The Half Decent Pharmaceutical Chemistry Blog

Although last week I brilliantly finished the semester with a tough exam and, after that, I had a whopping two-days-long holiday, I didn't post on any given day as I hoped I'd have done.

I wrote I was tired, but after sleeping for 9 consecutive hours, I felt fine. Unfortunately, I had to face nasty headache, which began on Wednesday and lasted until this morning.

I guess it was a sort of weekend headache. Annoyingly, it matched what I hoped would have been the "Relax Week": the new semester starting on Thursday, nothing to study and more free time than during the previous three months.

Headache isn't uncommon for me. As the majority of people, I often suffer from common headache. And that's fine because, two years ago, I experienced classic headache too.

Classic headache is characterised by the so-called aura, which is linked to visual and speech abnormalities. I have to add vomiting to the list, too.
I didn't like it...

There's no doubt there are many drugs you can choose to tackle pain. The ultimate, most powerful molecules are, anyhow, the ergot derivatives.
Not that I've ever tested them, but this week the sorrow made me think, often, about their pros and cons.

Mind you, there is a substance we all know for different reasons which, being an ergot derivative, should guarantee exactly the same effectiveness of, say, methysergide.
This molecule was discovered by a Swiss chemist. To be precise, a pharmaceutical chemist.

I am talking about Albert Hofmann and the molecule is, obviously, LSD (lysergic acid diethylamide).



Theoretically, every ergot derivative could be used for the treatment of headache. Not only do they relieve the pain (like NSAIDs), but they also act presynaptically on 5-HT1 receptors of the trigeminal nerve, so that no more CGRP is released. Amazingly, they even avoid vasodilatation, due to their direct effect.

However, LSD has a much stronger central activity, which explains why it's such a potent hallucinogen. LSD  has, infact, astonishing activity, as agonist, on 5-HT2 receptors.

Here we are: I'm a young pharmaceutical chemist, who suffer from headache. So, there must be a post dedicated to LSD on my blog.

First of all, I've to say I've never tried it and, probably, I'll never, either.
Nevertheless, if I'll do my PhD at prestigious Harvard University, I think, on my first day there, testing it could be the right tribute to Timothy Leary and a sort of initiation to the (old) campus life there.

Many people even ignore he was a brilliant researcher of psychology at Harvard University, before I was "convinced" to get away.
By the way, he is far from being a model for me, unlike Hofmann.

Surprisingly, LSD has huge therapeutic index: 20µg are sufficient to begin the trip, while 200mg are lethal. Not that bad for such a fiercely potent psychoactive drug.

Some effects are experienced after a couple of hours: vertigo, chills but also flushing and tachycardia.
Gradually, the drug begins to induce central effects: the brain gets incredibly more sensitive to stimuli, memory is increased, as well as freedom of thought and clarity of ideas.

The person feels a new sense of well-being. At the same time, anyhow, anxiety and hypomanic exaltation can take place.



None of these things are, however, the main reason of the success of LSD. What people look for are, mainly, the subsequent hallucinations and altered sense of time and surrounding space.

Bad trip is the expression which sums up its toxicity: terror, complete (albeit transient) loss of the sense of reality, retrospective sensations and lack of motivations.

You can hear lots of rubbish about LSD causing persistent damage to your neurons. There's nothing to prove it, but, it must be pointed out that this happens with lab animals and there are, undoubtedly, dramatic changes in metabolites of serotonin in humans.

Other ergot derivatives (including a less potent natural version of LSD) have similar hallucinogenic properties. Something which you can appreciate, oddly, in art galleries.

In fact, ergot is a fungus that infests grain: that was a terrible problem in the middle age, when the inhabitants of entire villages could avoid poisoning because they knew nothing about ergot.



Poisoning is associated with the psychotic effects of LSD and they are particularly well documented in Bruegel's paintings: check this out.

 

Many women were believed to be witches, solely due to behavioural changes.

There is another dreadful side effect of LSD and its congeners: catastrophic vasoconstriction, which leads to gangrene, and uterine contractions, abortifacient, especially for cattle, but also for humans.

Very deadly, but, still, effective for headache.

 

 

Although Spandau Ballet do not deserve to be on my MP3 player, apparently,  they can be in my proximal interphalangeal and metacarpophalangeal joints. (Mm, I bet this will rise my Gunning-Fog index to unprecedented levels.)

Gold is, in fact, the oldest (though now rarely used) remedy for a pretty common chronic inflammatory disease called rheumatoid arthritis.

Mind you, you can't just inject (or swallow) melted gold, but it has to be in the form of sodium thiomalate, for example.
However, such a formulation contains approximately a stunning 50% of elemental gold. Not bad, I think.
It has to be remembered that, back in the 18th century, gold had been tried as cure for a certain number of pathologies (including tuberculosis).

Like most of the other chronic inflammations, also rheumatoid arthritis has genetic and environmental causes.

Symmetric arthritis of small joints is a typical feature: the synovitis is the consequence of arthritogenic antigens reacting with T-cells.

