A randomized, double-blind, placebo-controlled study to evaluate botulinum toxin type A in essential hand tremor.

Twenty-five patients with hand tremor of 2+ (moderate) to 4+ (severe) on the tremor severity rating scale were randomized to receive either 50 U of botulinum toxin (BTX) type A (Allergan, Irvine, CA) or placebo injections into the wrist flexors and extensors of the dominant limb. If patients failed to respond to the initial injection, they were eligible to receive another injection of 100 U 4 weeks later. Rest, postural, and kinetic tremors were evaluated at 2- to 4-week intervals over a 16-week study period using tremor severity rating scales, accelerometry, and assessments of improvement and disability. A significant improvement (p < 0.05) was observed on the tremor severity rating scale 4 weeks after injection in patients treated with BTX as compared with placebo, and this effect was maintained for the duration of the study. Four weeks after injection, 75% of BTX-treated patients vs. 27% of placebo-treated patients (p < 0.05) reported mild to moderate improvement (peak effect rating > or = 2). There were no significant improvements in functional rating scales, although trends were observed for some items. Postural accelerometry measurements showed a > or = 30% reduction in amplitude in nine of 12 BTX-treated subjects and in one of nine placebo-treated subjects (p < 0.05). Although all patients treated with BTX reported some degree of finger weakness, no severe, irreversible, or unexpected adverse events occurred. Chemodenervation with BTX may significantly ameliorate essential hand tremor in patients who fail to improve with conventional pharmacologic therapy.

Botulinum toxin type A in the treatment of upper extremity spasticity: a randomized, double-blind, placebo-controlled trial.

Spasticity is a disorder of excess muscle tone associated with CNS disease. We hypothesized that botulinum toxin, a neuromuscular blocking agent, would reduce tone in spastic muscles after stroke. This randomized, double-blind, placebo-controlled, multicenter clinical trial evaluated the safety and efficacy of botulinum toxin type A (BTXA) in the treatment of chronic upper limb spasticity after stroke. Thirty-nine patients received IM injections of a total dose of either 75, 150, or 300 units of BTXA or placebo into the biceps, flexor carpi radialis, and flexor carpi ulnaris muscles. At baseline, patients demonstrated a mean wrist flexor tone of 2.9 and elbow flexor tone of 2.6 on the Ashworth Scale (0 to 4). Treatment with the 300-unit BTXA dose resulted in a statistically and clinically significant mean decrease in wrist flexor tone of 1.2 (p = 0.028), 1.1 (p = 0.044), and 1.2 (p = 0.026) points and elbow flexor tone of 1.2 (p = 0.024), 1.2 (p = 0.028), and 1.1 (p = 0.199) at weeks 2, 4, and 6 postinjection. In the placebo group, tone reduction at the wrist was 0.3, 0.2, and 0.0 and at the elbow was 0.3, 0.3, and 0.6 at weeks 2, 4, and 6 postinjection. BTXA groups reported significant improvement on the physician and patient Global Assessment of Response to Treatment at weeks 4 and 6 postinjection. There were no serious adverse effects. In this 3-month study, BTXA safely reduced upper extremity muscle tone in patients with chronic spasticity after stroke.

Discovery of an orally bioavailable NK1 receptor antagonist, (2S,3S)-(2-methoxy-5-tetrazol-1-ylbenzyl)(2-phenylpiperidin-3-yl)amine (GR203040), with potent antiemetic activity.

The antiemetic, pharmacokinetic, and metabolic profile of CP-99,994, a potent NK1 receptor antagonist, has been carefully evaluated. As a result we began a medicinal chemistry program which initially identified a 3-furanyl analogue (6) with improved antiemetic potency and a methyl sulfone (5) with enhanced metabolic stability and oral bioavailability. The improved pharmacokinetic profile of methyl sulfone (5) was associated with its low lipophilicity, and a therefore a number of heterocyclic analogues with reduced log D were synthesized. Out of this program emerged 19 (GR203040), a tetrazolyl-substituted analogue. Tetrazole 19 inhibits radiation-induced emesis in the ferret with high potency when administered both subcutaneously and orally, has a long duration of action, and has high oral bioavailability in the dog. Tetrazole 19 is currently undergoing evaluation as a novel approach for the control of emesis associated with, for example, cancer chemotherapy.

Unpreserved carboxymethylcellulose artificial tears evaluated in patients with keratoconjunctivitis sicca.

In order to evaluate the therapeutic value of an unpreserved carboxymethylcellulose-based artificial tear in treatment of keratoconjunctivitis sicca (KCS), 56 patients with severe keratoconjunctivitis sicca were enrolled, at a single study center, in a randomized, double-masked, 8-week comparison with a preserved hydroxypropylmethylcellulose (HMC)-based artificial tear. Patients treated with the carboxymethylcellulose (CMC)-based tear showed significant improvement in fluorescein staining, symptoms, and impression cytology grades. Patients treated with HMC-based tears showed minimal improvement in a few variables. Impression cytology specimens were analyzed by a modified technique that maps the distribution of the various grades present on the specimen. With this technique, improvement in the cytology grades was noted in the group of patients using CMC-based tears. The improvement correlated with observed decreases in symptoms of discomfort and with scores for superficial punctate staining. This study supports the observed therapeutic value of unpreserved CMC-based artificial tears and suggests the possible reversal of squamous metaplasia in patients with KCS. Further studies are required to separate the benefit of the CMC formulation from the benefits of preservative elimination.

[Comparison of the effectiveness and safety of levobunolol and timolol in ocular hypertension and chronic open-angle glaucoma]. / Vergleich der Wirksamkeit und Anwendungssicherheit von Levobunolol und Timolol bei okulärer Hypertension und chronischem Offenwinkelglaukom.

Twenty-six patients with open-angle glaucoma or ocular hypertension were studied in a concomitant double-masked clinical trial lasting three months, in which the ocular hypotensive efficacy and safety of levobunolol (0.5%) and timolol (0.5%), topically administered twice daily, were compared. At all follow-up examinations there was a significant decrease in mean intraocular pressure from baseline in both treatment groups, with no significant difference between them in this regard. Few changes were seen in either treatment group in cup/disk ratio, visual fields, visual acuity, biomicroscopy, or ophthalmoscopy. In both groups slight decreases in mean blood pressure were observed. Levobunolol and timolol were similarly effective and safe in reducing intraocular pressure in patients with chronic open-angle glaucoma and those with ocular hypertension.