Paul Fredrickson

Effect of Pramipexole in Treatment of Resistant Restless Legs Syndrome

OBJECTIVE To report the results of an open-label trial with a dopaminergic agent, pramipexole, in patients with treatment-resistant restless legs syndrome (RLS). MATERIAL AND METHODS We studied the response to pramipexole in a consecutive series of 16 patients with symptomatic RLS who had previously experienced failure with other dopaminergic therapies. Patients assessed their posttreatment change in symptoms of RLS on a visual analog scale and indicated drug-related side effects with use of a checklist. RESULTS With a mean dose of pramipexole of 0.3 mg, most patients reported clinically significant improvement. From 2 to 3 months after initiation of pramipexole therapy, nocturnal leg restlessness, involuntary leg movements, and insomnia had decreased in 12, 10, and 11 patients, respectively. The most frequent adverse effects were fatigue and stiffness, which occurred in a third of the patients. Overall, the drug was well tolerated. CONCLUSION On the basis of these findings, we propose that pramipexole, a D2 subgroup receptor agonist, is an effective agent for treatment of RLS.

High dose transdermal nicotine therapy for heavy smokers: safety, tolerability and measurement of nicotine and cotinine levels

Transdermal nicotine has been shown to relieve nicotine withdrawal and to double smoking cessation rates compared to placebo in clinical trials. A 21 or 22 mg/day dose provides a steady state serum nicotine that is less than obtained from smoking. Limited information is available about higher nicotine patch doses. To define better the optimal dosing of nicotine patch therapy, we undertook an open-label study to determine the safety and tolerability of 44 mg/day dose for smoking cessation in subjects smoking ≥ 20 cigarettes per day. Forty smokers received 44 mg/day of transdermal nicotine for 4 weeks followed by 4 weeks of 22 mg/day. Of the 40 subjects enrolled, 38 (95%) completed the 4 weeks of 44 mg patch therapy and 36 (90%) completed the entire 8 weeks of patch therapy. Non-smokers at week 4 had a mean serum nicotine level of 23.4±11.7 ng/ml and cotinine of 152.2±87.3 ng/ml. Percent replacement was calculated by dividing the steady state level at week 4 by the baseline level while the subjects were smoking their usual number of cigarettes. Percent nicotine replacement for non-smokers at week 4 (while on 44 mg nicotine patch) averaged 158%±108.4, and for cotinine was 112.0±73.8. For nicotine, 33% of non-smokers at week 4 had ≤ 100% nicotine replacement and for cotinine 63% ≤ 100% replacement. Biochemically confirmed point prevalence smoking cessation rates were 65% and 55% at weeks 4 and 8 of patch therapy, respectively, and self-reported smoking cessation at 3 months was 50%. The most common effect was skin irritation at the patch site. A single subject was admitted for myocardial infarction following step-down from 44 to 22 mg of replacement nicotine. The subject was not smoking and the adverse event was deemed to be not related to the patch therapy. Sleep complaints were reported in 33% of subjects during the 44 mg phase. Other complaints were infrequent. We conclude that 44 mg per 24-h nicotine patch therapy in heavy smokers is safe, tolerable, and without significant adverse events.

Bioactive analogs of neurotensin: focus on CNS effects.

Neurotensin (NT) is a 13-amino acid neuropeptide found in the central nervous system and in the gastrointestinal tract. It is closely associated anatomically with dopaminergic and other neurotransmitter systems, and evidence supports a role for NT agonists in the treatment of various neuropsychiatric disorders. However, NT is readily degraded by peptidases, so there is much interest in the development of stable NT agonists, that can be injected systemically, cross the blood-brain barrier (BBB), yet retains the pharmacological characteristics of native NT for therapeutic use in the treatment of diseases such as schizophrenia, Parkinsons disease and addiction.

