Drugs and addiction

Fly agaricMany people in the modern Western world delude themselves that their culture is generally free from the effects of intoxicating substances except in the criminal underworld, and that ‘nice people don’t take drugs’. But Richard Rudgley of the University of Oxford, a researcher of the oasis communities of Chinese Central Asia, shows that our culture and other cultures across the world have a rich tradition of using chemicals, mainly from plants, to produce altered states of consciousness. These range from the ritualistic use of the fly-agaric in Palaeolithic Europe to betel-nut chewing in Papua New Guinea, and from pretentious bone-china tea sets in Surbiton to the tragic inhaling of petrol fumes by Aboriginal Australians.

Although each intoxicant has its own effects on the mind – there is some overlap – but researchers have classed them as belonging to four types. Hallucinogens – compounds such as mescaline – are often found in ‘poisonous’ varieties of mushroom or South American weeds. Inebriants consist of generally simpler organic compounds such as alcohol, and the constituents of organic solvents and other volatile chemicals. Hypnotics are compounds that induce states of sleep, stupor or calm and include tranquilizers and narcotics. Stimulants increase mental activity and include caffeine, tobacco and the more potent cocaine and amphetamines.

Rudgley has scoured the scientific literature for examples and evidence from the European Stone Age to modern day Australia to improve our understanding of how these broad classes of intoxicants have affected society and religion. Beginning with evidence from the earliest days of hallucinogen use in Palaeolithic cave art, Rudgley describes in fascinating detail intoxicants and their cultural effects over the past few thousand years.

For example, peyote, the mescaline-containing cactus of Texas and Northern Mexico, apparently played an important role in the cultural development of indigenous peoples of that area, although the plant is now threatened with extinction because of increasing use by modern hedonists. On the Steppes biochemical evidence shows that Cannabis sativa and ethanol have been commonly used for many thousands of years.

Rudgley even has an explanation for the supposed flight of witches and the symbolism of the witch’s broom. A witch wanting to ‘fly’ to a witches’ sabbat, or orgiastic ceremony, would anoint a staff with specially prepared oils containing psychoactive plant matter, as well as rather gruesome ingredients such as baby fat and human blood. The potion could then be administered to areas of the body that could absorb the active components most rapidly. Rudgley quotes one researcher: ‘The use of a staff or broom was undoubtedly more than a symbolic Freudian act, serving as an application for the atropine-containing plant to the sensitive vaginal membranes. . .’ So now you know.

There is little spiritualism attached to the modern Western use of intoxicants such as caffeine and nicotine, and society more than frowns on the use of mind-altering drugs. The modern view is perhaps distorted to some extent by the development of highly addictive stimulants such as ‘crack’, with its potentially devastating effects.

Rudgley hopes that a deeper knowledge of intoxicants’ use in other cultures will result in a better understanding of our own culture of cafes and bars, and this in turn might help us understand the ‘importance of altered states of consciousness in both our collective and our personal lives’.

I wrote the original version of this item as a book review that was published in New Scientist magazine (The Alchemy of Culture by Richard Rudgley, British Museum Press, reviewed issue 1909, p43).

The professional staff at an addiction treatment facility knows how to help a drug addict, so you can rest assured your loved one is in good hands.

Christmas rose and hellebrigenin

Structure of hellebrigenin

Members of the plant family Ranunculaceae are ever-popular at this time of year, especially in Europe, where the Christmas rose, Helleborus niger, is wheeled out as a natural decoration for countless households. Interesting then, that extracts of this plant have been used as a heart tonic in herbal medicine alongside the likes of digitalin (from foxglove) and strophanthin from the West African plant Strophanthus gratus.

H. niger contains various potent toxins in addition to cardiac glycosides helleborin, hellebrin and helleborein and saponosides and the ranunculoside derivative, protoanemonine. It was searching for information on the compound hellebrigenin (3-acetate) that brought one Sciencebase reader to this site, so here’s the structure of the molecule. This biologically active compound, which also goes by the name (3beta,5beta,14beta)-3,5,14-trihydroxy-19-oxobufa-20,22-dienolide, is a cardioactive steroid compound as well as having been demonstrated (in the 1960s) to have activity against tumour growth.

More on the Christmas Rose here.

