Primidone - History

History

Primidone's effectiveness for epilepsy was first demonstrated in 1949 by Dr. Yule Bogue. It was introduced a year later by the Imperial Chemical Industry (ICI), now known as AstraZeneca in the United Kingdom and Germany. In 1952, it was approved in the Netherlands. That same year, Drs. Handley and Stewart demonstrated its effectiveness in the treatment of patients who failed to respond to other therapies; it was noted to be more effective in people with idiopathic generalized epilepsy than in people whose epilepsy had a known cause. Dr. Whitty noted in 1953 that it benefitted patients with psychomotor epilepsy, who were often treatment-resistant. Toxic effects were reported to be mild. That same year, it was approved in France. Primidone was introduced in 1954 under the brandname Mysoline by Wyeth in the United States.

The first report associating it with megaloblastic anemia came in 1954 from Drs. Chalmers and Boheimer. Between 1954 and 1957, twenty-one cases of megaloblastic anemia associated with primidone and/or phenytoin were reported. Most cases were due to folic acid deficiency; however, there was one that only responded to B₁₂ therapy and one that required Vitamin C. Some cases were associated with deficient diets; one patient ate mostly bread and butter, another ate bread, buns, and hard candy, and another could rarely be persuaded to eat in the hospital. The idea that folic acid deficiency could cause megaloblastic anemia was not new. What was new was the idea that drugs could cause this in well-nourished people with no intestinal abnormalities. In many cases, it was not clear which drug had caused it. It was speculated that this might be related to the structural similarity between folic acid, phenytoin, phenobarbital, and primidone. Folic acid had been found to alleviate the symptoms of megaloblastic anemia in the 1940s, not long after it was discovered, but the typical patient only made a full recovery—cessation of CNS and PNS symptoms as well as anemia—on B₁₂ therapy. Five years earlier, folic acid deficiency was linked to birth defects in rats. Primidone was seen by some as too valuable to withhold based on the slight possibility of this rare side effect and by others as dangerous enough to be withheld unless phenobarbital or some other barbiturate failed to work for this and other reasons (i.e., reports of permanent psychosis.

In Europe, up until 1963, it was not uncommon to prescribe primidone and phenobarbital in combination, often with a stimulant. They were believed to be the most useful for seizures occurring upon awakening, while phenytoin was the most useful for nocturnal seizures. Primidone and phenobarbital were prescribed in combination with phenytoin in diffuse epilepsies. They were third and fourth line-agents, respectively, in the treatment of partial seizures. By 1963, carbamazepine was marketed in most of Europe. It soon became clear that its efficacy in generalized tonic-clonic seizures was the same as phenytoin, that its ability to control partial seizures was superior, along with its tolerability. Sodium valproate was approved in France in 1967. Because the doses were so low (200–400 mg/day), it was viewed as a moderately effective anticonvulsant whose best quality was its nonsedating nature. In spite of the availability of carbamazepine and valproate, physicians practicing in Mediterranean countries still preferred phenobarbital. Other medications were seen as not usually necessary. Phenytoin was to be used as adjunctive therapy only. In spite of these advances, primidone was still considered to be a "sheet-anchor" anticonvulsant in the United Kingdom as late as 1969, along with phenobarbital and phenytoin, for the treatment of pediatric epilepsy in spite of its side effects and one of two drugs (the other being sultiame) that were tried in adult patients if a combination of phenytoin and phenobarbital failed to control seizures. A review published that same year stated that carbamazepine did not live up to the claims of those who advocated its use in epilepsy.

In 1968, a Dr. Meadow encountered six babies with cleft lip and palate in addition to other congenital abnormalities whose mothers had been taking anticonvulsants. Meadow wrote a letter in The Lancet asking for cases of cleft lip and palate in babies whose mothers had taken anticonvulsants. That same year, Milunsky, Graef, and Gaynor reported cases of cleft lip and palate associated with attempted abortion with methotrexate and aminopterin, which are folic acid antagonists. While it was widely accepted by 1969 that these drugs could interfere with folic acid and that folic acid supplementation might have beneficial somatic effects, it was believed that folic acid supplementation could exacerbate seizures; this included the routine supplements given to pregnant women to prevent megaloblastic anemia. By 1970, the doctor had collected thirty-two cases. Sixteen of them were born to women taking primidone. 25% of the thirty-two cases had congenital heart defects; the reported rate in cleft lip and palate was 3-5%. Meadow emphasized that there was no proof of an association, the immense value of anticonvulsants and the probably small odds of any one epileptic woman having a child with a congenital abnormality. Roman and Caratzali reported in 1971 that the offspring of mice treated with primidone had more abnormal bone metaphases than controls; this was due to chromosomal lesions. By the mid-1970s, it was obvious that this antagonistic effect of primidone was not due to the inhibition of dihydrofolate reductase, the enzyme responsible for the reduction of dihydrofolic acid to tetrahydrofolic acid, but rather to defective folate metabolism.

