James Berg

Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: A randomized trial

Background: Patients with ALS commonly exhibit pseudobulbar affect. Methods: The authors conducted a multicenter, randomized, double-blind, controlled, parallel, three-arm study to test a defined combination of dextromethorphan hydrobromide (DM) and quinidine sulfate (Q) (AVP-923) for the treatment of pseudobulbar affect in ALS. Q inhibits the rapid first-pass metabolism of DM. The effects of AVP-923 (30 mg of DM plus 30 mg of Q) given twice daily for 28 days were compared with those of its components. Patients were evaluated on days 1, 15, and 29. The primary efficacy variable was the change from baseline in the Center for Neurologic Study Lability Scale (CNS-LS) score. Secondary efficacy variables were laughing/crying episode rates and changes in Visual Analog Scales for Quality of Life (QOL) and Relationships (QOR). Efficacy was evaluated in intention-to-treat subjects who were not poor metabolizers of DM (n = 65 for AVP-923, n = 30 for DM, and n = 34 for Q). Safety was assessed in all randomized subjects (n = 140). Results: AVP-923 patients experienced 3.3-point greater improvements in CNS-LS than DM patients (p = 0.001) and 3.7-point greater improvements than Q patients (p < 0.001). AVP-923 patients exhibited lower overall episode rates, improved QOL scores, and improved QOR scores (p < 0.01 for all endpoints). Adverse effects were mostly mild or moderate; treatment-related discontinuation was 24% for AVP-923, 6% for DM, and 8% for Q. Conclusions: AVP-923 palliates pseudobulbar affect in ALS. Overall benefits of treatment are reflected in fewer episodes of crying and laughing and improvements in overall quality of life and quality of relationships.

Randomized, controlled trial of dextromethorphan/quinidine for pseudobulbar affect in multiple sclerosis†

To evaluate the efficacy and safety of DM/Q (capsules containing dextromethorphan [DM] and quinidine [Q]) compared with placebo, taken twice daily, for the treatment of pseudobulbar affect over a 12‐week period in multiple sclerosis patients.

Pharmacokinetics of dextromethorphan after single or multiple dosing in combination with quinidine in extensive and poor metabolizers.

Dextromethorphan (DM) pharmacological properties predict that the widely used cough suppressant could be used to treat several neuronal disorders, but it is rapidly metabolized after oral dosing. To find out whether quinidine (Q), a CYP2D6 inhibitor, could elevate and prolong DM plasma profiles, 2 multiple‐dose studies identified the lowest oral dose of Q that could be used in a fixed combination with 3 doses of DM. A multiple‐dose study in healthy subjects with an extensive or a poor enzyme metabolizer phenotype evaluated the safety and pharmacokinetic profile of a selected fixed‐dose combination (AVP‐923). Study 1 randomized 46 healthy subjects, who were extensive CYP2D6 metabolizers, to receive 0, 2.5, 10, 25, 50, or 75 mg Q twice daily in combination with 30 mg DM for 7 days. Plasma and urine samples were collected after the first and last doses for the assay of DM, dextrorphan (DX), and Q. Study 2 randomized 65 healthy extensive CYP2D6 metabolizers to 8 groups given twice‐daily 45‐ or 60‐mg DM doses combined with 0, 30, 45, or 60 mg Q for 7 days. The effects of increasing Q were not different with doses greater than 25 mg, whereas lower doses showed a dose‐related increase in plasma DM concentrations. Urinary ratios of DM/DX showed a Q dose‐ and time‐related increase in the number of subjects converted to the poor metabolizer phenotype that reached 100% on day 3 of dosing with 25 mg Q. Results from both studies indicated that 25 to 30 mg Q is adequate to maximally suppress O‐demethylation of DM. Study 3 evaluated 7 extensive metabolizers and 2 poor metabolizers given an oral capsule every 12 hours containing 30 mg Q combined with 30 mg DM. DM plasma AUC values increased in both groups of subjects during the 8‐day study. The mean urinary metabolic ratio (DM/DX) increased at least 27‐fold in extensive metabolizers by day 8. There was no effect of Q on urinary metabolic ratios in poor metabolizers. Safety evaluations, including electrocardiograms, indicated that the combination was well tolerated, with no difference between extensive and poor metabolizer phenotypes.

