Topiramate development

Sweat glands A 32-year-old man on topiramate developed hypohydrosis and subsequent hyperthermia [171 ]. Hypohydrosis is a rare but recognized adverse effect of topiramate that is typically reported in children, possibly due to incomplete development of autonomic mechanisms or changes in surface area as compared to mass or blood volume. Hypohydrosis as a side effect of topiramate has rarely been reported in adults. The mechanism by which topiramate causes hypohydrosis remains unclear. 

Metabolic acidosis Hyperchloremic, nonanion gap, metabolic acidosis is associated with topiramate treatment. This metabolic acidosis is caused by renal bicarbonate loss because of the inhibitory effect of topiramate on carbonic anhydrase. Generally, topiramate-induced metabolic acidosis occurs early in treatment, although cases can occur at any time during treatment. Bicarbonate decrements usually are mild to moderate rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose to acidosis may be additive to the bicarbonate lowering effects of topiramate. If metabolic acidosis develops and persists, consider reducing the dose or discontinuing topiramate. 

Kidney stones A total of 1.5% patients exposed to topiramate during its development reported the occurrence of kidney stones an incidence approximately 2 to 4 times that expected in a similar, untreated population. Kidney stones also have been reported in pediatric patients. 

At least three drugs are effective against absence seizures. Two are nonsedating and therefore preferred ethosuximide and valproate. Clonazepam is also highly effective but has disadvantages of dose-related adverse effects and development of tolerance. Lamotrigine and topiramate may also be useful. 

Risperidone has also been used in combination with topiramate in a Spanish multicenter study in 58 patients (28 men and 30 women mean age 41 years) with bipolar I disorder, with manic but not mixed episodes (20). Risperidone (mean dose 2.7 mg/day) and topiramate (mean dose 236 mg/day) were started with a maximum 48-hour time difference risperidone was used for acute manic symptoms and topiramate for longer-term stabilization and prevention of relapse. The incidence of any adverse event was 64%, mostly somnolence, paresthesia, dizziness, tremor, weight loss (n = 27 mean change -1.1 kg), extrapyramidal disorders, gastrointestinal effects, and cognitive disturbances. One patient developed tardive dyskinesia during the study and there were five dropouts because of adverse effects adverse effects that required withdrawal of risperidone but not topiramate were amenorrhea (n = 3) and sexual dysfunction (n = 1). 

Of 431 consecutive patients taking topiramate, 31 (7.2%) developed word-finding difficulties (642). This adverse event was not associated with a rapid titration schedule, but it correlated with the presence of simple partial seizures and left temporal epileptiform activity on the electroencephalogram, suggesting that there is a subgroup of patients with a specific susceptibility. 

A 41-year-old woman with a diagnosis of bipolar disorder developed severe suicidality when topiramate was added to her previous treatment (carbamazepine and levothyroxine) for mood stabilization (649). 

A 19-year-old man with focal epilepsy took carbamazepine 1000 mg/day and lamotrigine 300 mg/day. Because his seizures persisted topiramate was added up to 200 mg/day and the dose of carbamazepine was reduced to 300 mg/day. Behavioral problems started within a week and worsened over the following months. He finally developed obsessive-compulsive disorder. Citalopram was given in doses up to 60 mg/ day and topiramate was tapered within 2 weeks. The symptoms improved. 

The authors discussed the hypothesis of a coincidental finding as well as the development of an alternative psychosis but finally attributed the patient s psychiatric disorder to topiramate. 

Three patients with hypomania associated with topiramate have been reported. All had chronic mood disorders and all developed symptoms of hypomania soon after starting to take topiramate titrated up to 100 mg/day in addition to pre-existing psychotropic drugs (651). The authors speculated that the antidepressant effects of topiramate had caused hypomania by release of monoamine neurotransmitters. 

A 15-year-old boy with Lennox-Gastaut syndrome taking felbamate (3000 mg/day), topiramate(200 mg/ day), and lorazepam developed painful hematuria, bilateral urethral obstruction, and urinary retention. Kidney, bladder, and urethral stones were found. The stone material was identified as felbamate by chemical analysis. However, as the patient was also taking topir-amate the association with felbamate was uncertain. 

The efficacy and tolerability of topiramate have been studied in 170 patients with refractory epilepsy (7). The most common adverse effects resulting in withdrawal were fatigue, weight loss, irritability, paresthesia, depression, and headache. Three patients developed renal calculi but continued therapy. 

Hemiparesis developed in a 41-year-old man and a 59-year-old woman during the first few weeks on topiramate at dosages up to 250 and 200 mg/day respectively (20). The condition resolved gradually after drug withdrawal. 

