The Half Decent Pharmaceutical Chemistry Blog

This morning I’ve come across a couple of juicy articles during a lunch-time break pubmed session. Yes, I know it sounds ill to spend your free time pretty much doing research while eating but the problem is we usually don’t eat all together, despite being an only 5-people group, for which, theoretically, this sort of thing should be easy to arrange. Unfortunately, working on different projects results in spending most of our breaks on our own with little time to become intimate with your colleagues.

Nevertheless, those things I read were actually very interesting. To start with meaningful and, perhaps, shocking statistics, I didn’t know that HIV-encephalitis (quickly mentioned yesterday) is, by far, the leading cause of dementia among young adults. In fact, not only do neurological complications result from easy to spread opportunistic infections, but HIV itself is prone to seriously affect the nervous system. There are actually many disorders it can cause, both centrally and peripherally: primary encephalopathies, myelopathy, meningitis and vasculitis, as well as demyelinating neuropathies.

It has been noticed that meningitis can be an early symptom of the infection, which therefore implies that the nervous system is likely to be a major centre for the development of the infection. This is also consistent with the catastrophic, late, neurologic progress of AIDS: the so-called AIDS dementia syndrome. This particular complication of the disease is characterized by cognitive and motor disturbances, such as loss of memory, impaired fine motor control and progressive loss of central control of bladder and bowel.
The damages produced by HIV on the brain appear even more evident during autopsies. HIV-encephalitis leads to atrophy of the brain and there are many other histological abnormalities. In particular, a distinctive feature is the presence of products of the fusion of infected macrophages, which yields, in the end, giant, polynucleated cells.
There is plenty of weird people who cry out loudly whenever you mention antiretroviral agents. However, these evil chemicals seem to remarkably slow the development of this dramatic AIDS- related pathology, only when used at very high doses. That’s probably because some these molecule (including AZT) can jump across the blood-brain barrier, reaching the central nervous system.

Sadly, although scientists have revealed the impact of HIV on central nervous system, no one has yet come up with an explanation for how the infection attack this area and what regulates, at an early stage, the onset of this type of encephalitis.

We’re having a bit of a problem with the heating system in the lab. On Monday, the technical office of the university kindly listened to our complains and decided we were freezing sufficiently to turn the heat on in the whole department. Predictably, though, there’s now a sort of tropical climate in the rooms because the heating works very simply: if it’s off, no matter how cold it’s, you’ll carry out your assays wearing your raincoat; when it’s on, it’s simply on, you can’t set a temperature, so the building turns into a fireball.

This seems to be particularly disappointing when you set up a western blotting and, right at the beginning, you prepare your SDS-page. Plainly, yesterday it was so hot that the resolving (a.k.a. running) gel wouldn’t polymerize. First, however, my supervisor told me to make a new acrylamide/bisacrylamide solution, because the one we were using was pretty old and it could be an issue. As it turned out, that wasn’t the problem, because, again, it didn’t polymerized, until we opened the windows in the room (with the heating on…what a great way of saving money and the planet!) and let cold air in to cool down the environment.

While weighing the acrylamide, however, I was warned to be extra-careful. That’s because the monomer, not the acrylate polymer, is a vicious neurotoxin. Acrylamide causes axonopathy, a type of CNS toxicity in which either axon and myelin degenerate, whereas the soma is undamaged and still metabolically active: in fact, it begins to synthesise myofibrils as a response to the injury. Histologically, this gives a bulb onion-shape to the neuron, as myofibrils tend to accumulate upstream the first, damaged site.

Characteristically, the first symptom of an acrylamide axonopathy is the loss of mechanical and thermal sensitivity, at first limited to fingers, but then progressively affecting arms and legs. This is all very worrying, but you may think it’s something that has to do only with chemists and biologists, or some kind of workers (poly-acrylamide is utilized in a pretty wide range of industries, from petroleum industry to water purification). Thing is, acrylamide can be found in carbohydrates-rich foods, cooked at high temperature, such as potatoes and, obviously, pasta.

