The Half Decent Pharmaceutical Chemistry Blog

The fact that this blog will close in July is putting me in the situation of having to find good pretexts to talk about all those remaining themes I had planned to discuss here, before I definitely leave the world of pharmaceutical sciences.

Surprisingly, one of these inputs was provided by a person who is, and will always be, one of my most hated individuals in the world: my pathology professor. If you remember, I already told you the story of when she called me out of the room the exam was taking place to tell me, vies a vies, I had an arrogant behaviour, that would have caused me disappointment in my life.
Well, you can imagine my reaction when I saw the following scene: she was trying to go out of the department in her car, presumably in a hurry, under heavy rain, but the only way out was closed by a parked car.

She then started to attract a lot of attention from everyone working in the buildings nearby by savagely and angrily blowing the horn and (but I’m guessing here) shouting and cursing and sweating and assuming some pricelessly infuriated expression.

This memorable scene went on for more than 15 minutes until she got the car removed and drove away. In the meantime, I was setting up a RT-PCR and only towards the end realised not only what was going on, but also who actually was sitting in that blocked car. So, I apologize for the poor quality of the photograph (taken with a mobile phone): with hindsight, I would have recorded the whole scene and put it on YouTube (and then posted it here).

Anyhow, the most important thing I could make out of this satisfactory moment is that it serves the right introduction to talk about intra-arterial chemoembolization.
Targeting is obviously something of paramount importance for any drug, not to mention those with a low therapeutic index. One of the parameters one could try to adjust when the only reliable pharmacological solution is poorly selective is positioning. Generally speaking, this can be direct, passive, physical (endogenous or heterogeneous) or active.

Chemoembolization (which is an example of direct localisation) isn’t probably the wittiest but I’ve always found the idea behind it simply brilliant. In a few words, a drug is introduced, as micro-spheres, directly into an artery that leads to the target.

As the name implies, this approach combines intra-arteriolar chemotherapy with embolization: the latter, a less immediate to understand concept, involves the induction of an occluding thrombus in order to prevent further blood supply to a tissue, such as a solid tumour.

The techniques is based on 0.2-0.6 mm diameter micro-spheres to deliver the drug: this particular delivery system is employed because of its size, which is just what it takes to block an arteriole. This results not only in massively accurate targeting, as the drug is released right where it must operate, but the effect is associated with a progressive block in the vascularization of the tumour.

Finally, the time has come for me to handle really amazing stuff! Generally speaking, when you think of a drug, it’s huge and complicated, with a lot of banal elements such as carbon, hydrogen, oxygen and aromatic rings. Recently, however, I’ve embarked on an immunoprecipitation of chromatin of MRC-V fibroblasts treated with different concentration of one the things I like the most of pharma chem: Cisplatin. This structure features none of the said things. You look at it and instantly realise it’s a completely different animal: a central, shiny, loot-at-me platinum coordinated with pretty ordinary chlorides plus a couple of ammonias. Not an hydroxyl, not a methylene. Nothing.
Look at it: isn’t it a beauty?

Cisplatin started a trend of platinum-based, alkylating-like agents, which features Carboplatin and Oxaliplatin. Despite the shocking simplicity, the mechanism through which they trigger their cytotoxic effect is still partly unknown, although it’s reasonable to relate it with that of traditional alkylating agents. I mean, they obviously cannot alkylate anything as they have no alkylating group. Still, those chlorides might remind of molecules such as bischloroethylamines and nitrosureas and, so, what about a mechanism where both chlorides get removed and, through a nucleophilic attack, two guanines bind to the platinum, which, in turn, causes a catastrophic distortion of DNA? There is an unquestionable in vivo observation to prove this theory: platinum complexes inhibits the division in E. coli. This is also the reason why chemists looked at compound such as this cis-diamminedichloroplatinum (the extended name of cisplatin).
Unlike modern, precise anticancer drugs which (try to) sort of surgically operate and, therefore, are effective against a rather limited spectrum of tumours, cisplatin belongs to the old-school, which can be summarized as having a broad spectrum as well as a long list of frightening side effects. For what concerns the former, cisplatin has proved its worth in the treatment of head, neck, lung, oesophageal, gastric, bladder, ovarian and bladder cancer. Impressive, isn’t?

However, my supervisor forced me to handle it as you would do with homemade explosives. Although she may be exaggerated, cisplatin is indeed very dangerous and, in fact, is always used in combined regimens so that its dosage could be dramatically reduced. Most of the toxicity comes, unsurprisingly, from the very clinically relevant mechanism: the ability to efficiently and in a cell-cycle independent way massively damage to DNA in cancer cells, depends only on their peculiar feature of replicating at an abnormally high rate. Therefore, cisplatin is all but selective: it attacks every tissue, with the cytotoxic effect being particularly evident where replication or, generally speaking, metabolic activity is physiologically abundant. In a nutshell, alopecia, nausea and gastrointestinal toxicity, nephrotoxicity (due to free oxygen radicals), ototoxicity and neurotoxicity are all, common adverse effects experienced by patients taking cisplatin, although for all of them, except ototoxicity, it’s possible to reduce their incidence. Or, you can look at carboplatin (which causes myelosuppresion but less gastrointestinal toxicity and nephrotoxicity) or oxaliplatin (which triggers reversible, peripheral sensory neuropathy).

