Still hung over and just finished watching the 50s version of Alice In Wonderland. Ahhh, procrastination... 19 hrs ago
Any hardcore chemists out there might be interested in this paper, published in Organic Letters by a team of researchers from Niigata University. It details the synthesis of one of nature’s craziest compounds, Salvinorin-A, found in Salvia divinorum.
For a bit more background and pharmacology, you might want to check out my Salvia presentation.
Interesting stuff!
Don’t worry though! Our awesome Smoking Mixtures do the trick and are totally legal!
According to our government, amphetamine (speed) is as bad for us as cannabis – what other message could reclassification send?
Your typical cannabis smoker tends to
Your typical whizzkid tends to
*Not literally
I’m not necessarily knocking amphetamine or it’s users, just pointing out that drugs are a class apart. Oh no, wait.
Check out the (now out of date) graph below, placing drugs from most harmful on the left to least harmful on the right.
The score assigned to each drug takes into account harm to yourself and to society as a whole, and what’s that… alcohol and tobacco are more harmful than the class A drugs LSD and ecstasy! Considering that the link between cannabis and schizophrenia is as tenuous as ever (why isn’t the Netherlands one big psych ward?), why is our government ignoring it’s own scientists? Religion has more regard for evidence than Mr. Brown (and that’s saying something!) If you want to learn more about just how stupid our current classification system is, you can watch this episode of BBC’s Horizon, which tackles each drug in turn. (49 mins)
So, I’ve been playing around with Excel (read: procrastinating) a lot lately and produced these lovely looking graphs. Since they do look ever so lovely, and without revealing too much, I thought I’d post them here, along with a healthy dose of good advice. Also, the second two show the first month’s results from my little article experiment.
The X axis represents the months from Jan 2007 until Dec 2008. The extrapolated curves of best fit do not take into account December’s data.
I guess this first graph shows we’re here to stay – this is the number of orders placed with us each month. While the number of orders placed last month is a little lower than November’s data, this is consistent with most other e-commerce sites, who all see a slump in traffic (and sales) over the holidays. Who’d have thought people would prefer to spend time with their families rather than shop online? The same thing also occurs during December of last year. Still, not bad for a recession.
This graph shows overall traffic to the site. Internet marketeers may be interested to learn that the distinct peaks represent my limited foray into social bookmarking. Notice how the same months in the previous graph do not show any similar increases in the amounts of orders placed. This just goes to show that social bookmarking is shite for e-commerce.
One final point: traffic dropped significantly in December – far more than you’d expect over the holidays. Fortunately, this was exactly as I’d planned. December was when I moved all the old articles over to this blog, and articles are big traffic-generating machines. Take note, budding marketeers – article marketing can really drive traffic to your site! Compare the month of December on both graphs so far though – while traffic dropped significantly, the number of orders decreased only slightly. There are also plenty of other things you can do with old static content, so make sure you don’t let things stagnate.
This final graph shows each month’s conversion rate – that is, the percentage of visitors who go on to place an order. December’s data shows a significant increase as soon as I moved those articles, which just goes to show – traffic isn’t everything! It surprised me that before then, the conversion rate was still continually on the rise. I must have been doing something right. Unfortunately though, many, many things can affect your conversion rates, none of which have a particularly large effect. Here’s a great post on 108 ways you can increase your conversion rates.
There’s no doubt about it – our little hobby is kicking some ass, but it’s not all good news. More orders means more work, and right now me and my girlfriend are in the last term of our final year at university, so time is not something we have in abundance.
We might have to hire someone…
The most expensive part of growing Salvia Divinorum on a organic/semi-organic basis is actually buying a cutting or whole plant. I managed to get my plant for £12 including postage and packaging. After this follows compost and a suitable size pot.
There are many places to find salvia plants/cuttings, not only at local plant nurseries, but all over the internet; there’s at least one salvia plant on ebay at any one time. It’s worth noting that prices can vary significantly with little variation in quality, so make sure you shop around.
Try and buy a plant locally if you can. If not, definitely buy from a website based in your home country to minimise the time it spends in an envelope.
When your cutting arrives, remove it from it’s packaging extremely carefully and let it sit in luke warm water. Assuming your cutting already has roots, leave it in the water for a couple of hours. If no roots are present, leave it in the water for a week or so until there’s enough root growth present to allow for potting.