So, to sum up, most of what you eat contains a substance which has been proved to be a neurotoxin to human beings, a genotoxic carcinogen to rats. The question is: how much of this killing substance do we eat on a daily basis?

Fortunately, not much and, in particular, much less than the so-called NOEL (non-observed effect level), which means children, given the poor activity of their detoxifying enzymes and, if you think about it, the high quantity of backed carbohydrates present in their diet, are immune to the dramatic effects of an exposure to acrylamide. This is a case of ALARA (as low as reasonably achievable): we can’t get rid of acrylamide, but we can determine statistically a level of total safety (which is called, anyhow, virtual safety dose). In this case, the NOEL are (because one is for axonopathy and one for genotoxicity) 0.5 mg/kg and 2 mg/kg. The daily intake for a baby is estimated to be 0.3 – 0.8 μg/kg.
To sum up, we can go on eating our beloved spaghetti and French-fries.
Still, there are a few concerns about the long-term consequences of an exposure to low levels of acrylamide, regarding carcinogenesis. What’s more, although it’s been proposed for acrylamide the same mechanism demonstrated for hexane, which reacts with ammines (yielding pyrroles) and cytoskeleton proteins and yields derivatives (such as 2,5 – hexandione), the exact molecular action of acrylamide is yet to be determined.

You might think that Global Warming has become this age’s new boogieman: “Eat your soup or Global Warming will come and catch you!” Before you go back to burn all your rubbish, with all your electric equipments turned on, fed up with people who tell you how to behave, try to look at this issue from a different prospective. A pathological one.

Studying pharmacology at the university means you learn about pretty much every type of drugs, regardless the relative importance of the disease they are used to treat. Or, perhaps, that’s what you should do.
Inevitably, though, a medical doctor or a pharmacologist must focus on some areas. There are illnesses which are so rare in Europe or America that are extremely difficult to recognise promptly. And a prompt diagnosis is often (if not always) fundamental.

Can we blame the physicians for this? I don’t think this would be fair: I’m happy my family doctor knows perfectly how to cure my influenza or my grandma’s hypertension. And, honestly, I don’t care if he would have a hard time recognising a visceral Leishmaniasis or Chigas disease.

My pharmacology professor once recalled an accident that occurred during a trip to Nepal. One day, he and his fellows were having their dinner and a woman had a sudden attack of seizures. She was immediately taken to a local hospital where a turban-wearing doctor appeared, followed by a long queue of assistants. They weren’t that confident in the physician’s skills but they had to change their minds: first because Doctor Turban had a PhD from Harvard university and he instantly recognised that woman were suffering from falciparum malaria. Narrow-minded Europeans!

While your family doctor treats a huge number of patients with flu, African and Asian physicians have to do with many cases of malaria on a daily basis.

But, maybe, I shouldn’t be that happy anymore. You see Global Warming messes up the climate. When the climate changes the ecosystem is deeply affected. So, within few years there’s a chance you’ll be able to try delicious Italian bananas, as the weather conditions are becoming perfect for this kind of tropical fruit.
By the way, this doesn’t apply to plants solely. Insects, viruses, bacteria and algae need particular temperatures and weather conditions, which they begin to find in new areas.

This means that Global Warming is bringing back here diseases we thought to belong to the past or new ones, for which we have no preparation or practical, clinical experience.
Malaria, for instance, could be the first, as the WHO have recently declared.
Reading articles like this, I feel it’s time to start, every so often, to talk about pathologies we know little about.
Did you know that 200,000,000 people are thought to suffer from malaria? Did you know that only the female Anopheles mosquitoes are the vehicle of the four types of protozoa? Four protozoa, each causing a different kind of malaria: there’s Plasmodium falciparum, the deadliest, P. vivax, which is responsible for benign tertian malaria, P. malariae, quartan malaria, and P. ovale, the least common. The expression tertian or quartan comes from the frequency of merozoites release from red blood cells: every 48 hours for tertian forms and 72 for quartan.  

That release is characterised by convulsions, high fever, haemolytic anaemia. Long term consequences include brown skin pigmentation and splenomegaly, on the other hand.

