Topical diclofenac epolamine patch 1.3% for treatment of acute pain caused by soft tissue injury.

Acute pain caused by musculoskeletal disorders is very common and has a significant negative impact on quality-of-life and societal costs. Many types of acute pain have been managed with traditional oral non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 inhibitors (coxibs). Data from prospective, randomised controlled clinical trials and postmarketing surveillance indicate that use of oral traditional NSAIDs and coxibs is associated with an elevated risk of developing gastrointestinal, renovascular and/or cardiovascular adverse events (AEs). Increasing awareness of the AEs associated with NSAID therapy, including coxibs, has led many physicians and patients to reconsider use of these drugs and look for alternative treatment options. Treatment with NSAIDs via the topical route of administration has been shown to provide clinically effective analgesia at the site of application while minimising systemic absorption. The anti-inflammatory and analgesic potency of the traditional oral NSAID diclofenac, along with its physicochemical properties, makes it well suited for topical delivery. Several topical formulations of diclofenac have been developed. A topical patch containing diclofenac epolamine 1.3% (DETP, FLECTOR(®) Patch), approved for use in Europe in 1993, has recently been approved for use in the United States and is indicated for the treatment of acute pain caused by minor strains, sprains and contusions. In this article, we review the available clinical trial data for this product in the treatment of pain caused by soft tissue injury.

Type C Niemann-Pick disease: dimethyl sulfoxide moderates abnormal LDL-cholesterol processing in mutant fibroblasts.

Biochemical and cytochemical studies have revealed that abnormal processing of low-density-lipoprotein (LDL) cholesterol can be reversed in mutant Niemann-Pick C (NP-C) fibroblasts when 2% dimethyl sulfoxide (DMSO) is added to the culture medium. Both the excessive lysosomal accumulation of LDL cholesterol and the delayed induction of cellular homeostatic responses associated with the uptake of LDL by the mutant cells were substantially reversed by DMSO. DMSO appears to accelerate the intracellular mobilization of LDL-derived cholesterol through effects that may reflect enhanced membrane permeability or cholesterol solubilization.

Type C Niemann-Pick disease: cellular uncoupling of cholesterol homeostasis is linked to the severity of disruption in the intracellular transport of exogenously derived cholesterol.

A uniquely attenuated disruption of cholesterol homeostasis has been characterized in certain Niemann-Pick, type C (NP-C) fibroblasts. Uptake of LDL-cholesterol by cultured fibroblasts derived from two clinically affected brothers with this variant biochemical phenotype led to less intracellular accumulation of unesterified cholesterol than found in other typical cell lines. This limited cholesterol lipidosis in the variant NP-C cells reflected cholesterol processing errors that differed from the cellular lesions in classical NP-C cells in the following ways: (1) a more limited intracellular distribution of the excessive unesterified cholesterol; (2) shorter and more transient delays in the induction of cholesterol-mediated homeostatic responses; and (3) more efficient intracellular transport of exogenously derived cholesterol to the plasma membrane and the endoplasmic reticulum. Activation of acyl-CoA cholesterol acyltransferase (ACAT) was greater than 100-fold in both control and NP-C fibroblasts when cell cultures were preconditioned with 25-hydroxycholesterol, but the subsequent esterification of exogenous non-lipoprotein [3H]cholesterol remained deficient in all NP-C cells. In the variant NP-C cells conditioned with the oxysterol, this esterification of exogenous [3H]cholesterol was less affected than in classical NP-C cultures. The NP-C mutation affects a broad spectrum of metabolic responses related to the processing of exogenously derived cholesterol. Among this pleiotropic array of deficient responses, retarded intracellular cholesterol transport appears most closely linked to the primary mutation. This conclusion is supported by two current observations: (1) the degree to which sterol transport is affected in mutant cells in turn reflects the extent to which cholesterol-homeostatic responses are compromised; and (2) sterol transport remains deficient despite concurrent normal activation of other cellular responses, such as cholesterol esterification.

Clinical and genetic analysis of progressive dystonia with diurnal variation.

We examined 17 patients with progressive dystonia with diurnal variation, a dominantly inherited, generalized dystonia that begins in childhood. Dystonia was typically least severe in the morning, increased as the day continued, and markedly improved with low doses of carbidopa-levodopa. We also studied the patient's parents, children, and siblings from seven families. We observed a spectrum of neurologic involvement, phenotypic variability among siblings, and incomplete genetic penetrance. Progression of motor impairment over several years, which reaches a plateau during late adolescence, is useful in distinguishing progressive dystonia with diurnal variation from cerebral palsy and degenerative disorders. It is important to recognize the subtle, as well the extreme, manifestations of progressive dystonia with diurnal variation because it is treatable. Genetic counseling must consider that mildly affected parents with little or no disability may have profoundly affected children. Appreciation of the phenotypic variability and degree of genetic penetrance will permit detailed genetic and biochemical analyses.