Topiramate lowers serum bicarbonate by inhibiting carbonic anhydrase. In 20 of 29 children there was a greater than 10% fall in serum bicarbonate after starting topiramate (mean absolute reduction 4.7 mmol/1), but none had significant sjmptoms of metabohc acidosis, except possibly for anorexia in one (44). In another report, mild to moderate metabolic acidosis (bicarbonate concentrations, 16-21 mmol/1) developed in three topiramate-treated patients aged 25-51 years the condition was not considered clinically significant, but it led to diagnostic tests to exclude other causes (45). 

Two children developed symptomatic metabolic acidosis while taking topiramate (47). 

An 11-year-old boy with refractory partial epilepsy who had been taking topiramate 300 mg/day for 13 months developed hyperventilation. He had a hyperchloremic metabolic acidosis with partial respiratory compensation. The hyperventilation and acidosis resolved after the administration of sodium bicarbonate and reduction of the dose of topiramate. 

A 16-month-old girl developed increasing irritability associated with topiramate it resolved promptly on withdrawal. Venous blood showed a metabohc acidosis. 

The authors postulated that the mechanism of topiramate-induced acidosis is inhibition of carbonic anhydrase in the proximal renal tubule, resulting in impaired proximal bicarbonate reabsorption. Blood gases should be obtained in patients taking topiramate who develop hyperventilation and changes in mental status. 

Fulminant liver failure developed in a 39-year-old woman after she had taken topiramate for about 4 months, in addition to carbamazepine. The condition occurred after she increased the dosage of topiramate to 300 mg/day, and was preceded for a few days by tiredness and somnolence (50). She made an uncomplicated recovery after hver transplantation. Histological examination showed centrilobular necrosis, compatible with drug-induced fulminant liver failure. 

A 9-year-old boy with partial epilepsy taking topiramate 4 mg/kg/day developed hyperthermia, reduced sweating, and tiredness after exercise 4 months after the start of treatment (51). Sudomotor function showed 180 sweat glands/cm (normal 286, fifth percentile 221). After topiramate withdrawal he became asymptomatic and 5 weeks later he had 392 sweat glands/cm. ... 

Three children taking valproate developed hyperammonemia after topiramate was added (56). Ammonia was normalized after topiramate was reduced or withdrawn. Thus, topiramate could potentially enhance the risk of hyperammonemia in patients taking valproate. The authors did not discuss the mechanism of this purported interaction. 

Certain anticonvulsants developed initially for the treatment of epilepsy, such as topiramate and zonisamide, have been found to have a beneficial effect in mood disorders, particularly bipolar disorder. In addition, patients treated with these compounds lose weight. They were therefore seen as potential therapeutic agents for use in obese patients with BED. 

Topiramate, (15) - 1980 Developed by RW. Johnson Pharmaceutical Research Institute Synthesized by Matyanoff et al. ... 

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). 

Topiramate is a recently developed anticonvulsant with similar actions to phenytoin. It appears to block sodium ion channels and enhances the action of GABA. Topiramate is used, either alone or in addition, when other drugs do not provide adequate control. However, topiramate is teratogenic and should not be used in women of childbearing age. 

In a study in 12 epileptic patients topiramate titrated up to a maximum of 400 mg twice daily had no effect on the steady-state plasma levels of carbamazepine 300 to 800 mg every 8 hours or on its main metabolite, carbamazepine-10,11-epoxide. An earlier study in epileptic patients also reported that topiramate does not affect the pharmacokinetics of carbamazepine. In contrast, another report describes 2 patients taking a maximum tolerated dose of carbamazepine who started treatment with topiramate and subsequently developed symptoms suggestive of carbamazepine toxicity. In both these cases, the symptoms resolved when the carbamazepine dose was reduced, and this enabled continued titration of the topiramate dose in one. A review of the clinical use of these two drugs found another 23 cases that fitted this pattern. Carbamazepine levels were not reported. ... 

Six patients with severe epilepsy developed stuporous encephalopathy with marked cognitive impairment when taking topiramate with valproate (5 patients) or when taking topiramate alone (1 patient). Four of the patients had hyperammonaemia which resolved when topiramate or valproate were withdrawn. The toxicity was possibly due to a synergistic effect of valproate and topiramate on liver ornithine metabolism resulting in hyperammonaemia. It was also possible that the encephalopathy was due to topiramate toxicity in at-risk patients such as those with pre-existing chronic encephalopathy. ... 

In recent years, there have been some major developments in the medical field. Phentermine/topiramate ER combination was released in 2012, while naltrexone/ bupropion is currently under a premarketing trial to assure cardiovascular safety. In addition, a new formula for phentermine, the most successful weight loss drug in history, was developed from the old compound released in 1959. The focus of this chapter is on a fourth drug, lorcaserin (1), which was approved by the US FDA for chronic weight management in 2012. 

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