Actually, these antigens are very often IgM autoantibodies, which attack IgG (on their Fc portion, to be precise), so this is a proper autoimmunitary disease.

Still, the most important part of the story (why these autoantibodies are produced, remains unclear). Here, perhaps, the most plausible explanation lies in two genes (HLA-DR4 and HLA-DR1), which encodes proteins that bind easily to arthritogenic antigens.

There's also an intriguing hypothesis which focuses on viral infections (EBV, Mycoplasma, parvoviruses and mycobacteria).

Anyhow, not only do activated T-cells secrete cytokines, which will lead to increased quantities of either B-cells and macrophages, but they also massively increase the expression of RANK ligand, promoting bone resorption.

For what concerns the inflammation, then, synovial cells hyperplasia, angiogenesis, high levels of neutrophils and fibrin, are usual histological characteristics of the resulting, so-called pannus.

As the disease progresses. cartilages are eroded and, later on, bones as well. These phenomena are, sometimes, accompanied by calcification and chronic ankylosis.

To sum up, a chronic, painful erosion of joints which causes a disabling arthritis.

At this point, back in the groovy Sixties, a clinical trials proved dramatic effectiveness of gold derivatives in the treatment of RA.



After intravenous administration, in fact, gold nicely concentrates where it's most needed: synovial membranes.
Unfortunately, liver, kidney, spleen, lymph nodes and bone marrow are quickly reached too and this partly explains its adverse effects.

Since it reaches the liver, jaundice is a consequence; the effects on spleen and bone marrow end up in aplastic anemia, leukopenia, proteinuria and thronmbocytopenia. And so on: eosinophilia, enterocolitis, peripheral neuropathy, pulmunary infiltrates, rash...




Nevertheless, none of those drawbacks can pull me down. What I like is the lunacy: an impossibly beautiful element, helping relieving one of the most painful disease through a variety of mechanisms.

Speaking of which, I can't decide which is the best.

We begin with a mind-blowing modification of macrophages: functions and morphology are dramatically altered. This, predictably, leads to the inhibition of IL-8, monocyte chemotactic factor-1, etc.

Then, there is the complement system: gold massively inactivates the first components.

The same goes for the release of histamine from mast cells, lysosomalpolymorphonuclear leukocytes enzymes and .

To sum up, gold blocks a broad spectrum of those pathways involved in the chronic inflammatory response.

And all this massive power is garnished with a spicy metallic taste, it leaves in your mouth...

Well, after all, it's not that hard to understand why this is not the drug of choice any more, is it?

This is Chloroquine. Not that's much to shout about. It's the most common antimalarial drug, although Plasmodium falciparum is pretty resistant, through mutations in its putative transporter.

We all know that chloroquine is a derivative of quinine, which is extracted from Cinchona bark (in the background). A plant which has always been extremely common in warm, South American countries, like Peru, with high mountains: the perfect habitat for this small tree.

Chloroquine is a very reliable (and convenient) option for non-falciparum forms, even prophylactically.

Still, there are two, rather important, issues: the aforementioned resistance and the adverse effects.

All quinine derivatives cause hemolysis if the patient presents glucose-6-dehydrogenase deficiency.

However, among the other, most frequently reported toxicities there are: abdominal pain, headache, anorexia, blurring of vision, impaired hearing, confusion, seizures and hypotension.

Not to mention rarer, irreversible ototoxicity, myopathy and peripheral neuropathy.

All these drawbacks make this drug contraindicated in the presence of visual field abnormalities, psoriasis, porphyria and myopathy.

Nevertheless, chloroquine remains the best blood schizonticides for all those situation where P falciparum resistant stains aren't involved.

Now, however, there is a new, mighty contender, which comes from China, where it has always been an excellent antipyretic.

Its name is Artemisin (or, as they call it, qinghaosu) and wants to be taken seriously.



This beautiful molecule is a quick blood schizonticide for all, four types of malaria strains (P malariae, falciparum, vivax and ovale). No resistant strain has been isolated so far.

Moreover, it seems free from adverse effects, except for teratogenicity (reported in animals).

Of course, studies are still going on, but Artemisin is already a massive thing: an even cheaper choice for African countries, with (suspiciously, though) no toxicity and the broadest spectrum among all the traditional blood schizonticides.

Ok, so, this is the first post with the new template (but a new one will probably replace it soon: maybe next week).

Still, for this occasion, I've decided it's, finally, time to talk about an affair that thrilled Italy some years ago. As an Italian blogger, I feel the need to talk about this story.

Moreover, this gives me the opportunity to describe a great natural substance, too: Somatostatin.

Another man (now deceased), who should have been rather fond of Somatostatina (the Italian for Somatostatin), was Luigi Di Bella.

Yes, today I'm going to give you my opinion about the so-called Di Bella's therapy.

This doctor claimed to have found a miraculous cure for (every type of) cancer. However, he didn't discovered any new drug.

The therapy, in fact, is based on a mysterious cocktail of substances...

No one knows exactly all the ingredients of his mixture: certainly, anyhow, somatostatin is present as major component.