Carbamazepine was approved in the United States for the treatment of adult epilepsy in 1974. Its lack of sedating properties relative to phenobarbital and lack of somatic effects relative to phenytoin generated much interest. Within two years, primidone was no longer seen as the drug of choice for psychomotor epilepsy in the United States. This was because while carbamazepine and primidone are of roughly equal effectiveness, the former is less likely to cause sedation and cognitive impairment. Also, primidone has a greater tendency to cause undesirable psychiatric side effects compared with carbamazepine, which was noted to lessen pre-existing depressive symptoms. By 1978, it looked as if its superior side effect profile would increase its use in epilepsy in the United States. That same year, a review was published stating that primidone and phenobarbital were used less often in the United Kingdom due to their greater tendency to cause behavior disorders and interfere with learning in young children. Valproate was heralded by some as "the greatest thing since Greta Garbo" and carbamazepine had also risen in popularity.

By 1980, primidone was seen as not worth mentioning as an option for childhood temporal lobe epilepsy by doctors in the United Kingdom. In January 1981, Dr. O'Brien and colleagues reported that primidone had a positive effect on the essential tremor of one of their patients. This led them to initiate a twenty-person prospective study. Twelve of the participants responded well. By 1984, valproic acid was the drug of choice for juvenile myoclonic epilepsy and not the equally effective primidone. However, as late as 1985, primidone was still one of the most widely used anticonvulsants. At the close of the 1980s, primidone was still the preferred anticonvulsant for complex partial seizures in Germany. In 1989, Dainippon Pharmaceutical launched Exegran (zonisamide), the first new, chemically unique, non-benzodiazepine anticonvulsant in decades.

In 1990, primidone, along with phenobarbital, was a second-line agent in partial epilepsy with or without secondarily generalized tonic-clonic seizures and was one of four agents (the others being carbamazepine, phenytoin and phenobarbital) that was used along with ethosuximide or a benzodiazepine for any absence or myoclonic seizures when valproate failed to control tonic-clonics (at least in the United States). After zonisamide, other new anticonvulsants came onto the market: felbamate, gabapentin, lamotrigine, and vigabatrin. All four were structurally distinct both from other anticonvulsants already on the market. They all had larger protective indexes than conventional agents and unlike these agents, the new ones did not cause birth defects in laboratory animals or antagonize folic acid. They seemed to be relatively mild in terms of side effects. Out of all of them lamotrigine was the most similar to phenytoin in its pattern of efficacy. Felbamate was the most effective for Lennox-Gastaut syndrome and was seen as a second-line agent in juvenile myoclonic epilepsy after valproate. These new agents were aggressively marketed. In 1994, felbamate became the anticonvulsant of last resort after ten people out of 100,000 came down with aplastic anemia.

By 1994, primidone was no longer one of the most widely used anticonvulsants. Phenytoin was still regarded as the drug of choice for partial seizures due to its long half-life and low cost; but for children, carbamazepine was seen as the best one due to phenytoin's effects on physical appearance. Topiramate was approved two years later. It, along with the others, was mainly used in patients refractory to carbamazepine and valproate. These new agents were often described as having "innovative" and "selective" mechanisms of action; in reality, most of them also worked similarly to older agents. On February 28, 1998, Élan Corporation, plc, bought the trademark and exclusive product distribution rights for Mysoline from Wyeth in Canada and the United States at a cost of $46 million and a royalty on future sales. The actual manufacture and distribution was done by Athena Neurosciences; their name appeared on a Mysoline package information sheet dated June 1998. On November 30, 1999, levetiracetam was approved for the adjunctive treatment of partial epilepsy in adults in the United States.

By the year 2000, primidone was something that was prescribed in the event that the patient had tried all other anticonvulsants and was not a candidate for surgery in the United States. In April 2001, Élan decided to concentrate its efforts towards Zanaflex, Zonegran, Skelaxin, Abelcet, Azactam, Maxipime, Myobloc, and Cutivate. Mysoline was rationalized along with many other products that did not meet "certain commercial criteria." Yamanouchi Pharma Technologies, a Palo Alto-based subsidiary of Yamanouchi Pharmaceutical Co., Ltd, manufactured the actual drug. By 2003, most of the people taking primidone for epilepsy were elderly people who had been taking the drug for many years. In July 2004, Acorus Therapeutics Ltd. took over the manufacture and distribution of Mysoline from AstraZeneca February 3, 2005: almost four years after acquiring it from Elan, Xcel was acquired by Valeant Pharmaceuticals International. On April 1, 2005, Yamanouchi merged with Fujisawa Pharmaceutical Co., Ltd to form Astellas Pharma. As of 2005, it is widely used in the treatment of many forms of epilepsy in developing countries.