Some, at this point, will point out that, as this disease was somehow limited to Africa and Asia, no one invested money in new drugs, although more people are killed by malaria than HIV every year. Hmmm, I agree with you: pharmaceutical firms, as well as researchers, have almost totally ignored this emergency.
So, unless a pharma company will foresee a massive outburst of malaria and come up with a new antiprotozoal drug, we will have to go on with those we have at the moment.

At least, old as they are, they are cheap and we know everything about their adverse effects. Chloroquine causes pruritus, headache, anorexia, blurred vision, hypotension, hearing problems, confusion and other, less frequent, things.
Quinine leads to cinchonism (tinnitus, headache, visual disturbances), haemolysis, leukopenia, thrombocytopenia.
Mefloquine has neuropsychiatric toxicity and alters cardiac conduction.
Primaquine is linked to haemolysis and cyanosis and, moreover, it’s contraindicated to people with a history of granulocytopenia and methemoglobinemia.

You'd better get used to them...

Now, it’s the summer, which means there’s a very simple way to recognize someone who is preparing exams at the moment: paleness. If someone is bronzed, it can’t be a student, that’s for sure. On the other hand, a pale, grey, autumnal skin colour usually stems from spending most of your day studying (unless you’re a multi-millionaire and can do it in the garden of you huge mansion: if that’s how things are, would you mind inviting me?).

Because I’m obviously among the latter, I want to be mean and chose to write a post about the danger of lying in the sun and skin tumours, in particular.

Basal cell carcinoma is probably the least severe skin cancer, considering its growth rate and the incredible low propensity to metastasise. Still, it’s the most common (75%) and can lead to clinically relevant outcomes, such as ulcerations or invasions of bone and facial sinuses.

The link with sun exposure, in this case, is particularly evident, as it develops mainly in lightly pigmented people (black people are almost completely immune) and only in those parts of the body which are highly exposed to sunlight.
UV-light, in fact, can easily damage DNA, yielding, for example, thymine dimers which are particularly vicious for a cell if its repair systems don’t recognize such a distortion.

Interestingly, while in the past its incidence was greatest in the seventh or eighth decade of life, these days (partly due to the increasing popularity of sun beds) people in their thirties and forties are subject to this tumour.

Histologically,  neoplastic basal cells exhibit either multifocal growth (spreading on the skin surface) or nodular, downward growth (affecting the inner dermal tissues).
Clinically, telangiectasia (spider veins) is a distinguishing feature, appearing in the red, smooth papules which grow on the skin.

Squamous cell carcinoma is extremely common in elderly people. Not only does UV-light play a key role, but industrial carcinogens, arsenic, ionising radiations and xeroderma pigmentosum have great importance too.

Histologically, cells in the epidermis look weird and prone to spread into the basement membrane, where they often are characteristically polygonal, as well as rounded, and undergo keratinisation (up to clinically relevant hyperkeratosis, which marks the moment the tumour reaches nodular stage).
5% of squamous basal carcinomas result in metastases, but that’s more due to the quick diagnosis rather than a characteristic of the tumour itself. Generally, sharp plaques are a clear sign of the development of this pathology.

Finally, malignant melanoma is the least frequent skin tumour (5%), but it’s the one linked to the highest risk of mortality and its incidence has doubled in the last twenty years.

Oncologists spotted a trend for what concerns the hereditary component of this disease: the CDKN2A gene, which encodes for a cyclin-dependent kinase inhibitor, is mutated or methylated in a vast number of patients with melanoma.

The tumour grows radially, in the beginning, within the epidermis. Then, a vertical growth starts and, at this stage, nodules form, metastases tend to appear (although not clinically yet) and the tumour reaches the reticular dermis.
Generally, these cancers develops at already-existing moles, changing their colour, enlarging them and creating irregular borders.

That said, I’m looking forward to the end of all this and to the beginning of my holidays… 

 

Apparently, this summer I won’t go on holidays: first there are the last exams, which will last until the end of July, and then I’ll begin my internship, working at a chemist’, probably in August.

