The Half Decent Pharmaceutical Chemistry Blog

While I temporary ceased talking about pharmacology, I reckon the most interesting story about a drug has been the Tegaserod-gate.

On March 30 (surprisingly people at the FDA work on Saturday, too!) this serotonin 5-HT4 agonist was withdrawn from the American market. That was due to a worryingly high number of patients treated with Tegaserod, who began to suffer from cardiovascular disease. The FDA wanted to be sure whether the use of Tegaserod could be associated with high risk of heart attack and stroke.

Novartis, which manufacture the drug in the US, claimed that the data cited by the FDA (collected during the clinical trial) had been misinterpreted: according to the Swiss company, those figures couldn’t prove anything, given that they referred to people who already suffered from cardiovascular diseases or were associated with high risk of developing them in any case.

Still, if you suffer from irritable bowel syndrome with predominant constipation, we’ll have to look elsewhere. And that’s a pity, because, before March 30, Tegaserod looked like the perfect treatment for that disease.

For example, the only, main, adverse effect seemed to be headache, which is probably the most common side effect. To quote the 9th edition of Katzung’s “Basic&Clinical Pharmacology”: “Tegaserod appears to be an extremely safe drug.”

No doubt the way this molecule presents a rather smart mechanism: 5-HT4 receptors are located on the mucosal afferent nerve fibres and their stimulation enhances the release of neurotransmitters, including CGRP (calcitonin gene-related peptide), which greatly stimulates the peristaltic reflex.

As a result, the average number of bowel movements increases and the hardness of stool is reduced, helping relieving constipation.

This is all very interesting, but is this nice molecule also selective? I mean, serotonin receptors are involved in the regulation of blood pressure too: they can stimulate the contractility of vascular smooth muscles (lungs and kidney), whereas relax those of skeletal muscles, brain and heart. 5-HT2 stimulation is also linked to enhanced platelet aggregation.

Now let’s take a look at a similar story, where another substance that acts on serotonin receptor is the protagonist: its sister.

Alosetron was launched on the market in February 2000, as a treatment for IBS-related diarrhea, so exactly the opposite problem. This, in fact, is a 5-HT3 antagonist: it inhibits distension-induced sensory and motor reflex activation, but it also acts on the central serotonin receptors, reducing the response to visceral stimulation.
To sum up, this molecule increases stool hardness and reduces bowel motility. Interestingly, there’s no evidence that Alosetron is effective for men: that’s why this drug is prescribed to women only (that's why I called it "sister").

Although the aim is obviously to induce a certain degree of constipation, sometimes this could be a serious complication.
In November 2000 this drug was withdrawn from the market due to fatal ischemic colitis and was banned for 2 years until, in 2002, the FDA gave GlaxoSmithKline the green light and Alosetron was reintroduced, even if with strict restrictions because of the severe toxicity associated.

I guess this will be the same conclusion of the Tegaserod-gate. 

I told you, friends, that pharmacology would have made its comeback on this blog: because we are in the middle of the Camptothecin Week, today, after the massive, total synthesis of the parent drug, I’m to give you an overview of the two, major derivatives which are clinically used.

Like Campothecin, both Topotecan and Irinotecan are inhibitors of topoisomerase I, an enzyme which will be soon described in the very first post about molecular biology.

In a nutshell, however, the target-enzyme is fundamental for cells and impairing its activity damages the DNA, leading to cell death.

The structure of Topotecan closely resembles that of natural Camptothecin.

 

Nowadays, this anti cancer drug represents a valid option to treat platinum-resistant advanced ovarian cancer and as second line therapy of aggressive small cell lung cancer.

There are a few disadvantages, though: bone marrow depression (common adverse effect with anti tumour medications), arthralgias and problems for patients who suffer from renal dysfunctions (the molecule is almost entirely excreted in the urine) requires to adjust the dosage or even to avoid this drug.

Irinotecan was launched on the market more recently.