Validation of the CNS emotional lability scale for pseudobulbar affect (pathological laughing and crying) in multiple sclerosis patients

Pseudobulbar affect (PBA) or pathological laughing and crying (PLC) is a disorder of affect that occurs in about 10% of multiple sclerosis (MS) patients. The objective of this study was to validate the CNS Emotional Lability Scale (CNS-LS) in MS patients and to correlate the results with the frequency and intensity of episodes of PLC. Physicians at seven private practice referral centers in the United States made a diagnosis concerning PLC based on patient interviews. Clinical coordinators separately administered the CNS-LS, a self-report measure of PLC with seven questions, to MS patients, including patients known to exhibit PLC, patients thought to be free of PLC, and newly diagnosed patients where PLC status was unknown, and the physician was blinded as to the results. A receiver operating characteristic (ROC) curve analysis was performed to define a cut-off best correlating with the physician’s diagnosis. Of 90 MS patients selected to complete the survey, 50 were physician diagnosed with PLC; 40 were without PLC, and 15 of these 90 patients were newly diagnosed with MS (B-6 months). Scores of 17 or higher corresponded to a sensitivity of 0.94 and a specificity of 0.83 (LR -/5.5, LR -/0.07); 89% of patients were correctly diagnosed. The area under the ROC curve was 0.95. Symptoms were greater in patients diagnosed as PLC than in non-PLC patients as evidenced by mean number of episodes/week, number of days/week with episodes, duration of an episode and total time in an episode. Similar results were observed if patients were classified as PLC or non-PLC according to CNS-LS score]-17, suggesting that the CNS-LS is a valid measure for the assessment of PLC in MS patients and could be a useful instrument for clinical and research purposes.

Measuring pseudobulbar affect in ALS

to neurologists to further characterize the disorder. When it became apparent that pseudobulbar affect could be moderated with treatment, the need for a quantitative test instrument became apparent. About 10 years ago Robinson and his colleagues developed the Pathological Laughing and Crying Scale (PLACS), an interviewer-administered rating scale that was validated for use in patients with cerebral vascular disease.2 This has been utilized as a trial endpoint in several studies of the effect of serotonin uptake inhibitors. 3,4 A modified version of PLACS has been developed for use with ALS patients but it has not been used as an endpoint in a clinical trial. 5 In contrast to PLACS, the Center for Neurologic Study-Lability Scale (CNS-LS) is a self- administered scale that has been validated in a large population of ALS patients. 6 It is short – seven items in the simplest iteration that chronicles labile tearfulness and laughter, and about twice that size when subscales measuring labile anger and frustration are included. (see Appendix 1 for the CNS-LS.) Since its publication in 1997, the CNS-LS has proven to be a useful diagnostic instrument and a robust clinical trial endpoint in ALS.7 While pseudobulbar affect commonly occurs in the setting of ALS, particularly in patients with bulbar involvement, it also occurs in a variety of other disorders including multiple sclerosis, Alzheimer’s disease, and stroke. The lack of disease specificity suggests a common anatomical substrate which in our opinion is best conceptualized as a disconnection syndrome. Several lines of evidence implicate brainstem and/or cerebellar connections to the cortex that are probably disrupted as a result of pathological processes. In the traditional view, advanced by Wilson in the 1920s, lesions in descending cortical pathways disrupt a brainstem control center that is hypothesized to reside in the upper pons or midbrain. This paradigm has been challenged by recent evidence suggesting that the cerebellum moderates emotional responses. Using advanced imaging techniques Parvizi et al. have reconstructed three-dimensional images of the brain of a patient with florid emotionality resulting from a cerebral vascular accident. 8 The only lesions seen in this patient were

The Antiviral Drug Docosanol as a Treatment for Kaposi's Sarcoma Lesions in HIV Type 1-Infected Patients: A Pilot Clinical Study

Docosanol inhibits a broad spectrum of lipid-enveloped viruses in vitro including HSV-1, HSV-2, VZV, CMV, HHV-6, and HIV-1. These observations led us to conduct a pilot clinical study with docosanol 10% cream as a topical treatment for Kaposis sarcoma (KS) in HIV-1-infected patients. In this open-label study 28 cutaneous KS lesions in 10 HIV-1-infected patients were treated topically five times daily for 4 weeks with evaluation of lesion characteristics of area, edema, and color. All patients elected to enroll in an extended treatment protocol and continued to treat for up to 35 weeks. Within 28 days, 2 of 10 patients exhibited a partial response based on standardized criteria exhibiting 74 to 83% reductions in total target lesion areas. With extended treatment, a partial response was exhibited in two additional patients where total target lesion area was reduced by 52% in one patient and target lesions in another patient that had been large, swollen, and painful at study initiation were no longer visible. No patient experienced disease progression or signs of visceral disease. The average percent decrease in lesion area for all target lesions was 20% (p < 0.01). A patients response to therapy appeared to be independent of anti-HIV regimen, HIV viral load, or previous KS treatments. These results suggest that docosanol merits further investigation as a potential topical therapy in the treatment of AIDS-associated Kaposis sarcoma lesions.