Sleep and Breathing in Patients With the Prader-Willi Syndrome

The Prader-Willi syndrome is characterized by infantile hypotonia, early childhood obesity, mental deficiency, short stature, small hands and feet, and hypogonadism. Many patients also have hypersomnolence, experience daytime hypoventilation, and subsequently die prematurely of cardiorespiratory failure. Hypersomnolence and daytime hypoventilation are also common occurrences in the sleep apnea syndrome. For a better understanding of the relationship of sleep to the features of the Prader-Willi syndrome, we retrospectively reviewed five patients (two adults, one adolescent, and two children) with this syndrome who underwent polysomnography. All patients were obese; they had hypersomnolence and daytime hypoxemia, and they nored. In all patients, the apnea plus hypopnea index was less than 10 episodes per hour of sleep. During rapid eye movement sleep, nonapneic reductions in oxyhemoglobin saturation were detected in one adult and in one child. Despite the presence of morbid obesity and a history of snoring, patients with Prader-Willi syndrome seem to have only mild sleep-disordered breathing.

Neurotensin agonists: Potential in the treatment of schizophrenia

Neurotensin (NT) is a neuropeptide that, for decades, has been implicated in the biology of schizophrenia. It is closely associated with, and is thought to modulate, dopaminergic and other neurotransmitter systems involved in the pathophysiology of various neuropsychiatric diseases, including schizophrenia.This review outlines the neurochemistry and function of the NT system and the data implicating its role in schizophrenia. The data suggest that NT receptor agonists have the potential to be used as novel therapeutic agents for the treatment of schizophrenia, with the added benefits of (i) not causing weight gain, an adverse effect that is problematic with some of the currently used atypical antipsychotic drugs; and (ii) helping patients to stop smoking, a behaviour that is highly prevalent in those with schizophrenia.

Prevalence of Restless Legs Syndrome Among Native South Americans Residing in Coastal and Mountainous Areas

OBJECTIVE To determine the prevalence of restless legs syndrome (RLS) in native South Americans and identify the impact of geographic location. PARTICIPANTS AND METHODS An epidemiological telephone survey of RLS symptoms involving natives from coastal and mountainous areas was performed during July 2, 2004, through September 28, 2004. The process consisted of 2 phases: the creation of the epidemiological instrument and the telephone survey. RESULTS Five hundred adults, 250 from the mountainous regions and 250 from the coastal region (190 men and 310 women; age range, 25-85 years) were interviewed and subsequently divided on the basis of International Restless Legs Syndrome Study Group criteria into those who had RLS (RLS+ group) and those who did not (RLS- group). Ten (2.0%) had RLS. The overall rate of RLS in adults living in the mountainous region at 2816 m above sea level (3.2% [8/250]) was significantly higher than that for adults living in the coastal region at 4 m above sea level (0.80% [2/250]; P = .002). The mean age of the RLS+ group was 49.5 years (SD, 15.20 years; range, 25-85 years). CONCLUSION Native South American adults have a prevalence of RLS well below that reported in populations with European ancestry but similar to that in Asian and Turkish populations. Furthermore, in Ecuador, geographic differences were identified in areas of similar population density.

Blockade of nicotine-induced locomotor sensitization by a novel neurotensin analog in rats