This pro-drug is activated once it reaches the liver: there, a carboxyl esterase yields SN-38, which is a rather effective inhibitor of topoisomerase.


Interestingly, Irinotecan is the first choice, in association with fluorouracil, to treat (metastatic) colorectal cancer.

The main adverse effects are myelosuppresion (rather predictable) and diarrhea. Generally speaking, there is an acute toxicity (for which atropine can provide a reliable solution) and a delayed form: predictably, the latter is more severe, resulting in electrolyte imbalance and dehydration.

Last Sunday, here in Italy, an organization called LAV (which, translated into English, stands for Anti-Vivisection Society) held their annual Day against animal experiments. On their website you can still read the motto: "Experiments on animals are useless and cruel. Stop them".

At this point you might think I forgot to add a link to their webpage, but, to be honest, I just don't want to. That's because these people are simply very, very stupid: they claim we could easily use cells and get rid of experiments on lovely animals. And that is talking rubbish!

Maybe, in the future, that will be possible, I hope, but, at the moment, every schoolboy understands that you can't base a preclinic trial for a new drug solely on data collected from in vitro experiments: animal experiments greatly help us to find out adverse effects or to predict the right dosage for human beings.

Yes, they don't answer all our questions and, sometimes, they don't show dreadful adverse effects we find in humans, but since we can't create human clones, we have to go on using animals.

Of course, I'm not a bloody-minded sadist: I can see the thin red line which separates unavoidable experiments from useless cruelty. Mind you: is it all that thin?

Here's one for you: bile bears.

Ursodiol is the best drug to treat gallstones. It's a type of bile acid found in bear bile.



This acid decreases the concentration of cholesterol in bile by reducing its secretion from the liver. Moreover, it also acts as a sort of stabilizer for the membranes of the hepatic canaliculi.

To sum up, ursodiol is the best option for dissolving gallstones, as well as for avoiding their formation in obese people who are rapidly losing weight.

And now, after Italian animalist groups, let me find new enemies in China!
The extraction of bile acid from the gallbladder of bears can be carried out easily and with no pain for the animal: small quantities are needed and are taken every so often. Meanwhile, the animal can live its life in tranquillity.



None the less, enormous quantity are extracted by Chinese criminal organizations. In fact, bile is also used to prepare ointments and other products which claim healing properties and are then launched on the market (internet speeds things up and makes them safer for the producer).



Bears are kept in small cages. But there's more: terrifyingly, with the same care of a butcher, a tube is fixed close to their gallbladder. So, those bastards can collect all the secreted bile on any given day from many animals, with few costs and high yields. The perfect business.

Can you see the difference?

Why, the hell, do we have to sleep?!

This is the question every (under)graduate student should ask him/herself, in my opinion. Why are our days limited to, say, 16 hours out of the available 24? That's 66.67%!
I mean, if that was the yield of a liquid-liquid extraction you had performed, you would deserve to wash all the glassware used by your lab mates as a sort of punishment.

The problem I'm currently experiencing is pretty simple: I've lectures in the morning, which I can't (for some courses you must sign in every time) and don't want to miss. Meanwhile, in the afternoon, it's time for studying.

However, here is the problem: life has a completely different, better, taste, at night. When I study until midnight, I love wandering and taking pictures on the way to home.

Mind you, there are lots of other things I like to do, instead of wasting my time sleeping. There are amazing blogs to read; on my shelves, dust has become to cover interesting books; I've made a list of films that I want to watch...

Unfortunately, my body seems to have different needs and priorities and, as a result, I'm unable to perform all the said actions.

How unfair!



By the way, once you've reduced the hours I sleep and some lectures are extremely boring, you need stimulants.

And here they come.



On the left, caffeine: lovely in the morning and after lunch. To sum up, it works as some types of insulin, which provides a long-lasting basal level.

