Breaking Bad

Clever chemists can create designer drugs far more quickly than a government's drug enforcement agency can identify them, get them classified as illegal drugs, and begin to control their illegal distribution.

“Manufacturers turn these things around so quickly. One week you’ll have a product with compound X, the next week it’s compound Y,” said forensic toxicologist Kevin Shanks of AIT Laboratories, an Indiana-based chemical testing company.

“It’s fascinating how fast it can occur, and it’s fascinating to see the minute changes in chemical structure they’ll come up with. It’s similar, but it’s different,” Shanks continued. _Wired

Some of these drugs are very dangerous to particular persons who may use them, or be around others who are using them. Others may be generally benign -- but government agencies and their evolving penalties for sale and use of these designer drugs, are unlikely to be able to distinguish between the bad and the indifferent. Likely result: A lot more people in prison for questionable offenses.

via Wired

Fattore, whose research specialty is cannabinoids and the new wave of THC mimics, says the new drugs often contain unpredictable mixes of these extra-potent compounds. The same goes for synthetic stimulants and dissociatives.

In a May 14 Journal of Analytical Toxicology study, Shanks’ team described AIT’s tests of legal drugs purchased since the Drug Enforcement Agency’s 2010 bans of three synthetic stimulants and five synthetic cannabinoids.

A full 95 percent of the products contained compounds not covered by the law. They’d been subtly tweaked so as to possess a different, legal molecular form while performing the same psychopharmaceutical role.

“If you want any evidence that drugs have won the drug war, you just need to read the scientific studies on legal highs,” wrote Vaughan Bell at MindHacks, a neuroscience blog that’s covered legal highs in depth.

While it’s conceivable that laws could be adjusted to reflect each new ingredient, it would be highly impractical: Between 400 and 450 compounds were synthesized by Huffman alone, and those represent just one of four major groups of cannabinoid mimics.

Stimulant and dissociative derivatives are less numerous, the portfolio of possible derivatives still includes hundreds of forms. A compound-by-compound pursuit could last for decades. _Wired

Why do chemists go to so much trouble to generate such a wide range of designer drugs, when most of them are likely to be crap? Because a lot of people will do almost anything to get high, and governments have made it a criminal offense to get high on relatively safe drugs.

You know where all of this is going to lead? Gene-engineered food plants that produce opium, cocaine, hashish, and any number of other potent drugs -- inside beans, cucumbers, and potatoes.... Try regulating that!

Of course we are likely to move quickly to more refined types if "highs" such as electromagnetic brain stimulators, intense high resolution virtual realities, and other ways to generate thrills, chills, and unimaginable pleasures, which will ride the photons far beyond the control of drug enforcers.

People want to get high. Other people will bend or break the rules to help them, for a price. The profits from the breaking of the rules make their way back to drug enforcers, judges, lawyers, elected officials, respected bankers, etc. In fact, societies that try too hard to regulate every action of their citizens end up being corrupted, perhaps beyond repair. It is such societies as a whole that are breaking bad.

Human Rationality Has Designs on Itself

Human rationality -- such as it is -- seems to be looping back upon itself. It looks as if the human brain may become the beneficiary of "rational drug design." The methods of rational drug design are advancing by leaps and bounds, so that we should expect some significant benefits quite soon.  Researchers at Tel Aviv University are focusing rational design to create drugs for Alzheimer's, Parkinson's, and Huntington's diseases.

Since Prof. Eldar-Finkelman linked GSK3 to insulin resistance in diabetes more than ten years ago, a race has been on among drug manufacturers to find a drug that can potentially turn off the harmful effects of GSK3. But rather than build on existing drugs, Prof. Eldar-Finkelman and her colleagues worked from the ground up. "I decided to take a completely different approach from all the big drug companies rushing to find the ultimate drug," says Prof. Eldar-Finkelman. "I designed my own."

