Valium had many ancestors

[enquirewithin]

Doctors have long prescribed remedies for stress, but gentle sedatives are a fairly new one.

February 18, 2008

http://www.latimes.com/la-he-esoterica18feb18,1,7096075.column


FOR thousands of years, humans have sipped, swallowed and chewed endless remedies to soothe frayed nerves: fermented ales in medieval Europe, coca tea and tobacco in the ancient Americas, and kava kava concoctions in the South Pacific, to name a few. For the last century or so, with varied success, researchers have tried to perfect the packaging of anxiety relief into a simple little pill.

In the 1800s in the U.S. and Europe, an apparent epidemic of neurasthenia, or "weakness of the nerves," was attributed by doctors to the stresses of fast-paced, modern, urban living. (It was, after all, the era of the steam engine.) At the bedside, doctors prescribed bromide salts (to replace lost salts thought to be at the root of over-excited nerves), paraldehyde (which induced sleep -- and bad breath), and often even opiates. Meanwhile in the lab, doctors tried to come up with something better.

Around 1900, German scientists working for the drug company Bayer synthesized the first synthetic barbiturate sedative. Soon barbiturates were being used to treat seizures in epileptics and to calm troubled, shellshocked soldiers.

But treating anxiety with barbiturates was a bit like pushing a tack into a wall with a sledgehammer. Barbiturates depressed the entire nervous system, slowed thinking, impaired movement and induced sleep. They came with a high risk of dependence and were easy to overdose on -- all of which inspired research into gentler alternatives.

The first of the gentler sedatives -- the so-called minor tranquilizers -- was developed in the early '50s by a New Jersey drug firm, Wallace Laboratories. The power of the drug, named Miltown (Wallace was fond of naming drugs for nearby Jersey towns), was demonstrated in experiments on monkeys: On barbiturates, the primates were unconscious; undrugged, they were their wild selves; on Miltown, they were calm but awake.

Demand for Miltown was unexpected and unprecedented. Millions of Americans begged their doctors for prescriptions. By 1957, a prescription for Miltown was filled an average of every second in the U.S.

Suburbs became the site for Miltown parties, cocktails were named for the pill (a Miltown replaced the olive in a Miltini) and high-end jewelers designed rings with compartments to hold the "tranks." The "peace pills" were particularly popular in Hollywood, and television host Milton Berle joked on-air (and uncompensated by Wallace) that he was considering changing his name to Miltown.

Miltown revealed such an enormous market for minor tranquilizers that pharmaceutical companies scrambled to develop competitors. In 1960, Swiss drug maker Hoffmann-La Roche unveiled Librium, less sedating than Miltown but just as calming. In one famous experiment, the bitter-tasting drug tamed lions and tigers at the San Diego Zoo.

But Roche also had another drug in the works. Three years later, it rolled out Valium.

Valium quickly surpassed Miltown and Librium. Among its biggest selling points: no bitter taste, and it was nearly impossible to overdose on. (In one widely reported instance that came much later, a Reagan administration official tried to kill himself with a heavy dose of Valium but failed.)

By the end of the 1960s, Valium was the top-selling psychotropic drug in the country. In the '70s, it became the most widely prescribed drug of any kind. Like Miltown, Valium was everywhere: Mike Brady popped a couple on the television show "The Brady Bunch," and the Rolling Stones composed an ode to the drug, dubbing it "mother's little helper."

But at the height of its popularity, Valium became the target of critics who argued that people were becoming unhealthily dependent on the drug. The story of Barbara Gordon further eroded Valium's image. The television journalist's 1979 autobiography chronicled her addiction to Valium and the nervous breakdown -- and institutionalization -- she suffered when quitting the drug.

Jordan's story, "I'm Dancing as Fast as I Can," was made into a movie in 1982, the same year that Valium lost its coveted position as the bestselling drug in America.

Valium was replaced that year by the anti-ulcer drug Tagamet -- which perhaps signaled a new approach to anxiety altogether.

Doctors still write prescriptions for Valium today, but newer anti-anxiety drugs, such as Xanax and Ativan, are more commonly used. And increasingly, anxiety is treated with antidepressants. The top-selling drug these days is Lipitor, which perhaps suggests that these days, Americans are more concerned with their arteries than their nerves.

[silentghost]

Thanks for the article. Pretty informative.

Doctors still write prescriptions for Valium today, but newer anti-anxiety drugs, such as Xanax and Ativan, are more commonly used. And increasingly, anxiety is treated with antidepressants. The top-selling drug these days is Lipitor, which perhaps suggests that these days, Americans are more concerned with their arteries than their nerves.

SWIM thinks doctors are simply more likely to place patients on insanely-expensive yet unregulated lipitor rather then low-cost and DEA monitored valium :) I hope that the "most common" drugs do not represent us as a society, because most doctors SWIM meets are more concerned with themselves then their patients. When was the last time your doc told your grandparents to stop paying out-the-ass for lipitor and get on a generic equivalent for 1/10 the cost? When was the last time your GP spent more then 5 minutes doing a routine physical? I know many DF users are informed of BigPharma, but most of the older generations still go by "Well I just take what he tells me to get".