After it’s sat in water for a while, it’s time to plant it. You’ll need a pot at least 20-30cm wide to allow your cutting to grow without having to be repotted every couple of months. The first thing to do is place some gravel or broken crockery into your pot up to about 5cm from the bottom. This thin layer allows for superior drainage after watering. After that, fill the pot up with your loam based compost available from any gardening store and dig a little hole in the centre where your plant will sit. Next, take your cutting, splay out the roots gently with your fingers and place the cutting into the hole you provided. Backfill the hole with more compost and compress down lightly around the stem of your plant.
Travelling through the mysteries of the postal service and being stuck in some soil is thirsty work for a plant. Imagine you have been slaving away all day in the blistering sun, doing vast quantities of manual labour. How badly are you gagging for a pint at your local? This is how your plant is feeling right now. Although your plant needs a drink, don’t feel obliged to buy it any peanuts. Now your plant is potted, give it enough water so that excess water will drip from the bottom of the pot.
From here, I advise you to put the plant in a humid environment, at least at first, to promote healthy growth. Just like a fat kid loves cake, Salvia Divinorum loves indirect sunlight. This can be anywhere such as a light room with no direct sun blazing down on it all day, or even directly in the sun, but behind a net curtain. Provided your plant is not exposed to too much direct sunlight, it will do all right.
Leave it a few weeks and your cutting will start turning into a fully-fledged plant. Keep an eye on the compost, making sure it doesn’t dry up. Water once a week in summer and once every two weeks in winter. Just be careful to never over water your plant, or root rot could set in.
Growing an established plant is almost the same as growing a cutting. Salvia Divinorum can be very flexible about its growing conditions, but a quick change in conditions will most likely piss your plant right off. You have to consider that your plant has already been growing for probably quite some time in certain conditions, which it is now used to. These includes, but is not limited to, different light levels, compost, humidity, etc so it is very important to find out as much as you can about these conditions from the plant’s previous owner, then try to match those conditions as best you can. Once the plant has been repotted and is beginning to settle into it’s new environment, then you can slightly alter it’s environment a little each day until you have it growing in conditions easy for you to maintain.
The growth of the plant at first will be slow. Remember, it’s been shoved in an envelope for a few days with no light, so it’ll need to recover from that traumatic experience before it will even think about new growth. This can take up to around 2 weeks before any progress can be seen.
Look out for the leaves and edges of the plant turning brown, this means it is NOT in the right conditions. There are many things it could want, but chances are it’s something to do with humidity. Try misting the leaves if your environment is not very humid, or consider building a humidity tent or moving the plant into the bathroom, where people use the shower frequently. The stem, and possibly the leaves should return to normal in a couple of weeks. If not, cut the leaves off at the stem to facilitate new growth.
Sometimes the leaves might turn a yellowish colour. Never fear, it just means your plant could do with some more sun. This could be because other leaves on the plant are blocking out light, in which case, feel free to remove those other leaves and do with them what you will.
If your plant is wilting, it simply means it could do with more water. And if it’s bent, try rotating the pot 180 degrees. Plants will grow towards the sun, which could be causing the bowing in the stem.
Automatic Watering – One method for ensuring your plant always has enough water is by setting up a low maintenance automatic watering system. You’ll need some organic rope (NOT plastic), a drill and a tray. Firstly drill two holes near the base of your pot in the side and push your rope into one side and out the other. Make sure there is plenty of slack inside the pot. The next step is to pot your plant or cutting as described above, only this time, wrap the slack from the rope around the root system of your plant before you pack it out with soil. You should now have one plant in its pot with two bits of rope hanging down from either side. Finally, place a couple of bricks, a lump of wood, or some other object into your tray and fill the tray up with water. Place your pot onto the bricks, wood, or whatever and allow the two pieces of rope to dangle into the water. This will automatically deliver enough water to the plant all the time.
Pinching – Pinching is a method to promote bushiness and outward growth in your plants instead of growing too tall. At the tip of each branch, there is a section called the apical meristem. This is where all the new growth comes from and is responsible for regulating a plant hormone called indole-3-acetic acid (IAA). This hormone promotes the growth of the main stem and inhibits sideways growth from nodes along the stem. If this hormone weren’t present in the plant, it would grow outwards instead of upwards, so it follows that if you remove the apical meristem, this hormone will no longer be produced and your plant will bush out instead of grow tall.
When your plant has reached the desired height, cutting off the top of the main stem with a clean sharp pair of scissors will safely stop the plant from growing taller, while maximising leaf output.
