The effect of potent CYP2D6 inhibition on the pharmacokinetics and safety of deutetrabenazine in healthy volunteers.

PURPOSE: Deutetrabenazine is a deuterated form of tetrabenazine with a confirmed lower rate of CYP2D6 metabolism of the active metabolites, α- and ß-HTBZ. In this study, we assessed the effect of paroxetine, a potent CYP2D6 inhibitor, on the pharmacokinetics and safety of deutetrabenazine and its metabolites. METHODS: In this open-label sequential drug-drug-interaction study, 24 healthy adults who were CYP2D6 extensive or intermediate metabolizers received a single deutetrabenazine 22.5-mg oral dose on days 1 and 11 and a single paroxetine 20-mg oral daily dose on days 4-12. Pharmacokinetics of deutetrabenazine and its metabolites were assessed on days 1-4 and 11-14. Paroxetine trough concentrations were obtained pre-dose on days 9-13. Safety examinations occurred throughout the study. RESULTS: Paroxetine administered under steady-state conditions, increased exposure of the deuterated active metabolites, α-HTBZ (1.2-fold Cmax and 1.8-fold AUC0-∞) and ß-HTBZ (2.1-fold Cmax and 5.6-fold AUC0-∞), and correspondingly, 1.6-fold Cmax and threefold AUC0-∞ for total (α + ß)-HTBZ. Sixteen subjects reported 45 adverse events and most were mild. Headache was the most common AE reported 8 times by 7 subjects (5 following paroxetine alone; 2 following deutetrabenazine + paroxetine). CONCLUSIONS: Paroxetine-induced increases in exposure to the active deutetrabenazine metabolites were less than those previously reported for tetrabenazine, a finding expected to reduce the burden of drug interaction. In addition, single doses of 22.5 mg deutetrabenazine, when given alone or in the presence of steady-state paroxetine (20 mg daily), were safe.

Repeated dosing of botulinum toxin type A for upper limb spasticity following stroke.

The authors evaluated the long-term efficacy and safety of botulinum toxin type A (BTX-A) in poststroke spasticity patients who completed a 12-week placebo-controlled study and received multiple open-label treatments with 200 to 240 U BTX-A for 42 weeks. Significant and sustained improvements were observed for Disability Assessment and Ashworth scores. Adverse events were generally mild. This extension of a double-blind study demonstrates that repeated treatments of BTX-A significantly improve function and tone in spasticity.

Falling asleep at the wheel: motor vehicle mishaps in persons taking pramipexole and ropinirole.

The authors report a new side effect of the dopamine agonists pramipexole and ropinirole: sudden irresistible attacks of sleep. Eight PD patients taking pramipexole and one taking ropinirole fell asleep while driving, causing accidents. Five experienced no warning before falling asleep. The attacks ceased when the drugs were stopped. Neurologists who prescribe these drugs and patients who take them should be aware of this possible side effect.

Genetic analysis of three patients with an 18p- syndrome and dystonia.

Some patients with an 18p- syndrome show dystonia, and a focal dystonia gene has been mapped to chromosome 18p. The authors evaluated the extent of the deletion in three patients with an 18p- syndrome and dystonia using 14 DNA markers on 18p. A common deleted area, covering the DYT7 locus, places the putative dystonia gene between the telomere of 18p and D18S1104 (49.6 cM). Dystonia in these patients may be caused by haploinsufficiency of the DYT7 gene, a new dystonia gene on 18p, or may result from developmental brain anomalies.

Adult-onset MELAS presenting as herpes encephalitis.

