiline (10 mg/day) or matching placebo. We continued the monotherapy until the initiation of levodopa therapy became necessary. The disability of the patients was evaluated with three different rating scales at baseline, after 3 weeks, 2, 4, 8, and 12 months, and every 4 months thereafter. Fifty-two patients were eligible for the final analysis: 27 in the selegiline group and 25 in the placebo group. The median duration of time without levodopa was 545 +/- 90 days in the selegiline treated patients and 372 +/- 28 days in the placebo treated ones (p = 0.03). The disability of the patients was significantly milder in the selegiline than in the placebo group up to 12 months. More patients showed symptomatic improvement in the selegiline than in the placebo group. However, the symptomatic effect alone did not explain the prolongation of the time without levodopa in the selegiline treated patients. Selegiline was well tolerated and no severe side effects were encountered.

Selegiline and levodopa in early or moderately advanced Parkinson's disease: a double-blind controlled short- and long-term study.

Selegiline 10 mg per day was compared to placebo as an adjunct to levodopa treatment in this double-blind study of early or moderately advanced Parkinson's disease. Thirty-eight patients completed an initial cross-over trial comprising two treatment periods, each of eight weeks, with a four weeks' wash-out period between them. Thirty of the patients continued in a long-term, double-blind parallel trial with a mean duration of 16 months (range 6-30 months). Selegiline treatment allowed a significant reduction of the necessary daily levodopa dose in both parts of the study and of the daily dosing frequency in the long-term investigation. In spite of this reduction of levodopa dose, an improvement was noted in tremor during the short-term selegiline periods. The side-effects were slight and related to dopamine effects and disappeared after reduction of levodopa-dose. The results support the use of selegiline as an early adjunctive treatment in Parkinson's disease.

Pharmacokinetics and metabolism of selegiline.

Selegiline is readily absorbed from the gastrointestinal tract. It is distributed rapidly into the tissues, including the brain. It is the L-form of selegiline that is an active MAO-B inhibitor, the D-(+)-form being 25 times less active. Selegiline is metabolised into L-(-)-desmethylselegiline (DES), L-(-)-amphetamine (A) and L-(-)-methamphetamine (MA), mainly in the liver. We measured the steady state concentrations of the metabolites in the serum and cerebrospinal fluid (CSF) of patients with Parkinson's or Alzheimer's diseases who were on continuous selegiline therapy. The mean concentrations in serum and CSF were similar, and were not affected by the addition of levodopa. The mean concentrations of patients with Alzheimer's or Parkinson's disease were 6.5 +/- 2.5 ng/ml for A, 14.7 +/- 6.5 ng/ml for MA and 0.9 +/- 0.7 ng/ml for DES. The metabolites of selegiline were excreted in urine, and the recovery as metabolites was 87%. Due to the stereospecificity and the low CSF concentrations of the (-)amphetamine metabolites during the therapy with 10 mg selegiline, these metabolites do not seem to contribute significantly to the clinical efficacy of selegiline.

Pharmacokinetic aspects of l-deprenyl (selegiline) and its metabolites.

l-Deprenyl (selegiline), an irreversible and selective inhibitor of monoamine oxidase type B (MAO-B), is rapidly absorbed from the gastrointestinal tract and distributed into tissues. The reaction between MAO and selegiline takes place in two steps. The initial reversible reaction is followed by an irreversible reaction in which selegiline is bound covalently to the flavin part of the enzyme. Studies with positron emission tomography have shown retention of selegiline in brain areas with high MAO-B activity, including striatal structures, hippocampus, thalamus, and substantia nigra. Inhibition of MAO-B in vivo takes place rapidly; for example, platelet MAO is inhibited almost totally within the first 60 minutes after a single 10 mg oral dose of the drug. The recovery of MAO after inhibition depends on the organ and species in question. In rat brain the half-life of recovery in the brain is approximately 8 to 12 days; in rat liver it is shorter, 1 to 3 days. Selegiline is metabolized into l-(-)-desmethylselegiline, l-(-)-methamphetamine, and l-(-)-amphetamine mainly in the liver through the microsomal P-450 system. The stereoselectivity of the metabolites is maintained; no racemic transformation takes place. All three main metabolites are found in human serum, cerebrospinal fluid, and urine, and l-(-)-methamphetamine accounts for most of the metabolite pool. The metabolites are excreted mainly via urine l-(-)-Desmethylselegiline has been shown to be an irreversible inhibitor of MAO-B in the rat and in humans.