Pre-clinical results have been positive, and the new drug does not exhibit dangerous toxic side effects, a problem with existing formulations. While L803-MTS cannot reverse the onset of a CNS disease once it has started, Prof. Eldar-Finkelman believes it can slow down the devastating effects of CNS diseases, like impaired memory and depression, or insulin-resistance.

"Ours is the first lab that showed the importance of GSK3 as a target in Type II diabetes, and was among the first to introduce a specific inhibitor against the GSK3," she says. "Our approach became so popular that today many pharmaceutical companies, big and small, are competing to work on a GSK3 inhibitor."

..."One important thing to note is that our drug acts differently than other compounds," she says. "Most GSK3 inhibitors are developed on the basis of ATP competitors. Ours are substrate competitors, meaning that they bind to a different site at the surface of the protein. This strategy is completely different, and yields a better and safer compound."

Prof. Eldar-Finkelman is now conducting additional pharmacological and toxicological tests on the new compound. She believes it will be a lead compound for treating CNS disorders, "because it was based on rational drug design. We started from scratch and thought through the design of a specific compound that would be safe and effective. Our aim is to slow the progression of CNS diseases, but the new drug might also be used as a preventative therapy," she adds. _SD

Rational drug design has come a long way in the past 10 years since Vertex began making waves. Advances in protein simulation, protein imaging, atomic force microscopy, haptics, bioinformatics, and other tools of research are allowing researchers to bypass tedious approaches such as "rapid screening" in order to aim directly at a drug target. Of course it is never really "either-or." In the end, many more tools will be developed, and all of the tools will be used to get us where we wish to be.

Another Revolution in Pharmacology

Research into the effects of melanocortins is incredibly exciting in its potential to revolutionise medicine. Here are a few of the effects of melanocortin peptides on the brain:

Induction of spontaneous penile erections
Increase of [sexual] proceptivity and receptivity (in females)
Increase of motivation
Increase of attention
Improvement of short-term memory
Increase of visual retention
Lowering of auditory, gustatory and olfactory detection thresholds
Functional antagonism of opiate effects
Inhibition of feeding (satiety-inducing effect)
Antiinflammatory effect (sites of action: brain and immunocytes)
Antipyretic effect
Reversal of hypovolemic hypotension
Reversal of shock
Resuscitation after prolonged asphyxia
Improvement of recovery after traumatic brain lesions and spinal cord injuries
Delay of the aging-linked behavioural deficits
Beneficial influences in neurodegenerative disorders
Increase of regenerative capacity of peripheral nerves in postlesion repair
Improvement of diabetic and toxic neuropathies
_Pharmacological Research

Like I say, those are a few of the effects that have been discovered so far for the melanocortins (melanocyte stimulating hormones [MSH], ACTH). New drugs which can either block or stimulate these hormone receptors will likely revolutionise treatment for:

1. Alzheimer's and other neurodegenerative disease
2. Stroke
   
3. Diabetic Neuropathy
4. Hemorrhagic Shock
5. Sexual Dysfunction for males and females
   
6. Obesity
7. Anorexia and Cachexia
8. Depression
9. Anxiety
10. Various learning disorders

...and quite a few things more. It is only in the past decades that scientists have been able to distinguish different receptor types for the many peptides and neurotransmitters affecting the brain and nerves. Now, it looks like nothing can stop the steamroller of biomedical and biotech research -- except perhaps bad government that wastes precious resources on policies that have failed for many generations.

If you have an interest in any of the listed diseases or hormonal effects above, visit the linked article and skip down to the section that interests you particularly. It is a long review article that covers a wide range of effects and potential therapies. I strongly recommend learning to read scientific articles -- despite their dryness -- because any person who can draw meaning from the early stages of research can often see into the future, and profit from that vision. If you wait until "science journalists" spell it out and dumb it down for you, it may be too late.

When the baby revolutions of nanotechnology, biotechnology, information sciences, and cognitive sciences begin to grow up and converge, you will begin to understand how quickly things can change.