Today, I thought I’d share another one of my essays I had to do recently. This one looks at animal testing, problems concerning species differences and what we can do to avoid them. This essay is a little more sciency than my other one on living forever, so I’ll include the references this time. Here goes:
The use of non-human animals in the drug development process can attract criticism due to the issue of species differences. How significant is this problem and what strategies can be employed to minimise the impact of species differences?
Animal testing is a major tool in the drug development process, required by law before any new drug can enter the market. Animal models are set up to not only test the efficacy of a compound for its intended effect, but also to observe any potential side effects, to calculate a safe dosage for humans and to check for any addiction potential. Although animal testing is a legal requirement, implemented for our own safety, it is still only a model; a substitute for human physiology, whose results could be completely erroneous if they were derived from a poorly planned experiment. Differences between species are always a concern when setting up an appropriate animal model, and a lot of time is spent agonising over them to ensure any results obtained are both accurate and applicable to humans. When it comes to experimental design, species differences can be broadly classified into the following categories: anatomical/physiological differences, differences in metabolism and subsequent toxicity, pharmacological differences and behaviour.
This is perhaps the most obvious class of species difference. It is no good testing a drug on an animal and looking for effects that are physically impossible for the animal to manifest. Any tests carried out on one species with implications for another must only test parts of the physiology common to both species, or identify an analogous symptom that corresponds to the effect you are looking for.
A prime example of this kind of difference crops up when investigating the emetogenic potential of a drug – unfortunately, evolution has not provided rats with a vomiting reflex, so an different model would have to be devised looking for an alternative behaviour or using another species with a physiology closer to ours.
Different species also metabolise drugs differently – either via different metabolic pathways or with different kinetics. As such, a drug toxic to one species may have little effect on another, which is particularly important when trying to determine the toxicity in humans. A drug’s LD50, the amount required to kill 50% of subjects in a particular sample, is usually given in mg/kg of body mass, scaled up from animal experiments. If a drug’s toxicity or pharmokinetics are only determined from one animal species and extrapolated for the average human, the data would not take into account any differences in metabolism that may be present, resulting in potentially extreme inaccuracies.
For example, dogs should never be given coffee or chocolate, as they are poor metabolisers of theobromine1, a xanthine alkaloid occurring naturally in both, as well as being a metabolite of caffeine. As little as 50g of chocolate can result in theobromine poisoning for small dogs, while humans can metabolise it fast enough without issue.
Similarly, metabolism of NSAIDs shows a huge variation across different species. The plasma half-life of aspirin ranges from 1 hour in ponies up to 37 hours in cats2, due to their poor glucuronidation ability, while dogs are more susceptible to aspirin’s gastrointestinal side effects3.
One final example would be the varying MPTP toxicity between species. MPTP can be formed as an unintended byproduct in the manufacture of MPPP, a synthetic opioid with great potential for abuse. MPTP on its own is not harmful, but MPP+, the natural metabolite of MPTP, is a potent neurotoxin. MPP+ is produced via MonoAmine Oxidase B in neuroglia and the capillary endothelia comprising the blood-brain barrier, and results in rapid-onset Parkinsonian symptoms barely indistinguishable from typical Parkinson’s disease4. These symptoms are also reduced by L-DOPA, a drug commonly used in Parkinson’s disease. Rats, however, are almost entirely immune to MPTP toxicity, most likely due to a different level of expression of MAO B5. Mice, on the other hand, do produce MPP+, but clear it from their brain in a matter of hours, unlike the primate brain, in which clearance can take days.
The chemical pathways and their associated protein machinery will not necessarily be structurally identical, or indeed act in the same way. Pathways may be more or less complex, depending on the species, with more or less scope for modulation by other factors. Receptors too may also differ in structure, ligand affinity and the type of G proteins they may couple with. All of these factors may be of huge importance when designing a drug with a particular molecular target in mind.
A few interesting cases have resulted from these types of differences. For a while, Leptin was theorised to suppress hunger, as knockout mice that did not express leptin or its associated receptor got fat. Giving leptin to those that could not express it themselves, but still possessed the appropriate receptor, caused them to lose weight6 – a potential gold mine if the results were also applicable to humans. Unfortunately, they were not. Leptin showed little effect in humans, as weight problems tended to concern signal transduction rather than a lack of leptin7, in much the same way as insulin-resistant diabetes.