Selegiline in the treatment of narcolepsy.

We treated 17 narcolepsy patients in a placebo-controlled, double-blind, crossover trial with 10-, 20-, 30-, and 40-mg daily doses of selegiline, a monoamine oxidase inhibitor widely used in Parkinson's disease. There was a dose-dependent as well as a statistically and clinically significant improvement in narcoleptic symptoms and polygraphic measures. At 40 mg, there was a 36% reduction in the number of daytime sleep episodes and a 34% reduction in their duration (compared with placebo, mean values). The number of excessive sleepiness episodes decreased by 43%, and the duration decreased by 47%. The number of cataplectic attacks was reduced by 89%. On the multiple sleep latency test, the REM sleep latency increased from 5.0 to 13.3 minutes, and the number of sleep-onset REM periods decreased from 3.1 to 0.6. Sleep (S1) latency was not changed. No intolerable adverse events occurred. The effective dose range was 20 to 40 mg, requiring a low-tyramine diet, which was easy to maintain. In conclusion, selegiline alleviates both main symptoms of narcolepsy--the abnormal sleep tendency and cataplexy. Thus, treatment with selegiline makes it possible to avoid polypharmacy and to use a potent stimulant without known addiction risk.

Selegiline as initial treatment in de novo parkinsonian patients.

To investigate the efficacy and safety of selegiline in the early phase of Parkinson's disease (PD), we carried out a placebo-controlled, double-blind, parallel trial. De novo PD patients were randomized to receive either selegiline (10 mg/d) or matching placebo. We continued selegiline or placebo until levodopa therapy became necessary and assessed the disability using three different rating scales at baseline, after 3 weeks, at 2, 4, 8, and 12 months, and at every 4 months thereafter. Fifty-two patients were eligible for the analysis, 27 in the selegiline group and 25 in the placebo group. The median duration of time before levodopa had to be initiated was 545 +/- 90 days with selegiline and 372 +/- 28 days with placebo (p = 0.03). Disability was significantly less in the selegiline group than in the placebo group up to 12 months. The period of time during which the mean total Columbia University Rating Scale score stayed below the baseline was used to express the initial symptomatic effect of the treatments. The difference in this initial improvement time between the two groups was about 3 months and did not alone explain the difference in the delay of the need to start levodopa therapy. Selegiline was well tolerated and there were no severe side effects. We conclude that selegiline delays the need to start levodopa in de novo PD patients, has symptomatic efficacy, and possibly retards the progression of the disease.

Selegiline delays the onset of disability in de novo parkinsonian patients. Swedish Parkinson Study Group.

OBJECTIVE: The objective of this study was to investigate the effect of selegiline first as monotherapy and then in combination with levodopa in the early phase of PD. METHODS: A total of 157 de novo PD patients were randomized to receive either selegiline or placebo in a double-blind study until levodopa therapy became necessary. Thereafter, the drugs were withdrawn for an 8-week washout period to evaluate the possible symptomatic effect of selegiline. RESULTS: Analysis of Kaplan-Meier survival curves for each group showed that selegiline delayed significantly the need for levodopa therapy (p = 0.028). The semiannual rate of disability progression was slowed down significantly in the selegiline group analyzed with the Unified Parkinson's Disease Rating Scale (total and motor scores; p < 0.001). Selegiline had a "wash-in" effect (i.e., an initial symptomatic amelioration of PD at 6 weeks and 3 months). However, after the 8-week washout period, no significant differences in the deterioration of disability between the groups was revealed in any of the scales, suggesting that besides having a slight symptomatic effect, selegiline may also have neuroprotective effects. Similarly, the progression of symptoms from baseline to the end of the washout period was significantly slower (p = 0.033) in the selegiline group when the progression was adjusted by the time to reach the end point. Selegiline was well tolerated. CONCLUSIONS: Selegiline delayed significantly the need to start levodopa in early PD. After a 2-month washout period (before the start of levodopa therapy) no significant symptomatic effect of selegiline was seen in comparison with the placebo group, supporting the concept of neuroprotective properties of the drug.