Now, this 14-amino acids peptide has undoubtedly a huge importance and, in the presence of a neoplasia, clinical importance.

Although somatostatin is, above all, produced in the hypothalamus, delta cells of the pancreas secrete it as well.

Genarally speaking, it inhibits hormones secretion in the gut and anterior pituitary. Among the most important uses, the cure of either vagotomy- and AIDS-related diarrhea must be mentioned.

Moreover, a common consequence of gastrointestinal neuroendocrine tumors is catastrophic, persistent diarrhea, which is generally tackled with somatostatin.

This is possible due to three mechanisms: a reduction of pancreatic secretions and intestinal fluids, a dramatic decrement of gastrointestinal motility (including gallbladder) and, last but not least, a direct action of the said substance on vascular smooth muscles, which leads to decreased perfusion.

Its administration, though, has, unsurprisingly, dangerous drawbacks. Steatorrhea, for example, is an easy-to-predict complication.

Moreover, somatostatin suppresses the release of insulin (and, to a different extent, of glucagon as well): so, hyperglycemia can occur.

Once more: thyroid. Since it inhibit the release of anterior pituitary hormones, the levels of TSH are lowered to the point of severe hypothyroidism.

You might be thinking: "Yes, it has scary side effects, but which antitumoral molecule doesn't?"

Well, although you are certainly right, the problem is much more complicated.

As I pointed out, the exact composition of the Di Bella's cocktail is unknown: there are rumours going around.

Some say that many ingredients are from, in a nutshell, those products that spam emails always try to sell you.

Some say that cyclophosphamide and hydroxyurea are also present. The former is an alkylating agent (also used to treat rheumatoid arthritis); the latter a ribonucleotide reductase inhibitor generally prescribed for chronic myelogenous leukemia.

Dangerous drugs, which need accurate dosages, according to the patient. However, many people (not only Italians) blindly trusted that old, little man and came to his small clinic for the miraculous treatment.

The components of the mix, besides, are probably changed every time (yes, I have used the simple present...).

There has always been faith in the cure rather than scientific rationale.
Actually, some people claim they were literally saved by Di Bella and this man is still considered a saint, even by people who weren't cured by him.

Actually, many people believes in it just because all those scientists say it's rubbish...

Meanwhile, a political issue arose, here in Italy: right-wing parties love him, while left-centre ones say he gave false hopes (and earned money, since the treatment has never been for free).

When the Italian government began (in 1997) a massive clinical trial, it was soon evident that the cure didn't work.

Still, the Di Bellas (his sons continue to prescribe the cocktail) keep saying what their father declared: pharmaceutical companies know perfectly well his cheap cure works and they pay people like me to say that it's rubbish.

Needless to say, I'd like some pharma firm to give me money, appreciating that I wrote this article just because I wanted and becuase persuaded.

At this point I'd like to quote what one of my professors of organic chemistry (now, sadly, retired) told us during a lecture: pharma firms are certainly not stupid, when it comes to business.

They could have produced massive quantities of somatostatin but they didn't. Were they stupid?

Mafia, on the other hand, blackmarketed low quality somatostatin for some time.

 

What's for sure is that: the cure failed to pass an accurate clinical trial and (according to what we know) there's no scientific basis.

Sadly, at least in Italy, a cool molecule such a somatostatin will always be linked to this story.

 

From next month on, there will be much more biochemical stuff discussed here. This reflects my great passion for that aspect of industrial pharmacy: I've already decided my graduation thesis project will be carried out at the local department of Molecular Biology, for example.

I believe that everyone who would like to design new drugs or find new targets should concentrate on this kind of themes.

When I realised, four years ago, that I wanted to study industrial pharmacy, however, my aims were radically different: I wanted to synthesize drugs.
With the benefit of hindsight, that dream would have been, sadly, frustrated by a lack of lab courses dealing with organic synthesis, that could prepare those students who are interested in studying (new) preps.

I mean, if that was really my major interest, I should have opted for a more traditional B.S. in chemistry.

Fortunately, though, since the beginning of the second year, it was clear to me I definitely preferred the biological subjects.

Still, I am very fond of organic chemistry, but I can't fool myself: that is not what I hope to do for the rest of my life.

Anyhow, last here a drug showed, once again, what I really like. This drug is Imatinib and, to date, it's the smartest chemiotherapeutic agent I've ever studied.

The idea is simple and (because it's so simple) brilliant. There is this chromosomal translocation called the Philadelphia translocation, which results in chronic myelogenous leukemia.

The translocation induce the expression of a fusion oncoprotein: Bcr-Abl.

So, once this was discovered, people at Novartis said: "Now, how can we tackle this?"

Well, Imatinib inhibits the tyrosine kinase domain on it and its phosphorilation, for which ATP is responsible.

The drug is orally administered, so a great compliance is guaranteed, and there are few, mild adverse effects as well!

Moreover, this drug is effective against other tumors expressing the so-called c-kit tyrosine kinase too.

How can you resist such a phenomenal molecule?!