[GForce]

Good article. I find the evolution of anti-anxiety medications to be an interesting history. The fact that people were using harder drugs for anxiety and relaxation before specific anti-anxiety medication was produced really says a lot about how prevalent anxiety is among people, especially in the United States. Barbiturates were really one of the first targeted pharmaceuticals for anxiety since before then people were just taking substances that made them feel good as treatment for anything. But even by today's standards barbiturates are a relic, barely finding a place in medicine to treat migraines and other isolated problems. What I'm concerned about is the recent (past 5-10 years) shift from benzodiazepines to anti-depressants for the treatment of anxiety. To me using a SSRI or SNRI to treat general anxiety or social anxiety, with no depression, just seems like overkill, especially when benzodiazepines work great for most people. If they don't work, chances are there are other psychological reasons, such as depression, that would make a serotonin agent more useful. Unfortunately doctors are just as human as anyone else and can be swayed by marketing or simply money. Much of the shift towards anti-deppresants is pretty much a direct result of extensive marketing campaigns by pharmaceutical companies. Remember they have patents on many anti-depressants but you can get any benzodiazepine in a generic version.

[Laudaphun]

SWIM has been doing some research on benzos and their introduction into the market. A couple quick facts to add to the story of the original poster. Before Chlordiazepoxide and diazepam were released, Roche was a very small pharma company, mainly selling suppliments and vitamins and such. It was Chlordiazepoxide and a few years later diazepam that propelled this company into it's position of a major power as one of the pharma giants that we all have come to know, and the "Brand Name" status that it now holds.

Also, in the initial trials... SWIM read somewhere that 40 compounds were synthesized and 39 of these compounds were tested and none shown to have any sedative properties. Anyways the specific ring system characteristic of benzos was originally discovered by a series of accidents intersecting with careful observations.

In the mid-1950's, Leo Sternbach of Hoffmann-LaRoche's research laboratories in Nutley, NJ, was impressed with the sucess of chlorpromazine, the first antipsychotic drug, which had just been introduced by another pharma company. The structure of chlorpromazine reminded Sternback of a series of tricyclic compounds he had made as a post-doctoral student in Cracow some 20 years previously, which contained the ring system of a "benzheptoxdiazine" In the words of Sternbach in "The Benzodiazepine Story", he writes:

"At the time we were looking for new azo dyes or interesting dye stuff intermediates, and came across some substances known as 4,5-benzo-[hept-1,2,6-oxdiazines] in the German literature. From a chemical point of view, they were very interesting. They were formed in good yields and by interesting chemical reactions, but unfortunately did not lend themselves to transformation into usable dyes. With regret we dropped this group of compounds and turned to other things."

Sternbach's idea was to append a dimethylamino group like chlorpromazine's onto his ring system by reacting the old tricyclic compounds, containing the ring system of a "benzheptoxdiazine" with dimethylamine, which he presumed would form a certain compound that I can not immediately name just by looking at it's chemical structure.

All of the compounds fulfilled all of the criteria that Sternbach had formulated when he embarked on his research, but there had been a mistake. In a criticism of his own work, Sternbach had to admit that he had been unable to achieve the results he had hoped for, let alone the pharmacological evidence to back them up. The results of about 40 variations on this theme tested negative when submitted for pharmacological testing. Sternbach turned his focus to the substance which he thought had the benzheptoxdiazine structure... it turned out not to have this structure at all.

Apparently, the nitrogen of the oxime was more nucleophilic than the oxygen... In any case all but one single compound were tested and none showed any sedative effects, and so the project was abandoned.

As though this disappointment were not enough, he lost the conidence of his superior, who felt Sternbach was "barking up the wrong tree" and demanded that he abandon his work. The change of priorities forced Sternbach to cut back his activities. Not only that, but urgengly neeed working space in the laboratory had to be freed up, which requied a radical clearing out on his part.

Sometimes however, luck enters through the back door and determines from that vantage point who is right and who is wrong...

Almost 2 years later, Earl Reeder, a tidy fellow researcher with a sense for closre, decided to clean up the lab ench and noticed this last compound, which he sent in for testing. It turned out to have quite significant sedative and muscle-relaxant properties and a much lower toxicity than chlorpromazine. This last compound was the product formed in the reaction where the chemical had a most unexpected structure, by a most unexpected reaction, the methylamine reacted had not displaced the chlorine to form the anticipated compound, but had instead attacked the carbon between the two nitrogens, opening the ring up and allowing it to close again as a seven-memebered benzodiazepine ring, which was named chlordiazepoxide.

In April 1957, in the course of obeying the order to tidy up, somethign wonderful happened. As Sternback notes in the "Benzodiazepine Story:"

"During this procuedrue, Earl Reeder, my coworker, drew my attention to a few hundred milligrams of two products, a nicely crystallized base and its hydrochloride. That base was produced in 1955... and its hydrochloride in 1956. Pharmacological tests had no been run on these products at that time as they were busy with other problems. Because they were pure and had the expected composition, instread of thrwong them away, we submitted the water-soluable salt for pharmacoogical testing. We thought that the expected negative pharmacoogical result would cap our work on this series of compounds, and perhaps provide enough for a chemcal publication. We had no idea that this would be the start of a programthat would keep us occupied for years to come."

note: most of this information is quoted from "Good Chemistry: The Life and Legacy of Valium Inventor Leo Sternbach" published by McGraw-Hill and "The Chemistry of Mind-Altering Drugs" published by the American Chemical Society. Sorry if this post is a bit long and hard to read, SWIM will try to edit when she has some more time and make it a bit easier to read... perhaps SWIM will be able to work out the names of the chemical structures that Sternbach had anticipated.