Regular readers of this blog know headache is an important issue here. That’s partly because it’s the only thing I sometimes suffer from as well as billions of people all over the World. Nearly every drug features headache among its adverse effects, although I’ve always believed that, in this case, part of the problem lies in the irrational fear that many experience once they’ve swollen their prescription drugs: they believe so firmly they’re going to have nasty adverse effects, they immediately feel ill or sick (nausea comes close second after headache as the most common reported drawback).

There is an amazing class of drugs, which has rapidly become the drug of choice to treat acute migraine attacks but, for some reason, I’ve never properly “reviewed”: Triptans.
Perhaps, however, it’s not too late as the patents for most of their preparations are all about to expire in the next two years and, therefore, generic Triptans are likely to become a massively (ab)used headache remedy.

Let’s start from what usually comes last: drawbacks. Amazingly, despite being as effective at relieving acute migraine as dangerous ergot alkaloids, Triptans present a set of almost innocuous adverse effects, which encompasses mild sense of warmth, dizziness, weakness and minor muscular pains (especially whenever parentally administered at the injection site). The main problem with Triptans, hence, isn’t their toxicity, but is rather a direct consequence of their mechanism of action, which makes them contraindicated to people suffering from angina or coronary artery disease, as Triptans are capable of triggering vasospasms.

Like ergot derivatives, in fact, they induce vasoconstriction of meningeal vessels through selective agonism on serotonin receptors. This counterbalances the characteristic vasodilatation of cerebral and meningeal vessels taking place during migraine episodes. Both ergot derivatives and Triptans are symptomatically helpful as they also act as serotonin agonists on pre-synaptic terminations of the trigeminal nerve, which, in turn, leads to the inhibition of the release of CGRP and substance P, which would otherwise stimulate vasodilatation.
However, because their spectrum of action is limited to serotonin receptors, Triptans amazingly manage to deliver all this without the uncontrollable power of Claviceps Purpurea’s products.

The first Triptan to be marketed, Sumatriptan, had an annoyingly low oral bioavailability (15% only), but remains an interesting drug as it was found to present the nice characteristic of being administrable not only orally, but also parentally (resulting in 96% availability) and as a nasal spray.
Nevertheless, a subcutaneous injection might be appealing only if looking at very high bioavailability as it is, by a large margin, the least liked by patients. And although a spray is a nice alternative, the research on these compounds focused on increasing oral availability and, fortunately, it has produced a number of derivatives which covers a range that goes from 40% (Zolmitriptan) to 74% (Naratriptan).

All this amazingness, predictably enough, doesn’t come cheap, with generic formulation oddly not hitting the market yet. In particular, you would imagine that because its patent expired in 2006, injectable Sumatriptan is available in low-cost version(s) or, at least, it has become cheap. You are badly wrong: surfing through Drugstore.com you find out 5 vials of Imitrex (American, commercial name for the oldest of the Triptans) can be yours for $366.23 and nine 25 mg tablets (lowest dosage available) are only $202.97 (thanks to a special offer), which means each tablet costs more than $20 and other Triptans are only marginally better on this front, with an average cost of $10 per dose. Maybe 2009 will be the turning point as Sumatriptan won’t be “protected” by any patent any more.

In the meantime, if you have headache and your name isn’t Donald Trump, you’d better stick to aspirin.

I have thought of writing about homeopathy since the day I got this blog started, but never found a decent pretext to do it. Sure, while I was doing my internship at the chemist’s I prepared lots of Bach flowers remedies (which are not, strictly speaking, real homeopathic medications). What’s more, I also handled many boxes of proper homeopathic stuff and so realised how quickly this is getting a massive business. This, though, shouldn’t be a surprise because mass-producing them is a thousand times easier than designing, patenting, mass producing, marketing and distributing a traditional, allopathic formulation.

The pretext I was looking for was found here. That short article gave me the inspiration for finally collecting all the things I have learnt over the past four years and sum them up in a post which could clarify my opinion on homeopathy once and for all. Pretty much the kind of thing you would expect from an episode of Big Talk…

I imagine at this point many of  you will think I’ll embark myself on a long tirade against homeopathy-enthusiasts: freaks who blindly trust this sort of alternative therapies because they firmly believe that traditional drugs are the product of Nazi, evil-minded scientists, who work for even more evil big companies, who aim at taking control of the planet or something like that.

What I’m actually going to do is to explain what homeopathy is all about. More or less. For a kick-off, allopathic medicine is the traditional approach towards illnesses. To be more precise, it is the traditional way of considering symptoms and this is a key point to understand the difference between conventional therapy and homeopathy. One of the fundamental concept regulating traditional medicine is that you find what is not working in an organism and choose the appropriate remedy to cure the symptoms. From the point of view of homeopathic practitioners, however, a disease is the way an organism has to regain a lost equilibrium. Therefore, symptoms must be enhanced rather than tackled.