OBJECTIVE: To report an unusual presentation of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) manifested in late life with a clinical picture of herpes simplex encephalitis. DESIGN: Case report. SETTING: Clinical neurology department in a tertiary care hospital. CASE DESCRIPTION: A 55-year-old woman developed aphasia and delirium during ophthalmic herpes zoster infection treated with oral prednisone and ophthalmic steroids, which was followed by progressive cognitive decline without acute neurologic events for 5 years. At age 60, the patient presented with new onset of seizures, hemiparesis, and hemianopsia. Subsequently she developed cortical blindness, multiple traumatic soft tissue injuries from falls, acute psychosis, and severe dementia with periods of agitation. She died in a nursing home in March 1997, 6 years after initial presentation. RESULTS: Magnetic resonance imaging scan of the brain showed hyperintensity on T2-weighted images involving temporal, parietal, and occipital lobes bilaterally as well as mild atrophy of brainstem and cerebellum. Single photon emission computed tomographic imaging showed hypoperfusion of temporal, parietal, and occipital lobes. Results of video electroencephalographic monitoring showed periodic lateralizing epileptiform discharges in temporal and occipital areas. The serum lactate level was normal in May 1996 and elevated in October 1996. The creatine kinase level was elevated with a 100% MM fraction in August 1991 and normal in March 1996. Results of repeated cerebrospinal fluid analyses indicated elevated protein levels. Analysis of DNA was diagnostic of MELAS by mitochondrial DNA point mutation at position 3243. The results of autopsy showed moderate cerebral, cerebellar, and brainstem atrophy with signs of infarction in temporal and parietal lobes bilaterally. CONCLUSIONS: The clinical presentation as well as age at onset of MELAS are highly variable. Onset of mitochondrial disorders can be provoked by febrile illness when there is mismatch between energy requirements and availability. In the differential diagnosis of herpes encephalitides, MELAS syndrome should be considered.

From apprenticeship to academia: an adult branch programme.

This paper describes aspects of the introduction an adult branch programme of a Diploma of Higher Education in Nursing course in a Scottish college of nursing and midwifery. It is argued that the Diploma of Higher Education in Nursing course represents a move from a so-called apprenticeship approach, that is the Scottish 1982 Modular Scheme of General Training, to a so-called academic approach under the auspices of the Project 2000 proposals which have been described as the most major development in the preparation of nurses in the UK for many years (UKCC 1986). This paper will discuss the challenges and difficulties encountered when designing the theoretical aspects of the course with respect to the nursing component. The implications of some of the major changes within the scheme of preparation for the clinical areas where the students gain experience will also be discussed. It will be suggested that practice supervision, a development of apprenticeship, is the way ahead.

Dystonia in a patient with deletion of 18q.

This is the first reported case of dystonia with a partial deletion of the long arm (q) of chromosome 18. Neurologic findings in the 18q- syndrome include mental retardation, seizures, nystagmus, incoordination, tremor, and chorea. A 36-year-old woman with an 18q terminal deletion [karyotype 46,XX,del(18)(q22.2)] had hypothyroidism, diabetes mellitus, borderline intelligence, short stature, short neck, sensorineural hearing loss, and sensorimotor axonal neuropathy. Parents' karyotypes were normal. She had had incoordination and writing difficulty since childhood. Posturing and tremor of the head began at age 16, followed by arm tremors. She had jaw deviation and tremor, neck tremor with retrocollis, involuntary pronation of the right arm, coarse postural and severe action tremor, and tight pen grip with dystonic wrist extension on writing. The 18q- syndrome should be added to the list of genetic causes of secondary dystonia. A karyotype analysis should be considered in secondary dystonias, particularly when there are associated features such as short stature and endocrinopathies.

Bismuth subsalicylate toxicity as a cause of prolonged encephalopathy with myoclonus.

Bismuth subsalicylate preparations are over-the-counter products for gastrointestinal complaints. Bismuth toxicity causes delirium, psychosis, ataxia, myoclonus, and seizures and is reversible over several weeks or months, when bismuth intake is stopped. We report a 54-year-old man with a 6-week history of progressive confusion and memory difficulty and a 2-3-week history of involuntary movements and gait impairment. His encephalopathy was further characterized by marked multifocal myoclonic jerks, coarse postural tremors, postural instability, and gait ataxia. He gradually improved. Extensive toxic, metabolic, and infectious workup demonstrated bismuth toxicity. Spinal tap and brain magnetic resonance scan were normal. Electroencephalography showed bihemispheric slowing. As his encephalopathy cleared, he reported using bismuth subsalicylate long term (daily intake of 8 oz). Bismuth levels 5 weeks after cessation of bismuth were elevated and normalized after 12 weeks. He followed a typical course for bismuth toxicity with subacute progressive encephalopathy and gradual recovery. Creutzfeldt-Jakob was strongly considered due to his rapidly progressive encephalopathy, multifocal myoclonus, and ataxia. Due to its rarity, bismuth toxicity is often overlooked. We hope this presentation will increase recognition of bismuth toxicity. We believe more detailed labeling of bismuth products is needed to avoid similar toxicity from this readily available product.