This means I may have only a couple of weeks left: the odds are that I’ll stay at my aunt's country house, where, unfortunately, there’s no internet connection (so, I’ll sort of hibernate this site) but, on the other hand, lots of silence, peace, lovely country roads for cycling and, above all, COUNTRY!

Long before it became cool to like nature and environmentally friendly stuff, I’ve always been incredibly fond of the country side. Actually, I feel it’s the ideal place, for me.
So, I probably ought to explain that, from now on, I’ll post, every so often, something about nature and pharmacology (or related subjects, like today).

Following the successful post about broccoli, today I’m to outline some of the most dreadful things you could find in agriculture: unless you are a mushroom hunters or you just cook every type of mushroom you could find anywhere, Micotoxins are a much more dangerous, and easy to be found, thing.

These toxins are naturally produced by a great variety of fungi. They look rather different from each other but they are all associated with threatening toxicity: cancer, teratogenesis, nephrotoxicity, skin toxicity, etc.

According to IARC, Aflatoxins, for example, are class I cancerogens. AFB1 is the most potent: it’s genotoxic and teratogen, its main target is the liver, where it causes acute toxicity (necrosis and haemorrhages) as well as chronic (cancer). Terrifyingly these toxins, synthesized by Aspergillus Flavus and Parasiticus, infect corn, wheat, spices and peanuts, which are eaten in great quantity by children. So those who are less able to detoxify these substances are exposed to great danger.

These molecules are converted to the derivative epoxide, which binds covalently to the DNA and proteins.

Ochratoxins are synthesized by Aspargillus and Penicillum and contaminate primarily corn, beer, coffee and cacao. And wines from Apulia.

Teratogen, immunotoxic, nephrotoxic, this substances are responsible for Balkan endemic nephropathy in cattle and urethral cancer in human beings.

They  tightly bind to albumin and are metabolised by cit. P450: their active derivatives cause lipid peroxidation, through oxidative stress and enhanced iron(III) reduction, inhibit the synthesis of phenylalalnine, impair mitochondrial metabolism and calcium homeostasis.

To sum up, Ochratoxins inhibit carrier proteins, reduce ATP levels and alter cell membranes morphologically.

Fumonisin are mycotoxins synthesised by Fusarium, which can infest corn, wheat and fodder (this often results in dramatic magnification of Fumosins at every step of the food chain).

Horses can develop equine leucoencephalomalacia after eating contaminated food, rats show clear signs of hepatotoxicity and hepatic cancer, pigs can suffer from pulmonary edema.

On human beings, these toxins lead to fetotoxicity (suppressing the normal bone development and growth), inhibit N-acetyltransferase (impairing cellular differentiation and growth), alter the incorporation of palmitic acid and reduce physiologic levels of cholesterol (making the cell membranes less fluid).

Trichothecenes are produced by Fusarium and Cephalosporium and infect, mainly, wheat. They act primarily on the gastrointestinal and haematopoietic system: weight loss, necrosis of lymphoid tissue and bone marrow, thymus atrophy and non-regenerative anemia are the most common pathologies caused by these toxins.

Generally speaking, it’s impossible to get rid of all these mycotoxins or just reducing their concentration: every step of the manufacturing process could increase their levels and this is an irreversible phenomenon.
All we can do is to maintain their concentration from the beginning to the end of the process.

That’s why, when it comes to mycotoxins, we stick to the so-called ALARP (as low as reasonably practicable) safety-standard: given that we can’t remove them, all we can do is to keep them below a reasonably low level, so that the risk could be statistically irrelevant.

Actually this particular case is an extreme example of ALARP: no matter how carefully the material is manufactured, there will always be a (remote) risk.

Still, we can and must do a lot to protect our harvest: some genetically modified plants are resistant to fungi, stress should be kept to a minimum, drying has to be performed right after the harvesting and the crop should be stored in a low humidity and temperature environment and under controlled atmosphere, in anaerobiosis, employing antioxidizers and preservants.