Let’s take excessive stomach acidity as an example. Normally, you’d be tempted to take antacids to counterbalance the overproduction of HCl, coping with the problem symptomatically, at least. On the contrary, homeopaths generally prescribe preparations containing acids to help the symptom increase.

A second difference is that, whatever allopathic drug is prescribed, its concentration has to be equal or higher than the so-called effective dose (ED-50), which is statistically defined as the dose yielding a positive response in half the patients. Anyhow, one of the key assumptions of homeopathy is that, by diluting a substance, you actually increase its effectiveness. In fact, to make homeopathic tinctures, you begin with a concentrated solution and dilute it up to a million-fold. If you think about it for a second, you’ll realise that, bearing in mind the Avogadro’s number, there is a chance the final solution won’t contain ANY active substance at all. And that’s very good because, in the restless quest for symptom-enhancement, this kind of preparation often contains poisons.  
Going back to the example of stomach acidity, your homeopathic, acidic remedy may have a neutral pH. This explains why it so easy for very small company to produce these products: the concentrations of active substances are always so low, that there is almost no regulation the manufacturer has to strictly follow. All it’s asked to demonstrate is the purity of materials and that the quantity of active substances is below a certain threshold (and it always is).
At this point, you might be disgusted with what you’ve read but I have to tell you something that will probably shock you and make you think I’ve gone mad. Homeopathy works. Well, maybe, this is not the correct way of saying that. What I should actually point out is that some types of treatment with a tight bond to some of the principles of alternative medicine just described work perfectly.
What is, for instance, a vaccine? It consists of very diluted bacterial antigens (if inactivated, that’s even better), administered to healthy people so that their body could simulate the response it should be able to provide. Even more shocking is that, statistically, babies and…pigs can actually heal when treated with alternative, homeopathic remedies.

But don’t be fooled. Neither of these two facts could actually provide any scientific, valid support to homeopathy. In fact, you shouldn’t forget about the placebo effect: it is not the cure itself, but the feeling of being cured, treated in a certain, instinctively expected way that triggers an undoubtedly positive reaction.

So, the only, really effective, alternative remedy has to be based on the assumption that the human mind has an incredible and poorly understood, to date, healing power.

What’s probably the worst, social consequence of AIDS has always looked like a bitter irony to me; you could even say it’s funny, if we weren’t talking about such a terrible disease. In a nutshell, ignorant bastards (and, sadly, there are plenty of them out there), whenever they meet a person known to have been infected with HIV, start to take the same precautions you’d need to bear in mind when having to do with leprosy. Stupid as it may sound, they believe AIDS to be the sort of infectious disease that spreads through the air. Not to mention how scared they look even when they only consider the possibility of shaking hands or drinking from the same glass. What makes me smile is that the only people who should try to avoid contact with the others are immunocompromised individuals, because, of course, they are progressively losing all their defences against even the least dangerous illness. That’s the same reason why no one dies of AIDS or HIV-infection, strictly speaking: they are killed by an increasing number of different diseases which can easily spread in an organism that is shunting down all his defences. And the more under pressure the (few) remaining defences the person are, the easier new infections spread. Until there’s nothing left against them and the organism succumbs.

The main threats for immunocompromised patients are opportunistic infections which are the ultimate responsible for nearly 80% of death among HIV-infected people. A frequent infection is toxoplasmosis of the brain. Medical guide lines shows clindamycin as the most reliable treatment for this condition. Mycobacterium tuberculosis can easily cause infections as well: isoniazid is considered the drug choice, partly due to its effectiveness against latent forms.
A mucosal candidiasis can be a nuisance for a normal individuals, but it turns into an endless nightmare if you body can’t stop its development. That’s why fluconazole becomes as familiar as AZT to people suffering from AIDS, being used even for prophylaxis against candidiasis.
Although the patient is being administered a considerable amount of antiviral medications, these aren’t sufficient to prevent or tackle cytomegalovirus infections: so, ganciclovir is employed to treat CMV-related pneumonia and intravitreal injections of fomivirsen help with retinitis. Cidofovir, on the other hand, is another antiviral drug, which is chosen every time a polyomavirus-related progressive, multifocal, leukoencephalopathy syndrome is detected.

Nothing, though, is more characteristic than AIDS-related Kaposi sarcoma, which would otherwise be a really uncommon tumour. The reason why it’s so common is still unknown and, perhaps, this could help better understand the mechanisms involved in the HIV infectious cycle and AIDS itself. Paclitaxel is the best treatment for this particular neoplasm to date.
There are other, general, phenomena that mark the critical phase of AIDS: fever, weight loss, lymphadenopathies and catastrophic diarrhea. For the last issue, somatostatin is often used.
Last but not least, there’s another, predictable and sometimes lethal, common complication which is faced once the patient is aware of his situation: depression. The mechanisms involved are yet to be fully understand, and this is certainly not the sole effect of AIDS on the central nervous system. Actually neurologic disorders can be the first manifestation of the viral infection..
Drugs with mild, anticholinergic properties, such as buspirone or trazodone, are the most used antidepressants in this context.

To sum up, healthy people are an incredibly more dangerous threat to infected ones than vice versa. Far and away.