Tetrahydrobiopterin administration in biopterin-deficient progressive dystonia with diurnal variation.

We administered tetrahydrobiopterin (BH4) to 4 patients with progressive dystonia with diurnal variation (PDDV). One patient improved clinically. Deficient CSF concentrations of HVA and 5-HIAA were unchanged despite marked elevation of CSF biopterin concentration. Variable effectiveness of BH4 in PDDV may reflect reduced number or function of biopterin-metabolizing neurons or variable entry of BH4 into these neurons.

The effect of cholesterol-lowering agents on hepatic and plasma cholesterol in Niemann-Pick disease type C.

Niemann-Pick disease type C (NP-C) is a neurovisceral lipidosis characterized by defective intracellular trafficking of cholesterol and lysosomal accumulation of unesterified cholesterol, believed to be an offending metabolite. We studied the effect of cholesterol-lowering agents on hepatic and plasma cholesterol levels in NP-C by randomly assigning 25 patients with NP-C to one of five treatment regimens containing different combinations of cholestyramine, lovastatin, nicotinic acid, or dimethyl sulfoxide (DMSO). Unesterified cholesterol content was measured in liver biopsies before and after 4 months' treatment. All drug regimens except DMSO alone reduced hepatic and plasma cholesterol levels. Toxicity was limited and did not prevent any patient from completing the study. The combination of cholestyramine, lovastatin, and nicotinic acid lowered cholesterol levels in liver and blood with minimal side effects. A controlled clinical study will be necessary to determine if this regimen influences the rate of neurologic progression.

Resolution of chronic cluster headache after resection of a tentorial meningioma: case report.

Cluster headache is almost always idiopathic, but, in rare cases, associated intracranial lesions have been found. We describe a patient who had chronic cluster headache for more than 20 years. The headache immediately resolved upon resection of a tentorial meningioma. Prior reports of cluster headache as a manifestation of structural disease are briefly reviewed. In the patient described, the pain was referred from the right tentorium cerebelli to the right side of the face, in accordance with reported studies on the subjective localization of pain referred from posterior fossa structures. The accompanying abnormalities of autonomic function may have been mediated by central autonomic reflexes that are also involved in the pathogenesis of idiopathic cluster headache.

New analgesics for neuropathic pain: the lidocaine patch.

Despite the availability of different pharmacologic agents for the treatment of various chronic neuropathic pain syndromes, complete symptom reduction and/or complete functional restoration is rarely achieved. New, safe, and effective treatments for chronic neuropathic pain, therefore, must be developed. One such agent, the lidocaine patch (Lidoderm, Endo Pharmaceuticals, Inc., Chadds Ford, PA), has been approved recently by the US Food and Drug Administration for the treatment of postherpetic neuralgia. Like other local anesthetics, the lidocaine patch results in sodium channel blockade, dampening, both peripheral nociceptor sensitization and, ultimately, central nervous system hyperexcitability. The Lidoderm patch is a topical agent and, consequently, insignificant serum levels are achieved even with chronic use. This fact enhances its safety. Recent studies have suggested that the lidocaine patch may be effective for chronic neuropathic pain conditions other than postherpetic neuralgia as well.

Gastrointestinal symptoms and delayed gastric emptying in Fabry's disease: response to metoclopramide.

The pathophysiology of gastrointestinal symptoms in patients with Fabry's disease is uncertain, despite the demonstration of histological and radiographic abnormalities of the gastrointestinal tract. The aims of this study were to determine if the gastrointestinal symptoms reported by patients with Fabry's disease are associated with abnormal gastric emptying and, if they are, whether prokinetic drug therapy would be beneficial. Ten patients with Fabry's disease had radionuclide gastric emptying studies performed to determine if gastrointestinal symptoms correlated with objective evidence of abnormal gastric emptying. A second study was performed in seven patients who received 5 days of therapy with oral metoclopramide. The mean percent solid gastric emptying for Fabry's patients was significantly less than that of a normal control group (40 vs 67%, P < 0.005). Five of seven patients with symptoms had abnormal gastric emptying. Six of seven symptomatic patients reported clinical improvement with metoclopramide. Of four symptomatic patients who had a repeat study after treatment, two showed improved emptying. In conclusion, our results suggest that gastrointestinal symptoms in Fabry's disease are frequently associated with delayed gastric emptying and that treatment with metoclopramide produces symptomatic and sometimes functional improvement.

