1.
Pharmacotherapy for Pain in a Family With Inherited Erythromelalgia Guided by Genomic Analysis and Functional Profiling.
Geha, P, Yang, Y, Estacion, M, Schulman, BR, Tokuno, H, Apkarian, AV, Dib-Hajj, SD, Waxman, SG
JAMA neurology. 2016;(6):659-67
Abstract
IMPORTANCE There is a need for more effective pharmacotherapy for chronic pain, including pain in inherited erythromelalgia (IEM) in which gain-of-function mutations of sodium channel NaV1.7 make dorsal root ganglion (DRG) neurons hyperexcitable. OBJECTIVE To determine whether pain in IEM can be attenuated via pharmacotherapy guided by genomic analysis and functional profiling. DESIGN, SETTING, AND PARTICIPANTS Pain in 2 patients with IEM due to the NaV1.7 S241T mutation, predicted by structural modeling and functional analysis to be responsive to carbamazepine, was assessed in a double-blind, placebo-controlled study conducted from September 2014 to April 21, 2015. Functional magnetic resonance imaging assessed patterns of brain activity associated with pain during treatment with placebo or carbamazepine. Multielectrode array technology was used to assess the effect of carbamazepine on firing of DRG neurons carrying S241T mutant channels. MAIN OUTCOMES AND MEASURES Behavioral assessment of pain; functional magnetic resonance imaging; and assessment of firing in DRG neurons carrying S241T mutant channels. RESULTS This study included 2 patients from the same family with IEM and the S241T NaV1.7 mutation. We showed that, as predicted by molecular modeling, thermodynamic analysis, and functional profiling, carbamazepine attenuated pain in patients with IEM due to the S241T NaV1.7 mutation. Patient 1 reported a reduction in mean time in pain (TIP) per day during the 15-day maintenance period, from 424 minutes while taking placebo to 231.9 minutes while taking carbamazepine (400 mg/day), and a reduction in total TIP over the 15-day maintenance period, from 6360 minutes while taking placebo to 3015 minutes while taking carbamazepine. Patient 2 reported a reduction in mean TIP per day during the maintenance period, from 61 minutes while taking placebo to 9.1 minutes while taking carbamazepine (400 mg then 200 mg/day), and a reduction in total TIP, from 915 minutes while taking placebo over the 15-day maintenance period to 136 minutes while taking carbamazepine. Patient 1 reported a reduction of mean episode duration, from 615 minutes while taking placebo to 274.1 minutes while taking carbamazepine, while patient 2 reported a reduction of the mean episode duration from 91.5 minutes while taking placebo to 45.3 minutes while taking carbamazepine. Patient 1, who had a history of night awakenings from pain, reported 101 awakenings owing to pain while taking placebo during the maintenance period and 32 awakenings while taking carbamazepine. Attenuation of pain was paralleled by a shift in brain activity from valuation and pain areas to primary and secondary somatosensory, motor, and parietal attention areas. Firing of DRG neurons expressing the S241T NaV1.7 mutant channel in response to physiologically relevant thermal stimuli was reduced by carbamazepine. CONCLUSIONS AND RELEVANCE Our results demonstrate that pharmacotherapy guided by genomic analysis, molecular modeling, and functional profiling can attenuate neuropathic pain in patients carrying the S241T mutation.
2.
Dipyridamole and paracetamol overdose resulting in multi-organ failure.
Cullis, PS, Watson, D, Cameron, A, McKee, RF
Scottish medical journal. 2013;(3):e14-7
Abstract
Dipyridamole intoxication is rare and few reports exist amongst the current literature. A case of dipyridamole and paracetamol overdose is described in a previously healthy 58-year-old woman, which resulted in multi-organ failure requiring dialysis, inotropic support, ventilation and extensive surgical intervention for small bowel ischaemia. This case highlights the dangers of an unusually large overdose of a commonly prescribed drug, and reviews current knowledge of dipyridamole intoxication.
3.
Acetaminophen-induced nephrotoxicity: pathophysiology, clinical manifestations, and management.
Mazer, M, Perrone, J
Journal of medical toxicology : official journal of the American College of Medical Toxicology. 2008;(1):2-6
Abstract
UNLABELLED Acetaminophen-induced liver necrosis has been studied extensively, but the extrahepatic manifestations of acetaminophen toxicity are currently not described well in the literature. Renal insufficiency occurs in approximately 1-2% of patients with acetaminophen overdose. The pathophysiology of renal toxicity in acetaminophen poisoning has been attributed to cytochrome P-450 mixed function oxidase isoenzymes present in the kidney, although other mechanisms have been elucidated, including the role of prostaglandin synthetase and N-deacetylase enzymes. Paradoxically, glutathione is considered an important element in the detoxification of acetaminophen and its metabolites; however, its conjugates have been implicated in the formation of nephrotoxic compounds. Acetaminophen-induced renal failure becomes evident after hepatotoxicity in most cases, but can be differentiated from the hepatorenal syndrome, which may complicate fulminant hepatic failure. The role of N-acetylcysteine therapy in the setting of acetaminophen-induced renal failure is unclear. This review will focus on the pathophysiology, clinical features, and management of renal insufficiency in the setting of acute acetaminophen toxicity. CASE A 47-year-old female was found lethargic at home and brought by ambulance to an emergency department. History from family members suggested an inadvertent acetaminophen overdose, and she had last been seen a few hours earlier. She reportedly ingested 18 tablets of 500 mg acetaminophen (APAP) over the previous two days because she had run out of her prescription pain medication. Her past medical history was significant for fibromyalgia, arthritis, and a prior gastric bypass procedure. She had no history of alcohol abuse or renal insufficiency. She was lethargic. Vital signs: BP 128/96 mmHg, pulse 112/min, respirations 32/min; pulse oximetry 98% on 2L nasal cannula oxygen. Laboratory studies: BUN 9 mg/dL, creatinine 0.9 mg/dl, acetaminophen 12 mcg/mL, AST 5409 u/L and ALT 1085 u/L. A urinalysis was negative for blood with trace protein and ketones. A urine drug screen was positive for marijuana and opioid metabolites. At the initial hospital, she was treated with N-acetylcysteine (NAC) orally. Subsequently, she developed fulminant hepatic failure with elevated transaminases, hypoglycemia, and coagulopathy (Tables 1A and 1B). She was transferred to our facility two days after initial presentation for liver transplant evaluation. At that time, her APAP level was 2.0 mg/L. Oral NAC therapy was continued after transfer. The patient's liver function subsequently improved and she ultimately did not require transplantation. She did develop acute renal failure during the course of her hospitalization, with a creatinine of 2.3 mg/dL on transfer, which increased to 8.1 mg/dL nine days later (approximately 11-13 days post-ingestion). Medical toxicology was consulted by the intensive care unit team to address whether this was acetaminophen-induced renal failure and if there was a role for NAC in this setting.
4.
The critically ill liver patient: fulminant hepatic failure.
McGuire, BM
Seminars in gastrointestinal disease. 2003;(1):39-42
Abstract
Fulminant hepatic failure is a challenging medical condition that requires intensive care management to prevent-major complications (cerebral edema, infections, and multi-system organ failure) and assistance from a liver transplant team when it is believed that liver regeneration is unlikely. Unfortunately, there are no specific medical therapies or devices to correct all of the functions of a liver. N-acetylcysteine is used for the treatment of acetaminophen overdose, but for most other causes of fulminant hepatic failure therapy is supportive care. This case illustrates many of the problems that are encountered during medical management of fulminant hepatic failure.