New Alzheimer's Treatment Approach

An excess of Beta amyloid protein in Alzheimer's patients leads to amyloid plaques and eventual neuronal death. One new approach to treating Alzheimer's is to block the enzymes that cleave the longer protein "APP" into Amyloid Beta, or A Beta.

The molecule, called a beta-secretase inhibitor, prevents the first step in a chain of events that leads to amyloid plaque formation in the brain. This plaque formation creates fibrous clumps of toxic proteins that are believed to cause the devastating symptoms of Alzheimer's.

The study of 48 healthy volunteers showed dose-related reduction in plasma amyloid beta, a protein believed to be a key biomarker of Alzheimer's. Results showed a single dose of the drug produced a greater than 60 percent reduction of the biomarker. Subjects received one of six different doses or a placebo, and the study measured levels of the therapeutic drug and levels of the biomarker in the bloodstream.

"The phase I clinical results are very exciting," Ghosh said. "We hope that this beta-secretase inhibitor drug will be one of the first disease modifying treatments that stops or reverses the symptoms of Alzheimer's disease."

Science Daily

Several new approaches to Alzheimer's treatment are aimed at the A Beta protein--either in preventing its overproduction, or in speeding its elimination. Here is an interesting approach--a vaccine against Amyloid Beta. These approaches have the potential to prevent the onset or full manifestation of Alzheimer's, once diagnosed or strongly suspected. Better screening tests and genetic tests should allow good selection of candidates for various primary and secondary preventive strategies.


Image credit

Wake Up! Hypocretin 1 Makes Sleep Optional

Orexin A (hypocretin-1) is a peptide hormone that according to recent research has the ability to keep monkeys awake. Now the US Military is attempting to show that it can do the same for humans.

Orexin A is a promising candidate to become a "sleep replacement" drug. For decades, stimulants have been used to combat sleepiness, but they can be addictive and often have side effects, including raising blood pressure or causing mood swings. The military, for example, administers amphetamines to pilots flying long distances, and has funded research into new drugs like the stimulant modafinil and orexin A in an effort to help troops stay awake with the fewest side effects.

...The research follows the discovery by Siegel that the absence of orexin A appears to cause narcolepsy. That finding pointed to a major role for the peptide's absence in causing sleepiness. It stood to reason that if the deficit of orexin A makes people sleepy, adding it back into the brain would reduce the effects, said Siegel....Any commercial treatment using the substance would need approval from the Food and Drug Administration, which can take more than a decade.Wired

What else can the orexins do besides help monkeys stay awake? Orexin reportedly also increases the craving for food.

Clearly there is a lot to be learned about the effects of these peptide hormones. This hormone has the potential to be a drug of abuse, if the FDA drags its feet too long.

Hat tip Impact Lab

Chimeric Mice Help in Drug Development

Chimeric mice developed with human liver cells growing inside mouse livers will prove to be valuable toxicity screens for pharmacologic development, improve understanding of infectious disease, and promote regenerative medicine.

The work, which will be published in this week's online edition of the Proceedings of the National Academy of Science also holds promise for a better understanding of infectious diseases that affect the liver. "It is basically impossible to grow human hepatocytes in the lab, which was a big hurdle for the study of viruses such as hepatitis A and hepatitis B," says senior author Inder Verma, Ph.D., a professor in the Laboratory of Genetics.

But most importantly, Bissig says, the mice will be an invaluable tool to advance regenerative medicine. "Many inherited disorders affecting liver metabolism could be cured if only five percent of all hepatocytes would express the missing enzyme," he says.

Salk Institute

Hat tip Medgadget

Replicator! Yes Captain? Replicate 50 Grams Globamycin Immediately!

Researchers at Scripps and Harvard have taken the early conceptual steps necessary to create an antibiotic replicator, for rapid synthesis of potentially lifesaving drugs.

