Gabapentin development

Mettler and co-workers also developed another procedure to produce gabapentin (1) as the free amino acid (Griffiths et al., 1991). Cyanoacetate intermediate 18 was treated with... 

The Ghemical Development team assumed that pregabalin, like gabapentin, would be a compound with low toxicity and that large quantities of material would be required for drug safety evaluation. The initial medicinal chemistry synthesis shown in Scheme 8.1 had several issues for scale-up namely ... 

A 28-year-old woman with bipolar depression developed clinical and biochemical evidence of hyperthyroidism, ascribed to thyroiditis, while taking gabapentin (4800 mg/day) in a clinical trial (429). The condition cleared after withdrawal, and subsequent exposure to a lower dose of gabapentin (1500 mg/day) was uneventful. 

Gabapentin [Neurontin] Adult initially, 300 mg TID. Can be gradually increased up to 3600 mg/d based on desired response. Children (3-12 years of age] Initially, 10-15 mg/kg body weight in 3 divided dosages increase over 3 days until desired effect or a maximum of 50 mg/kg/d. Developed originally as an anticonvulsant may also be helpful as an adjunct to other drugs in treating spasticity associated with spinal cord injury and multiple sclerosis. 

Chollet et al. [39] developed an isocratic HPLC method for simultaneous determination of vigabatrin and gabapentin in human serum after precolumn derivatization with o-phthaldialdehyde and fluorimetric detection at 435 nm with excitation at 235 nm. A column (25 cm x 3.0 mm) of Nucleosil Ci8 (5 /im) with a mixture of 0.022 M phosphoric acid (pH 2)-acetonitrile (45 55) as a mobile phase (flow rate 0.6 ml/min) was used. The calibration graph was rectilinear from 2.0 to... 

A 51-year-old man developed priapism 16 hours after attempting suicide by taking olanzapine 100 mg and gabapentin 1500 mg (241). Detumescence was produced by two injections of lidocaine and 8 hours later an intracorporeal shunt. 

A 35-year-old woman with epilepsy without a history of psychiatric disorders developed elevated mood after being stabilized on gabapentin monotherapy (3200 mg/ day). After 5 months she developed a manic episode, which remitted when gabapentin was withdrawn. 

Two women, aged 37 and 38 years, took gabapentin and after a few days developed behavioral changes associated with euphoria (281). In one case the symptoms were transient and in the other they resolved after withdrawal. The behavioral changes were not related to seizure activity. 

Developmenf of new fumors or worsening of tumors has occurred in humans taking gabapentin it is unknown whether gabapentin affected the development or worsening of tumors... 

Of the newer anticonvulsants, lamotrigine, gabapentin, tiagabine, and vigabatrin have little or no teratogenic potential in animals, whereas oxcarbazepine and topira-mate are teratogenic in rodents. However, animal studies are not necessarily apphcable to humans and chnical data are stiU insufficient to assess the effects of newer drugs on the development of the human fetus (153). 

Propranolol and gabapentin are both effective in essential tremor. However, pindolol, which has substantial partial agonist activity, can cause tremor (130), and gabapentin can occasionally cause reversible movement disorders. A patient who developed dystonic movements after the combined use of gabapentin and propranolol has been described (131). 

In an uncontrolled trial using dosages up to 6000 mg/day in 50 patients with refractory partial epilepsy, tiredness, dizziness, headache, and diplopia were the most common adverse effects (4). At dosages above 3600 mg/day three patients developed flatulence and diarrhea and two had myoclonic jerks. At least in some patients, gabapentin gastrointestinal absorption did not become saturated within the explored dosage range. 

Gabapentin-induced myoclonus may be more common than initially thought. In a retrospective survey, 13 of 104 consecutive patients developed myoclonus at gabapentin dosages of 800-3200 mg/day (11). Six of the patients had severe chronic static encephalopathy. Three had focal myoclonus, contralateral to the epileptic focus, and two had exacerbation of pre-existent myoclonus. In aU cases the myoclonus was mild and did not interfere with daily activities. The fact that in three patients the electroencephalogram did not show epileptiform discharges suggests that, at least in some cases, the myoclonus is non-epileptic in nature. 

A 60-year-old woman with post-herpetic neuralgia developed asterixis after having taken gabapentin for 4 days (18). The authors proposed that the mechanism was GABAergic. 

Urinary incontinence occurs rarely (SEDA-22, 88). Of 119 adults with partial seizures, 5 (4%) developed urinary incontinence which resolved after gabapentin withdrawal (30). Four of the five patients had signs of spasticity, suggesting that this may be a predisposing factor. 

A renal transplant recipient with a long-term stable functioning allograft developed reversible acnte renal dysfunction after beginning gabapentin therapy for chronic pain in diabetic nenropathy (32). The authors suggested that this was due to renal afferent vasoconstriction. 

Gabapentin has been used to treat morphine-induced myoclonus in a 54-year-old patient with gallbladder cancer (13). Effective pain control was maintained with morphine 300 mg, but after 24 hours the patient developed generalized muscular movements while asleep. Gabapentin 300 mg bd produced complete resolution of symptoms after 12 hours. In another case gabapentin 600 mg/day was used to treat a 1-month history of spontaneous jerking of both wrists after an increase in the dose of morphine to 120 mg/day the myoclonus disappeared over the next 24 hours (8,13). 

In 15 patients with metastatic colorectal cancer who were given gabapentin (100 mg bd or tds) if neuropathic symptoms developed with oxaliplatin, the sjmiptoms disappeared in all patients, even in those who received up to 14 courses of oxaliplatin. Withdrawal of gabapentin resulted in recurrence. However, a controlled trial is required to verify these encouraging prehminary results. 

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). 

---