Another, rather more serious example is that of TGN1412, a monoclonal antibody with not only a high affinity for the human CD28 receptor, but a strong agonist ability too. Originally intended to help patients with rheumatoid arthritis and B cell chronic lymphocytic leukaemia, TGN1412 was initially tested on animals and an apparently safe dosage calculated. Of the 6 volunteers hospitalised, each given a dose 500 times smaller than that given to their animal counterparts, 4 developed multiple organ failure as a result of cytokine storm8. Hopefully, this example highlights the importance of species difference; that it is a real issue and not just a theoretical concern.
The final category, and perhaps least obvious, is that concerning animal behaviour. Unfortunately for us, animals are not able to clearly express their feelings, so we are left to try and interpret that behaviour, which can be particularly difficult. Humans seem to have an intrinsic penchant for anthropomorphism – we are always unconsciously trying to attribute characteristics that are uniquely human, such as complex emotions or intention, onto animals and even non-living objects. Children are especially guilty of this, smacking a rock, perhaps, as a punishment because it tripped them up. It is only as we grow older and put in a little more thought that we realise that perhaps the rock was not to blame. With animal models, we must also put in that extra thought when it comes to interpreting an animal’s behaviour, instead of opting for the instinctive, humanised interpretation.
Other problems are encountered when we assume a particular behaviour is a result of a particular effect. For example, in the tail flick assay, designed to measure effects on nociception, analgesia is associated with an increased latency in moving the tail away from a heat source. Approving a new drug as an analgesic based on only this interpretation could be disastrous if the increased tail flick latency was instead due to a loss of muscle control or paralysis.
One final thought concerning animal behaviour, is that some behavioural responses may be unique to the species in question. For example, a hedgehog might curl up into a ball as a typical fear response. While this may be easy to interpret, other idiosyncratic responses may not.
A number of strategies have been devised for combating the issues species difference brings up, ranging from simple common sense to the rather more complex. An in-depth knowledge of the species under investigation is a good start. Experience and familiarity with a particular species will naturally lead to a better ability to read an animal’s behaviour, just as we become better at reading the people around us the longer we spend in their company. Someone new to animal work will be more likely to anthropomorphise, drawing instead from their experience with other people, whereas someone with ample experience could make a more accurate judgement. Another benefit from experience is that any of the more subtle differences between that species and us is more likely to spring to mind, reducing the risk of something important being overlooked. For example, rat models are a useful tool when studying the intestinal bioavailability of drugs, but are a poor choice when it comes to intestinal metabolism9.
Another strategy to reduce the risks imposed by any unknown or overlooked differences, and one that is required by law, is to test on more than one species. Doing so greatly reduces the chances that any observed response is unique to one species in particular, and is therefore likely to be exhibited by humans too.
Although there are an incredible number of individual species, some proteins remain relatively conserved. Working with these specific proteins that share a great deal of similarity between their human counterparts will likely lead to more reliable results. For example, the muscarinic receptor family has remained much the same throughout evolution such that the human and rat receptors share a very similar agonist/antagonist profile10. It is very likely that something acting on rat muscarinic receptors will elicit the same response in humans, making this an accurate model.
More recently, the latest tools and techniques of the genetic engineer promise to make animal models even more relevant. Genetic manipulation has already delivered knockout animals, not expressing particular genes, and transgenic animals, expressing genes belonging to another species, but in 2008 a chimeric mouse with 90% human hepatocytes (liver cells) was produced11. Until now, the best tool for studying the effects of drugs on the liver would be to use actual human liver (another strategy for overcoming species differences is to use human cells if possible), but the chimeric mouse has already shown great potential. The liver is mainly responsible for the pharmacokinetics of a drug, as it is the primary place that drugs are metabolised, which has subsequent effects on the toxicity and efficacy of that drug. The chimeric mouse has shown a similar pharmacokinetic profile to the human donor, as well as human-specific metabolites not ordinarily found in mice, making this an excellent model with which to study pharmacokinetics and toxicity. This advancement brings with it all the benefits of testing drugs on an actual human target, without any of the ethical considerations raised with human testing.
We humans are an animal species like any other, and we may have our own species-specific responses that are impossible to capture or anticipate with any animal model. It is important to remember that an animal model is just that – a model. Species differences will always be an issue; there are even idiosyncratic reactions to drugs within the same species, such as some humans being allergic to penicillin, so we can never eliminate these differences completely. Increasing research, awareness, criticisms from the animal rights campaigners and new genetic techniques will continue to help us reduce the severity of these issues until they can be reduced no further.
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