Assessment: Botulinum neurotoxin in the treatment of autonomic disorders and pain (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

OBJECTIVE: To perform an evidence-based review of the safety and efficacy of botulinum neurotoxin (BoNT) in the treatment of autonomic and urologic disorders and low back and head pain. METHODS: A literature search was performed including MEDLINE and Current Contents for therapeutic articles relevant to BoNT and the selected indications. Authors reviewed, abstracted, and classified articles based on the quality of the study (Class I-IV). Conclusions and recommendations were developed based on the highest level of evidence and put into current clinical context. RESULTS: The highest quality literature available for the respective indications was as follows: axillary hyperhidrosis (two Class I studies); palmar hyperhidrosis (two Class II studies); drooling (four Class II studies); gustatory sweating (five Class III studies); neurogenic detrusor overactivity (two Class I studies); sphincter detrusor dyssynergia in spinal cord injury (two Class II studies); chronic low back pain (one Class II study); episodic migraine (two Class I and two Class II studies); chronic daily headache (four Class II studies); and chronic tension-type headache (two Class I studies). RECOMMENDATIONS: Botulinum neurotoxin (BoNT) should be offered as a treatment option for the treatment of axillary hyperhidrosis and detrusor overactivity (Level A), should be considered for palmar hyperhidrosis, drooling, and detrusor sphincter dyssynergia after spinal cord injury (Level B), and may be considered for gustatory sweating and low back pain (Level C). BoNT is probably ineffective in episodic migraine and chronic tension-type headache (Level B). There is presently no consistent or strong evidence to permit drawing conclusions on the efficacy of BoNT in chronic daily headache (mainly transformed migraine) (Level U). While clinicians' practice may suggest stronger recommendations in some of these indications, evidence-based conclusions are limited by the availability of data.

Type C Niemann-Pick disease: documentation of abnormal LDL processing in lymphocytes.

Type C Niemann-Pick disease (NPC) is an autosomal recessive neurovisceral storage disorder in which defective intracellular cholesterol processing has been demonstrated in fibroblasts from NPC patients and obligate heterozygotes. In the present paper, the ability to esterify LDL-cholesterol was examined in cultured lymphocytes from 8 NPC patients, 8 obligate heterozygotes and 8 controls. Cholesteryl ester synthesis was 8% (+/- 5%) and 45% (+/- 16%) of controls in homozygous and heterozygous cell lines, respectively. Histochemical and electron microscopic examinations confirmed that this biochemical lesion was associated with abnormal intracellular accumulation of unesterified cholesterol in mutant lymphocytes. These results demonstrate that measurement of cholesterol esterification in cultured lymphocytes offers a quick and reliable means of confirming the diagnosis of NPC and that these cells may be useful for probing the primary molecular lesion of NPC.

Replacement therapy for inherited enzyme deficiency--macrophage-targeted glucocerebrosidase for Gaucher's disease.

BACKGROUND AND METHODS: Gaucher's disease, the most prevalent of the sphingolipid storage disorders, is caused by a deficiency of the enzyme glucocerebrosidase (glucosylceramidase). Enzyme replacement was proposed as a therapeutic strategy for this disorder in 1966. To assess the clinical effectiveness of this approach, we infused macrophage-targeted human placental glucocerebrosidase (60 IU per kilogram of body weight every 2 weeks for 9 to 12 months) into 12 patients with type 1 Gaucher's disease who had intact spleens. The frequency of infusions was increased to once a week in two patients (children) during part of the trial because they had clinically aggressive disease. RESULTS: The hemoglobin concentration increased in all 12 patients, and the platelet count in 7. Serum acid phosphatase activity decreased in 10 patients during the trial, and the plasma glucocerebroside level in 9. Splenic volume decreased in all patients after six months of treatment, and hepatic volume in five. Early signs of skeletal improvements were seen in three patients. The enzyme infusions were well tolerated, and no antibody to the exogenous enzyme developed. CONCLUSIONS: Intravenous administration of macrophage-targeted glucocerebrosidase produces objective clinical improvement in patients with type 1 Gaucher's disease. The hematologic and visceral responses to enzyme replacement develop more rapidly than the skeletal response.