Latest chemical discoveries

The latest bumper Xmas issue of Reactive Reports, actually the 61st issue I’ve produced for the site is now online. In this issue we cover:

photovoltaic power station 
Molecular Light Switch
– According to Nobel laureate Roald Hoffmann, “Nanotechnology is the result of the marriage of the synthetic talent of Chemists with a device-driven ingenuity.”

 Blood, Light, and Water – Two molecules that occur naturally in blood have been engineered by scientists from the UK and Japan to use sunlight to split water into hydrogen and oxygen.

stent and fastener Plastic Shape Shifter – Temperature-controlled “triple-shaped plastics” that can change shape from one form to another, then another, have been developed by researchers in Germany and the US.

Top Chemical Discoveries of 2006

My good friend Stu Borman and his colleagues at Chemical & Engineering News (C&EN) have come up with a fascinating mash up of the most important chemical discoveries of 2006.

First up, is the total synthesis of UCS1025A, this esoteric-sounding compound is actually a potential inhibitor of the enzyme telomerase, and the incredibly compact synthesis was achieved by Tristan Lambert and Samuel Danishefsky of the Sloan-Kettering Institute for Cancer Research and Columbia University (J. Am. Chem. Soc. 2006, 128, 426). Inhibiting this enzyme could retard the growth of tumours.

Another synthesis published in JACS is second in Stu’s list. The scheme comes from Elias J. Corey’s group at Harvard University and represents a cheaper and faster way to construct the flu drug oseltamivir phosphate, better known as Roche’s antiviral Tamiflu (J. Am. Chem. Soc. 2006, 128, 6310).

Another synthetic achievement this year is the construction of the compound 2-quinuclidone by Brian Stoltz and Kousuke Tani at California Institute of Technology (Nature 2006, 441, 731). A quick glance at this simple-seeming structure might have you reaching for your Merck Index thinking that surely it must have been synthesised decades ago. But, no, this is the first synthesis of this bicyclic. Their synthetic scheme may provide new insights into biological amide hydrolysis as well as representing a rather aesthetically pleasing synthesis.

You can read about the other syntheses picked out by Borman and his colleagues in C&EN.

Also on their list is research at the frontiers of carbohydrate chemistry, where researchers have developed a high-throughput technique for screening mutant glycosyltransferases (GTs) for biomedical activity. The work could lead to a new generation of designer sugars for a range of medical conditions. Advances in structural biology (chemistry by any other name) achieved Nobel status this year, and crystallography also produced some amazing results in revealing the structure of Dicer, an enzyme that initiates RNA interference (RNAi). Also in this field a new NMR technique, SAIL, on which I reported for SpectroscopyNOW earlier in the year, could revolutionize solution structure determination of proteins.

Molecular biology (also chemistry by another name) features in Borman’s round-up with researchers gaining important insights into the molecular mechanisms of cellular protein production, Alzheimer’s disease, and RNA interference.

In the field of analytical chemistry, a new approach to nanoscale secondary ion mass spectrometry (nanoSIMS) was developed for imaging lipid bilayers at below 100 nm resolution and computational chemistry produced a 3000-member family of artificial cytochrome P450 enzymes for studying how these enzymes metabolize drugs and toxins.

In inorganic chemistry, says Borman, researchers produced previously elusive molecules and atoms, such as P2. Nuclear, polymer, and space chemistry also feature in this year’s round-up as does nanotechnology, not surprisingly.

But, one highlight of the chemical year not mentioned in C&EN, but certainly on my list was the culmination of work at a small laboratory in Northern Ireland that has led to the maturation of work I first wrote about for New Scientist back in the early 1990s and that has now, in its teens, reached a level of application its detractors said could never be – AP de Silva’s research on molecular logic.

Marrying up lost chemistry and chemists

British-born Dick Lewin Wife followed a traditional educational path, receiving his chemistry first degree from the University of Leeds in 1969 and staying on to do an organic PhD with David W. Jones. Research fellowships then took him to London, New York, and finally California, after which he returned to a job in the UK with Shell in 1976, moving to The Netherlands with the company in 1979. He stayed with Shell until 1987 at which point he founded SPECS and BioSPECS BV, in The Netherlands. In 2005, he co-founded a new company, SORD, which aims to find “lost chemistry” and make it accessible to the scientific world.

Read the full story in the latest issue of Reactive Reports online now.