Effect of selegiline on mortality in patients with Parkinson's disease: a meta-analysis.

INTRODUCTION: The Parkinson's Disease Research Group of the United Kingdom (PDRG-UK) reported increased mortality in PD patients treated with levodopa plus selegiline compared with those treated with levodopa alone. METHODS: We performed a meta-analysis on five long-term, prospective, randomized trials of selegiline in patients with untreated PD. Included in the analysis were four randomized, double-blind, placebo-controlled studies and one randomized, double-blind, placebo-controlled study of 2 years' duration followed by long-term, open follow-up. RESULTS: The mean duration of follow-up was 4.1 +/- 1.8 years. There were 14 deaths in 297 selegiline-treated patients (4.7%) and 17 deaths in 292 non-selegiline-treated patients (5.8%). The hazard ratio for mortality was 1.02 (95% CI 0.44 to 2.37; p = 0.96). An analysis restricted to patients receiving only levodopa with or without selegiline noted 11 deaths in 257 levodopa/selegiline-treated patients (4.3%) and 11 deaths in 254 patients treated with levodopa alone (4.3%). The hazard ratio was 1.06 (95% CI 0.44 to 2.55; p = 0.90). Death rate per 1,000 patient years was 11.4 in the selegiline group and 14.2 in the nonselegiline group. Kaplan-Meier survival curves reflecting pooled survival data showed no significant difference in duration of survival. The hazard ratio was 0.84 (95% CI 0.41 to 1.70; p = 0.63) for selegiline- versus non-selegiline-treated patients and 1.05 (95% CI 0.46 to 2.43; p = 0.91) for selegiline/levodopa- versus levodopa-treated patients. CONCLUSION: These results contrast with those of the PDRG-UK study and demonstrate no increase in mortality associated with selegiline treatment whether or not patients also received levodopa.

Independent release of supranormal acetylcholine quanta at the rat neuromuscular junction.

This electrophysiological study deals with the occurrence and with the mode of release of unusually large miniature end-plate potentials at the rat neuromuscular junction during physiological conditions. A specific limit for the normal miniature end-plate potential amplitude at each cell studied was determined after fitting the observed frequency-amplitude histogram to a Gaussian distribution. The relative abundance of giant miniature end-plate potentials was 4.15% at room temperature. The occurrence of giant miniature end-plate potentials was temperature dependent. The percentage of giant miniature end-plate potentials was 5.8% and 0.61% at 35 degrees C and at 16 degrees C, respectively. The amplitude-independence of the intervals between miniature end-plate potentials was demonstrated at room temperature as well as at 35 degrees C and at 16 degrees C. The results of this study show that giant miniature end-plate potentials are produced by acetylcholine packets which are released independently and that they are not a consequence of the synchronous release of several normal-sized quanta. Moreover, the results indicate that during physiological conditions a minor but regular proportion of the spontaneous release of acetylcholine is made up of larger packets, which produce miniature end-plate potentials of supranormal amplitude.

Low affinity binding to glutamate receptor sites correlates with depolarizing responses induced by glutamate and quisqualate in striatal synaptoneurosomes.

In the present study, binding affinity of glutamate and quisqualate to striatal synaptoneurosome membranes in the guinea-pig was compared with concentration-dependence of depolarizing responses induced by these agents. The displacement of radioactive glutamate from receptor binding site by unlabelled glutamate and quisqualate revealed a nonhomogeneous population of binding sites. A high affinity component of binding was observed with an inhibition constant of 0.04 microM for glutamate and 0.45 microM for quisqualate, as well as a low affinity component with an inhibition constant of 10 microM for glutamate and 87 microM for quisqualate. Changes of the membrane potential in striatal synaptoneurosomes induced by glutamate and quisqualate were detected by measuring the absorbance of a potential sensitive cyanine dye. Glutamate and quisqualate induced constantly a depolarization in synaptoneurosome particles. Concentration-response curves showed that half-maximal depolarization was obtained with 10 microM glutamate and 100 microM quisqualate. The comparison of the displacement data with the changes in the membrane potential in the present investigation indicate that in vitro glutamate and quisqualate depolarize striatal synaptoneurosome particles through low affinity binding to receptor site for glutamate.