Levetiracetam development

Mode of action. Piracetam is a drug with an unusual history. It was initially developed as a memory enhancing drug for use in age associated memory impairment and in the early stages of dementia. However, the efficacy of piracetam has proven to be contentious and it has not been licensed for such indications in either the UK or the USA. In 1978 the antimyoclonic effect of piracetam was demonstrated. This property has since been verified in several clinical trials. Levetiracetam is closely related chemically to the L-isomer of piracetam, but unlike piracetam it has a broader spectrum of action. The precise mode of action of piracetam is uncertain but there is experimental evidence that it acts as a metabolic stimulant that increases cerebral metabolism and the synthesis of ATP. How this relates to its antimyoclonic action, if at all, is unknown. 

Four patients with refractory epilepsy taking carbamaze-pine were given added levetiracetam and developed central nervons system effects (ataxia, diplopia, nystagmns) suggestive of carbamazepine toxicity (18). Rednction in the dose of carbamazepine resolved the symptoms in three cases. Carbamazepine and carbamazepine-epoxide blood concentrations were not altered dnring levetiracetam co-medication. Thns, a pharmacodjmamic interaction between carbamazepine and levetiracetam is likely. 

A review of the second-generation anticonvulsants reveals that screening or serendipity led to the development of felbamate (10), 1am-otrigine (11), zonisamide (13), topiramate (15), and levetiracetam (16) on the other hand, clobazam (4d) and oxcarbazepine (12) were developed by structural variation of known agents (78). Only three, vigabatrin (8), gabapentin (9), and tiagabine (14), were developed by mechanism-based rational development (78). 

An adult with phenylketonuria who developed generalized seizures later in life, despite strict dietary control, had seizures aggravated by levetiracetam... 

A patient with glioblastoma multiforme and partial epilepsy developed thrombocytopenia probably induced by levetiracetam [214 ]. 

Liver A 58-year-old woman with epilepsy developed a significant increase in gamma-glutamyltransferase activity while taking levetiracetam monotherapy [215 ]. Levetiracetam was progressively withdrawn and replaced with lamotrigine 200 mg/day, and over the next 2 months, the yGT activity gradually fell. 

Skin A 46-year-old woman with a malignant brain tumor developed a reticular eruption after the initial postoperative dose of 1000 mg/day was increased to 2000 mg/day [216 ]. The adverse reaction recurred on rechallenge when the dose of levetiracetam was slowly titrated to 1500 mg/day. 

A 4-year-old previously healthy girl presented with new-onset seizures associated with fevers, headache, and malaise. She developed status epilepticus resistant to intravenous tenzodiaz-epines, fosphenytoin, levetiracetam, valproate, pentobarbital, and ketamine. An initial MRI brain scan was unremarkable. Isoflurane was begun, and an MRI scan 14 days later showed hyperintense T2 signals in the cerebellar vermis and cerebellar hemispheres. The isoflurane concentration was reduced to 0.5% and a further scan after 31 days of isoflurane therapy showed improvement in the signal abnormalities. Her isoflurane exposure was 1382% concentration-hours/1257 MAC-hours. She remained minimally conscious. 

Levetiracetam and phenytoin have been retrospectively compared in the prophylaxis of early and late postoperative seizures in 315 patients [182 ]. Levetiracetam (n = 105) was at least as effective as phenytoin ( = 210) and significantly better tolerated. Adverse effects that prompted a change in antiepileptic drug therapy occurred in one patient taking levetiracetam, who had visual hallucinations, compared with 38 patients taking phenytoin (18%). In patients who were followed for at least 1 year and developed epilepsy, levetiracetam also had a higher retention rate. 

A 73-year-old black man with stage 4 kidney disease was given levetiracetam 500 mg bd for treatment of partial seizures. After 5 months he developed new-onset depression, with low mood, weight loss, and fatigue. Levetiracetam was withdrawn and 4 weeks later the depressive symptoms had nearly completely resolved. 

A 76-year-old woman with seizures secondary to ischemic stroke developed status epilepticus despite treatment with clonazepam. She was given intravenous levetiracetam 1000 mg/day and 2 days later developed pancytopenia, with a hemoglobin concentration of 9.8 g/dl, a platelet count of 83 x 10 A, and a white blood cell count of 5.7 x 10 /1. These changes worsened during the next 4 days and she required blood transfusion. Levetiracetam was withdrawn and 2 days later the blood cell count improved. When rechallenge with oral levetiracetam 0.5 g/day 1 year later pancytopenia rapidly recurred. 