Sniffing out our sense of smell

How we smellOur sense of smell is much better than we give it credit for. A report in Nature Neuroscience puts paid to the notion that the human reputation for having a poor sense of smell compared to other animals.

Noam Sobel and colleagues laid down scent trails in a grassy field, and asked human subjects to find the trail and track it to the end. Subjects were blindfolded and wore thick gloves and earplugs to force them to rely exclusively on smell. Contrary to expectations, the volunteers exhibited some of the same tracking strategies used by dogs and were certainly capable of following the trail.

In follow-up experiments, the authors also demonstrated that this ability partially depends on comparisons of odour information in each nostril, it’s almost like smelling in stereo.

When subjects had one nostril plugged their tracking performance was much worse.

Admittedly, the volunteers were much slower than dogs at following the scent trail, but with practice they got quicker.

the findings raise the intriguing possibility that our sense of smell is far better than we think and that using it more effectively is simply a skill we don’t teach our children so it gives us the impression that we don’t have it.

For more on a provocative theory of how we smell check out this page from the Sciencebase archives.

Influenza’s long tail

A long protein tail found in all influenza A virus raises the possibility of novel drugs that can grab on to it and stop the virus in its tracks. The protein tail is present in common human influenza A which kills thousands of people every year as well as rare forms such as bird flu.

US scientists used crystallography to study the long flexible tail of the influenza virus’ nucleoprotein. They found that even seemingly insignificant changes to the structure of this protein tail prevent it from fulfilling a key role in viral replication. That is, they prevent them from linking together to form structural columns used by the virus to transmit copies of itself.

More…

Flu mechanics

With the holiday season almost upon us, that means only one thing, flu is also on its way and if the scaremongers are to be believed the long-forewarned bird flu epidemic might follow in its wake any time soon.

Now, US researchers have put to work the 15-ton 900 MHz NMR machine at Florida State U to help them figure out the mechanics of infection by influenza A virus. The common human form of the disease already kills several hundred thousand people every year, and forecasters predict the emergence of a human transmissible form of avian influenza could kill millions more.

“Using NMR helps us build a blueprint for a virus’s mechanics of survival,” explains FSU’s Tim Cross, “The more detailed the blueprint, the better our chances of developing drugs capable of destroying it.” The researchers have found that the virus’ protein coat contains channels that control various biochemical reactions crucial to viral infection and replication.

Read on…

Emerging environmental contaminants

Lake ContaminationMore than forty research papers highlight the effects of emerging contaminants on human health and the environment in the December 2006 issue of the journal Environmental Science & Technology, among their number are reports on nanoparticles, pharmaceuticals, disinfectant by-products, and fluorochemicals.

“It might be tempting to define emerging contaminants as one thing or following certain criteria but it’s not that simple,” says the journal’s guest editor Jennifer Field of Oregon State University. The following Spotlight editorial reveals some of the issues and diversity of materials studied as well as highlighting a significant technology that might allow decontamination for certain materials to be carried out. An audio summary from the journal’s editors is available as an mp3 download courtesy of ES&T.

Read the full article under Intute’s Spotlight

Cholesterol drug withdrawal

According to the FierceBiotech pharma newsletter, Pfizer has been forced to halt development of its cholesterol drug Torcetrapib. The report says that the Data Safety Monitoring Board recommended the withdrawal of the drug from trials because of an “imbalance of mortality and cardiovascular events”.

I presume that’s management speak for “too many patients were having heart attacks and dying”.

The drug was set to become a Pfizer blockbuster, although I’d have hoped the marketing people would have come up with a snappier name before it went to market. “Based on all the evidence we have seen regarding Torcetrapib and in light of prior study results, we were very surprised by the information received from the DSMB,” the company stated. The DSMB has privileged access to the blind trials information so that it can make such decisions in the public and patient interest, but Pfizer claims the announcement was “totally unexpected and disappointing”.

The drug was set to replace Lipitor, a $12b a year blockbuster the patent on which is soon to expire. The FB newsletter says, that Pfizer “continue to invest in a wide range of pipeline opportunities across a diverse range of therapeutic areas.” Which, I presume, is management speak for “back to the drawing board”.

Apparently, just two days before this withdrawal, the company was enthusing about its benefits? Should we be policing drug trials even more stringently than we are now to prevent products getting so far before it is discovered there are serious issues with a particular trial?