“This study may signal the start of a new era in how drugs are synthesized,” said Moore, a professor in the Center for Marine Biotechnology and Biomedicine at Scripps. “Assembling all the enzymes together in a single reaction vessel is a different way to make a complex molecule.”

While much more work is needed to employ this process on a mass scale, the achievement proves that such synthesis is possible relatively cheaply and easily—without the use of man-made chemicals.... The antibiotic synthesized in Moore’s laboratory, called enterocin, was assembled in approximately two hours. Such a compound would normally take months if not a year to prepare chemically, according to Moore.

Rather than a “eureka” moment that led to the breakthrough, Moore said the process was achieved incrementally. The time-consuming work was spent beforehand identifying and preparing the enzymes that would ultimately catalyze the synthesis, also known as assembling the “biosynthetic pathway.”

“We’ve been preparing for some time now a ‘biological toolbox,’” said Moore. “In this new process the enzymes become the tools to do the synthesis.”

....The new research also carries the potential to combine certain natural enzymes to produce new molecules that typically cannot be found in nature with the goal of developing new drugs. Moore calls these “unnatural natural products.”

Physorg

Medical workers and replicators could be airlifted into remote areas in case of mass casualty epidemics. Rapid testing of body fluids from victims allows the medics to quickly set the necessary enzyme pathways and potential resistances. In short order, lifesaving supplies of exactly the right drug are being replicated from raw material. Backup replicators can be set for auxiliary treatments as needed.

For now, this type of tool will be developed in research labs, to facilitate commercial drug synthesis and other chemical synthesis techniques. Researchers will be able to play with this tool for quite some time.

Pharmaceutical Innovation--Squeezing the Last Bastions

For several years, analysts have warned about the decline in innovation in the pharmaceutical industry. When profits of drug companies are held artificially low by government regulation, there will be less money available for R&D.

# For over 100 years, Europe has been a powerhouse of pharmaceutical progress and innovation. Over the last decade, however, Europe has gradually lost its leadership in the pharmaceutical sector, with a steady transfer of its R&D to the US - where policies and market conditions are more favourable to pharmaceutical innovation.
# Key benchmarking indicators show that between 1990 and 2002, R&D investment in United States rose more than fivefold, while in Europe it only grew 2.5 times.
# In 1990, major European research-based companies spent 73% of their worldwide R&D expenditure on the EU territory. In 1999, they spent only 59% on the EU territory. The USA was the main beneficiary of this transfer of R&D activity.
# The latest data on new molecular entities (period 2001-2005) show the predominance of the US which has now become the leading inventor of new molecules in the world (61 against 51 for Europe)
# The top 20 companies worldwide shows the leadership of US companies. In 2005, nine (9) of the top 20 pharmaceutical companies in the world are of American origin (against 8 for Europe).
# US companies significantly increased their share in the world's top selling medicines. On the top 30 worldwide products in 2005, 21 originate from the US against 8 from Europe.
# US companies are more successful in disseminating their new medicines at international level: 70% of the sales of new medicines launched on the world markets during the period 1998-2002 were made in the US, compared to only 18 % in Europe.
# Whereas the European pharmaceutical market was still the world's largest market in 1990 (representing 37.8% of the world market), it now only represents 30% of the world market (compared to 47 % for the North American market).

Source

There is much more at the source above. Andrew Sullivan and Kevin Drum have been sparring about this issue recently. The basic gist of their argument is that Sullivan wants to keep US politicians from recapitulating the failures in Europe. Drum seems to want to copy Europe's approach exactly.

Government regulations and controls often bring many adverse consequences to a financial market or industry. For those who are committed to ever increasing government control over the marketplace, these adverse consequences are easily ignored and denied.

Economies are like biological ecosystems. It is easy to "overcontrol" an ecosystem, resulting in loss of vitality and diversity. The same is true in economic systems.

Socialists will never understand the issue, because ever increasing control of society is a socialist's lifeblood. For Europe, it may be too late. For most of the Anglosphere, there may still be some time.