Urinary tract A 17-year-old patient with epilepsy and normal renal function developed interstitial nephritis and renal failure while taking levetiracetam [200 ]. 

A woman developed status epilepticus during the first trimester of pregnancy, which might have been caused by a fall in her levetiracetam blood concentrations [202 ]. The clearance of levetiracetam increases during pregnancy, particularly during the third trimester, probably due to increased renal blood flow. 

Hematologic CBZ has been associated with thrombocytopenia. This typically manifests within the first 2 weeks of CBZ use and may be asymptomatic. A 17-year-old girl developed symptoms of thrombocytopenia (hematuria, generalized petechial, and ecchymotic purpura) 2 weeks after starting CBZ 600 mg/d. She was also taking levetiracetam 1000 mg twice daily, VPA 1000 mg twice daily, and topiramate 25 mg twice daily. The thrombocytopenia resolved after CBZ was discontinued, recurred when CBZ was restarted, and resolved again after CBZ was withdrawn [52 ]. 

A prospective study evaluated the safety and efficacy of levetiracetam for perioperative anticonvulsive therapy of patients with suspected brain tumors undergoing neurosuigery [89 ]. Thirty patients received levetiracetam 500 mg twice daily for 72 h, after which the dose was increased to 1000 mg twice daily. Two of the 30 patients had adverse events potentially attributable to the medication. One developed paresthesias and a visual field defect. The other also... 

Psychiatric A 32-year-old woman was started on levetiracetam for generalized epilepsy. She developed auditory hallucinations described as the sound of a saw cutting tire wood. This was distressing to her, and necessitated a change to an alternative AED. Levetiracetam has rarely been associated with hallucinations [94 ]. 

A patient without any history of psychiatric disorder was reported to develop acute onset major depression with a near fatal suicide attempt after starting levetiracetam. The authors suggest that psychiatric evaluation and assessment of risk factors for suicidal behaviors may be indicated in treating patients with epilepsy with levetiracetam [95 ]. 

A 44-year-old woman developed hypersexuality and increased frequency of masturbation while taking levetiracetam 2000 mg/day. These symptoms resolved after levetiracetam was tapered and discontinued [96 ]. Conversely, two young men, ages 22 and 30, were reported to experience loss of libido and anhedonia after starting levetiracetam 2000 mg/day and 3000 mg/day, respectively [97 ]. As levetiracetam has not been shown to affect hormone levels, it has been speculated that the sexual dysfunction described in association with this medication may be related to alterations in brain excitatory transmission due to xmbalancing of the dopamine/serotonin ratio [98 ]. 

Fluid balance A 33-year-old woman with focal epilepsy developed angioedema after starting levetiracetam. This patient had previously developed skin rashes while on both phenytoin and lamotrigine [100 ]. 

Pancreas A 17-year-old boy with autism developed acute pancreatitis 15 days after starting levetiracetam, and 4 days after his dose increase from 500 mg/day to 1000 mg/day [102 ]. He was also taking chlorpromazine. Both levetiracetam and chlorpromazine were discontinued and symptoms resolved. 

Urinary tract A 69-year-old woman developed biopsy-proven acute granulomatous interstitial nephritis while on levetiracetam 1000 mg/day. She made a complete recovery after cessation of the levetiracetam [103 ]. A 45-year-old man similarly developed interstitial nephritis with intractable nausea and vomiting while taking levetiracetam for seizures in the setting of a low grade glioma. The medication was changed and his renal function rapidly improved to his baseline [104 ]. 

Skin A 2-year-old girl with a complicated medical history developed SJS 9 days after starting levetiracetam. She had previously developed a rash to oxcarbazepine. This is the first report of levetiracetam-induced SJS in a child [105 ]. 

Immunologic A 31-year-old patienf wifh low-grade astrocytoma and seizures taking levetiracetam 2000 mg/day developed DRESS S5mdrome, which resolved after withdrawal of levetiracetam [106 ]. This is the second report of levetiracetam-induced DRESS s3mdrome. 

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