Although many people believe energy drinks improve physical skills only, I've to say that I find them particularly usefull when concentration levels, predictably, drop at midnight. Moreover, their taste is awful, but I reckon you quickly get used to it.
So, energy drinks act like short-acting insulin: they guarantee nothing more than an extra hour when it's really late.

Mm, last but not least, some "funny" guy may introduce you to...that molecule: MDA, a close relative of MDMA.
Both drugs are synthetic analogs of amphetamine and both catastrophically increase the release of serotonin and dopamine.

Once again, I'd like to tell you the whole truth about this drug of abuse.
MDA undoubtedly gives a sense of well-being, makes interpersonal interactions easier and increases physical performance, by reducing fatigue.

Moreover, MDA and MDMA do not cause distorted perceptions.

Unlike the two drugs of abuse I previously described, anyway, these substances have overwhelming toxicity.
Not to mention overdose, nausea is generally the first and almost unavoidable adverse effect. It's therefore followed by a much more alarming, uncontrolled contraction of neck muscles and mydriasis (both are sympathomimetics, in fact).

Even if they certainly reduce fatigue, people taking these pills are often exhausted for the following two days.
Unlike LSD, neurological damages are a common result of a long addiction to MDA and MDMA.

However, the worst drawback is, in my opinion, a consequence of the lack of loss of self-consciousness: the person is perfectly conscious of what is going on (spasm, nausea, etc.) and gets suddenly terrified thinking this will last forever. This phenomenon is often called acute toxic psychosis and is not something addicts get used to, either.

So, the message here is simple: drink good coffee and take lovely pictures on the way back home.
Leave crappy MDA to techno music-freaks.

Good night! :)

As I see it, Cannabinods are the last resort, when it comes to anti-emetic drugs. Dronabinol, above all, is just astonishing: this (major) component of Marijuana is the most potent remedy for nausea and vomiting caused by anti-cancer chemotherapy and for AIDS-related anorexia.

Now, for what concerns the latter effect, Δ⁹-tetrahydrocannabinol (another name for Dronabinol) seems to stimulate appetite through its action at the hunger centre, located in the hypothalamus. This phenomenon is often experienced by healthy people, who smoke Marijuana too...

Many anti-tumor drugs damage cells of the intestinal mucosa. As a result, vomiting is awfully common. Moreover, nausea frequently occurs BEFORE the patient has to take chemotherapeutics: this is a psychological issue, of course, since it's just an anticipatory response to a sadly well-known adverse effect.

Unsurprisingly, because it's a central effect, only a drug with marked central activity can help.



At this point, you're probably wondering how THC works, from a molecular point of view. Interestingly, there are specific G-coupled-receptors for these substance, either centrally and peripherally.
If there's an exogenous substance which reacts with its own receptor, there must be, obviously, an endogenous molecule normally binding there.

This substance is called Anandamide, from ananda, a Sanskrit expression which means "beatitude". Rather appropriate, eh?



Back to Dronabinol, this drug is orally administered. Although this doesn't eliminate most of the (side) effects you could experience when smoking marijuana, at least, it avoids pulmonary complications: the pyrolysis of THC, in fact, yields pretty toxic products (more toxic than those you get from cigarettes).

Still, sedation, euphoria (feel-good mood), dysphoria, hallucination, tachycardia and orthostatic hypotension remain drawbacks of Dronabinol.
It must be highlighted, by the way, that this drug is prescribed to terminal patients: anorexia, for example, usually arise in advanced AIDS, not at the onset.

So, long-term complications such as dependence and amotivational syndrome are far from being a major concern.

Multiple sclerosis and glaucoma are conditions for which Dronabinol is sometimes prescribed, too. THC has undoubtedly analgesic properties, which are welcome by people suffering from MS.

Parents all over the world regularly check their teenager sons' and daughters' eyes, looking for alarming redness of their eyes. However, THC has also proved its worth in lowering intraocular pressure, which explains its effectiveness in the therapy for glaucoma.