Monday, September 6, 2010


Par-a-noi-a will Destroy-a

During the 31 and a half years that I worked as a medicinal chemist, I have worked on many projects: cancer, cognition activators (Alzheimer's), manic depression, inflammation, female sexual dysfunction, diabetic retinopathy, obesity, Parkinson's, manic depression, insomnia, anxiety, fibromyalgia but the project I have spent the most time on, in several iterations, was Schizophrenia. What do all those projects have in common? Not much although for years our department was divided into neurochemisty and chemistry. Neurochemistry was then subdivided into psychiatric disorders (schizophrenia) and neurological disorders (stroke being the biggest effort). Even then, certain projects would crossover these artificial lines. Fibromyalgia for instance combines anxiety (psychiatric), insomnia with inflammation. Although biologists are highly specialized, chemists not so much. Compounds are compounds. Although an anticancer drug may have completely different properties than an antipyschotic and a chemist should know the difference, we can be easily switched from one project to another.We do not get to select which project we work on. If we did, the personnel involved would weigh heavier into our decision. Some people are  just not fun to work with. I was very lucky for the most part: I worked only briefly for someone I truly could not stand and after 6 months of pure hell, adjustments were made.

We are to target areas that have an unmet need, preferably a large (lots of patients, chronic condition) unmet need. Malaria would seem to fit the bill in terms of huge numbers of inadequately treated patients (worldwide, not here) but that is not attractive to the company as who will pay for them? Still our company or at least the smaller part that got swallowed whole had a program working in concert with the anticancer program. What does malaria and cancer have in common? A need for dehydrofolate reductase, the enzyme targeted. Both protozoa and cancer cells need it for rapid growth. That's all old news of course. Other approaches are in the works for both diseases. Cancer is not a single disease but many, many diseases. There will be no magic bullet that will cure them all. Even my enemy, TNBC, is not all the same: PARP inhibitors may have more value against one type vs another.

Despite the many drugs on the market for it, schizophrenia remains an 'unmet need'. It affects 1 to 2% of the population directly but as it is a chronic condition that develops fairly early in life, particularly with males, it affects a much greater number indirectly. The family is forced to deal with a delusional person, who can not hold a job or be trusted to care for oneself. It is a heartbreaking and extremely frustrating condition. Our family is part of the greater number that is 'indirectly' affected. As hideous and cruel of a disease as Alzheimer's is, there is an endpoint. In my mother's case, she needed constant care for 3 years and probably had it for 3 years previously. Six years versus close to a lifetime.

 Although there is a genetic component to it, it is not clear what causes schizophrenia. There is over activity of dopaminergic neurons in the parts of the brain involved in thought; too much dopamine. All right, we will block that and stop the delusions, agitation and aggressive behavior (known as the 'positive symptoms' not positive in the sense of good just as a 'positive' biopsy result isn't good) so now the patient is placid and easier to deal with. However the 'negative' symptoms remain: apathy, lack of drive, anhedonia (one of my favorite words: inability to experience pleasure. Woody Allen was going to name one of his movies that but didn't as he feared no one would no what he was talking about. Instead he went with Annie Hall). Furthermore, there are side effects for knocking out dopamine. For one thing, dopamine is necessary in the parts of the brain responsible for movement so patients start developing Parkinson's disease symptoms (caused by dopaminergic neurons dying in their movement areas). On the flip side, some of the early medications for Parkinson's can cause psychosis. We find subtypes that are found mainly in the targeted part of the brain. These don't work as well as we hoped. And other neuroreceptors are involved too. We try to balance out serotonin with dopamine, on and on. And by we, I mean the whole industry. Even with the new generation antipsychotics in which the negative symptoms are controlled along with the more annoying positive symptoms, new side effects emerge: metabolic syndrome in which the patient becomes morbidly obese and diabetic.

But the biggest problem: compliance. Many patients refuse to take their medications. Even though the medications make them much easier to deal with and now able to become a productive member of society, the patient does not necessarily feel better taking them.It is legally difficult to make a patient take something they don't want to. Also the disease process itself; if you are paranoid and distrusting, why should you do something that THEY tell you to. Sample conversations we've had with someone with the disease:

You must not call me. THEY are listening. Only communicate by mail.
Who are THEY and why would THEY care?
I can't tell you. THEY wouldn't want me to.

For the past 6 months, THEY have taken my oxygen away. As you know, oxygen is necessary to live...
I have no heart. It is gone. The doctors don't know what they are talking about.

Bad Nazi, bad Nazi, bad Nazi.
(under her breath when disagreeing with someone of partial German

Sometimes she is funny: we once asked her if she was still hearing voices.
I don't know. My hearing isn't what it used to be.

She refuses any medications for this condition. It is difficult to convince her to take medications for more pressing conditions. She will self-medicate with no good effect with the readily available ethanol. The voices come and go; fortunately they seem to be  quiet lately (or she can't hear them). Most of the time, she seems like a nice, friendly lady interested in her family. Other times: very scary with behavior that drove the family to financial ruin not to mention the emotional toll. As she does have long stretches of normal behavior, I suppose she does not have a severe case. Heaven help those dealing with  more severe cases. They are on the streets now. No more involuntary hospitalizations and their families have given up.

Sunny goes home in an hour. She misses her dog parents. We take her for walks and throw her the ball but at night, she whines for them.


Teri Bernstein said...

I love your comment, "That's old news, of course." You were referring to the protozoan and cancer cell need for dehydrofolate reductase. Believe it or not, Sue--that whizzed by over MY head at umpteen mph....thanks for the update.

Sue in Italia/In the Land Of Cancer said...

Yeah, I am such a boring science nerd. Today on my Statcounter, I got a hit from Dunn, NC. Could my friend Teri be on a road trip? But the search for 'dark lump on side of chihuahua' somehow led them to my blog. Afraid it wasn't much help to them either.


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