The use of clozapine in neurologic disorders.

The advent of clozapine has marked a major advance in the treatment of schizophrenia because of its low incidence of extrapyramidal side effects and superior efficacy. Because of a relatively high incidence of agranulocytosis, approved indications for use are limited to treatment-refractory or neuroleptic-intolerant patients with schizophrenia. However, an emerging body of literature suggests that clozapine may be preferable to typical neuroleptics for treating psychosis in certain neurologic disorders. In addition, clozapine may have a place in the treatment of movement disorders that are caused by or are a result of the pharmacologic treatment of some neurologic illnesses. In general, clozapine doses used in these settings are lower than that for treating psychosis in schizophrenia. This article reviews the experience with clozapine in selected neurologic disorders.

A study of idiopathic torsion dystonia in a non-Jewish family: evidence for genetic heterogeneity.

A gene (DYT1) for idiopathic torsion dystonia (ITD) was mapped to chromosome 9q34 in non-Jewish and Jewish families; the dystonia in these families usually began in childhood, with the limb muscles affected first. The role of the DYT1 gene in adult-onset and cervical- or cranial-onset ITD is unknown. We examined 53 individuals from four generations of a non-Jewish North American family with adult-onset ITD. There were seven affected family members, with a mean age at onset of 28.4 years (range, 7 to 50 years). In six of the seven, the neck was affected first. All seven developed cervical dystonia, and dysarthria or dysphonia occurred in five. Linkage data excluded the region containing the DYT1 locus, indicating that DYT1 was not responsible for ITD in this family. This study provides evidence that a gene other than DYT1 is responsible for some cases of adult cervical-onset dystonia.

Therapeutic trial of milacemide in patients with myoclonus and other intractable movement disorders.

We performed a therapeutic trial with the glycine precursor, milacemide, on 10 patients with intractable movement disorders. Six had myoclonus of various etiologies and one each had progressive supranuclear palsy, Filipino X-linked dystonia with parkinsonism, painful legs and moving toes, and stiff-person syndrome. Milacemide was initiated at a dose of 2,400 mg/day, orally, and increased gradually to a maximum of 4,800 mg/day. No clear-cut observable improvement occurred. There were no serious adverse effects.

Drug-induced meningitis.

Meningitis is usually produced by an infectious agent, but there are multiple noninfectious causes. Medications may produce both acute and recurrent meningitis. We present a patient with 3 episodes of aseptic meningitis due to trimethoprim-sulfamethoxazole, and then review the topic of drug-induced meningitis.

Eales' disease presenting as stroke in the young adult.

Eales' disease is an uncommon idiopathic disorder characterized by retinal perivasculitis and recurrent vitreous hemorrhages in young males. Associated neurological involvement is rare. We report a 38-year-old man who presented with stroke attributed to Eales' disease.

Ten year follow up of farmers with farmer's lung.

Twenty-nine patients previously diagnosed as having suffered from farmer's lung in or before 1970 were asked whether the condition had recurred and what measures they had taken to avoid such recurrence. Those who had retired from farming had been least affected by recurrence, while those who continued to farm had been protected by making silage instead of hay or by wearing protective respirators. To be effective, a respirator should be worn on every occasion that farm dust is encountered and must be properly maintained.

Trends in recent systemic lupus erythematosus mortality rates.

National death rates from systemic lupus erythematosus (SLE) were calculated for the period 1972 to 1976 according to age, sex, and race and were compared to rates for 1968 to mid-1972. The time trend in the age-adjusted death rates from SLE was also analyzed for the entire period 1968 to 1977. The previously reported variable sex and race ratios persist through the recent period, particularly the greater mortality rates among black women during middle and early adulthood. An overall decline in the adjusted death rates in the younger age groups (1-49 years old) in each race-sex group is seen in the recent period.