Neurotensin is a tridecapeptide with anatomic and functional relationships to dopaminergic neurons. Previously we showed that one of our brain-penetrating neurotensin analogs, NT69L (N-met-L-Arg, L-Lys, L-Pro, L-neo-Trp, L-tert-Leu, L-Leu), blocks cocaine- and D-amphetamine-induced hyperactivity in rats. We have now performed a similar study in rats sensitized to nicotine over 15 days of administration. Male Sprague-Dawley rats were randomly assigned to receive daily injections for 15 days with one of the following combinations: saline/nicotine (0.35 mg/kg), NT69L (1 mg/kg)/nicotine, saline/saline, or NT69L/saline with a 30-min period between injections. On day 15 each group was given saline/nicotine or NT69L/nicotine and tested in an activity chamber. One-time administration of NT69L attenuated nicotine-induced activity with an ED(50) of 1.6 microg/kg. Rats injected with nicotine over the 15 days had a significant increase in locomotor activity, consistent with nicotine-induced locomotor sensitization. A single injection of NT69L on day 15 prior to nicotine markedly decreased nicotine-induced hyperactivity. Although daily injections of NT69L lessened its effect, statistically significant reductions in hyperactivity to nicotine persisted throughout the study. There was no significant difference in activity between rats injected with NT69L/saline and saline/saline. Thus, the activity reduction was not due to sedation. Acute and chronic nicotine injection caused an increase in cytisine binding in prefrontal cortex. NT69L significantly reduced the increase caused by acute but not chronic injection of nicotine. Nicotine injection resulted in an increase in dopamine levels in the striatum and dopamine and norepinephrine levels in the prefrontal cortex. NT69L lowered the norepinephrine and dopamine levels in the prefrontal cortex but did not affect striatal dopamine. The present study is the first report, to our knowledge, of a possible role for neurotensin in the development of nicotine dependence, and suggests that neurotensin analogs such as NT69L may be explored as treatment for nicotine and other psychostimulant abuse.

Studies of humoral immunity to preprohypocretin in human leukocyte antigen DQB1*0602-positive narcoleptic subjects with cataplexy

BACKGROUND Canine models for narcolepsy have mutations of the hypocretin receptor 2 gene, and preprohypocretin knockout murine lines exhibit narcoleptic-like behaviors. Human narcolepsy with cataplexy is associated with human leukocyte antigen DQB1*0602 and reduced hypocretin levels in cerebrospinal fluid, suggesting an autoimmune diathesis. We tested the hypothesis that DQB1*0602-positive narcoleptic subjects with cataplexy have immunoglobulin (Ig)G reactive to human preprohypocretin and its cleavage products. METHODS Serum samples of 41 DQB1*0602-positive narcoleptic subjects with cataplexy and 55 control subjects were studied, as were 19 narcoleptic and 13 control samples of cerebrospinal fluid. We tested for IgG reactive to preprohypocretin and its major cleavage products (including hypocretin 1 and 2), using immunoprecipitation assays (IP), immunofluorescence microscopy (IF) of Chinese hamster ovarian cells expressing preprohypocretin, and Western blots. RESULTS There was no evidence for IgG reactive to preprohypocretin or its cleavage products in CSF of subjects with narcolepsy as measured by IPs, Western blots, and IF. Although the IP with CSF and the C-terminal peptide showed significant differences by two methods of comparison, the control subjects had higher counts per minute than narcoleptic subjects, which was opposite to our hypothesis. CONCLUSIONS The hypothesis that DQB1*0602-positive narcoleptic subjects with cataplexy have IgG reactive to preprohypocretin or its cleavage products was not supported.

Diverse Roles of Neurotensin Agonists in the Central Nervous System

Neurotensin (NT) is a tridecapeptide that is found in the central nervous system (CNS) and the gastrointestinal tract. NT behaves as a neurotransmitter in the brain and as a hormone in the gut. Additionally, NT acts as a neuromodulator to several neurotransmitter systems including dopaminergic, sertonergic, GABAergic, glutamatergic, and cholinergic systems. Due to its association with such a wide variety of neurotransmitters, NT has been implicated in the pathophysiology of several CNS disorders such as schizophrenia, drug abuse, Parkinson’s disease (PD), pain, central control of blood pressure, eating disorders, as well as, cancer and inflammation. The present review will focus on the role that NT and its analogs play in schizophrenia, endocrine function, pain, psychostimulant abuse, and PD.

Novel neurotensin analog blocks the initiation and expression of nicotine-induced locomotor sensitization.

Neurotensin is a tridecapeptide that participates in regulation of dopaminergic pathways implicated in nicotine addiction. Previously, we showed that one of our brain-penetrating neurotensin analogs, NT69L, blocks nicotine-induced locomotor sensitization. The present work demonstrates that NT69L blocks both the initiation and the expression of sensitization. In addition chronic NT69L administration blocked the acute effects of nicotine on norepinephrine and serotonin in prefrontal cortex.