Measles On the Rise

Our greatest medical achievement is not open-heart surgery, not penicillin, but vaccination.  Everything else is a bandaid compared to the ability to actually prevent disease.  Smallpox ravaged communities until Edward Jenner developed a vaccine which has eradicated the disease and saved countless lives.  It became possible to immunize people from the deadliest pathogens on the planet.  Since that time, we can now prevent Small Pox, Chicken Pox, Tetnus, Diptheria, Whooping Cough, Pneumococcus, Hepatitis B, Measles, Mumps, Rubella, and even a vaccine against the cervical cancers caused by HPV.  Every year the number of deaths to preventable infectious diseases goes down.

Well, it did go down.  The CDC now reports that the number of cases of Measles has hit a 20 year high.  Ten years ago, measles was officially eradicated from the US (no transmission for 12 months).  Almost every case this year involves a person that was not vaccinated or without a vaccination history.  The same story happens for many of the diseases.  The high school I taught at was hit by Whooping Cough which is prevented by the P in the Tdap vaccination you should get every 10 years.  Thank fully the number of deaths stays low, because we do have the bandaids of modern medicine.  But eradicated diseases should not be making come backs.

I lay all of the blame on the Anti-Vax crowd.  Concerned that vaccinations, or the components within the vaccination, cause the cause of autism, Jenny McCarthy and others have led a crusade to scare people from vaccinating their children.  Somehow, it worked.  To some extent, their children are still protected from the worst diseases as smallpox and polio have been eradicated.  This is called herd immunity.  But some diseases still linger in the US from anti-vaxers and immigrants coming from places without vaccinations.  There is no evidence that vaccines cause autism.  None.  Well, there was one published paper, that the author had to retract as he admitted to cheating with the numbers.  So, we're back to none.

It is far better to prevent disease than to treat it.  From hand washing and sanitation, medical science finds ways to prevent diseases.  Vaccinations have been a successful part of that history.  More vaccines are introduced each year to prevent new diseases, to improve old vaccines, and to make administration easier without needles.  I know the anti-vaxers mean well, but they have been fed false information.  Which is the hardest kind to refute.

Buying Drugs on Amazon

Apparently, it is pretty easy to buy medications on Amazon.  Ford Vox wrote on Slate about his wife's purchase of prescription medications on the world's largest online retailer.  Everyone know that drugs are expensive.  Unfortunately, many patients fail to treat their disease states because they can't afford the therapy.  Some places off discounts on generics and manufacturers offer some assistance, but you have to qualify for these programs.  Buying from Canada could be an option for desperate patients, but the action is illegal.  Apparently, some people have turned to Amazon for help.  Keep in mind that the process is also illegal.

When looking for an acne treatment, Vox's wife recieved a product from Thailand that contained a major antibiotic called clindamycin.  Highly regulated, use of clindamycin brings about worries of C. diff infections, Stevens-Johnson Syndrome, and general antibiotic resistance.  I did a quick search and found prednisolone, a potent steroid.  He also found the antibiotic norfloxacin and muscle relaxant methocarbamol.  This is a very dangerous situation for peddling pharmaceuticals without a license.  The FDA is now getting involved and seizing such packages at the international ports.  Hopefully, they can get Amazon and other retailers to stop selling these things.  But it will probably be a long fight through the legal system.

Intranasal-to-Brain Drug Delivery - A Review

Neurodegenerative diseases impact the lives of patients and their families.  As the brain slowly deteriorates, patients lose control of their bodies, thoughts, and ultimately succumb to the disease.  An aging population generates a higher incidence of Alzheimer’s disease, Parkinson’s disease, and other neurological disorders.  Concurrently, the rise of Autism Spectrum disorders has become an interesting area of potential research.  As of now, neurological medicines only treat the symptoms and rarely address the root cause – dying or misfiring neurons.  Getting drugs into the brain has proven a difficult task because of the impermeable blood-brain barrier (BBB).  Newly developed tools circumvent the BBB by going through the nose.  Intranasal-to-brain (INB) delivery provides a hopeful avenue to slow, treat, and prevent the progression of the diseases of the central nervous system (CNS) with greater efficacy, less invasion and reduced toxicity.  Medical professionals should recognize the difficulty of delivering drug to the brain and the need for easier, direct route such as nasal administration.

The Blood Brain Barrier

As the controlling organ of the body, the brain is locked behind two major defense mechanisms.  The cranium provides a hard case that limits access to only highly invasive techniques that inject drugs through the skull directly into the parenchyma or cerebrospinal fluid.  The BBB internally protects the CNS from potentially damaging foreign chemicals travelling through the bloodstream.  Toxins and potential medications are blocked from neurons by several mechanisms.  Despite the rich network of blood vessels reaching all areas of the brain, the endothelial lining of the capillaries are fused together with extremely tight junctions preventing the passage of many molecules.¹  Only the smallest hydrophilic molecules can enter the brain through the paracellular route around the tight junctions.  Some small, lipophilic molecules can cross through the epithelial cells via the transcellular route.²  Prodrugs can increase lipophilicity and nanoparticles can hide polar regions inside a PLGA liposome.  Larger endogenous molecules are selectively allowed across the barrier through transport proteins, like insulin and transferrin, which we can use to transport drugs across.¹  While we can make drugs lipophilic or hijack transporter proteins to cross the membrane, P-gp efflux pumps work to actively remove foreign compounds.  Some drugs can be given with P-gp inhibitors to increase the chances of remaining inside the brain.³  All of these defense mechanisms make getting drugs into the brain incredibly difficult.  Indeed, as little as 1% of an intravenous dose may reach and remain within the CNS.  The larger doses required leads to toxic side effects elsewhere in the body.⁴  To treat the growing problem of neurodegenerative disorder, we need a less invasive, patient directed route of administration that provides rapid onset of action, higher brain concentrations, and lower systemic distribution and side effects.  Going through the nose to the olfactory bulb provides each of our requirements.

The Nasal Anatomy

The nasal cavity performs three functions for the human body: warms air, filters large particles, samples odors.  In direct contact with the external environment, the cavity is lined with mucosal epithelium.  Mucus, secreted from surrounding glands, traps foreign bodies, while the cilia continuously push the mucus to the esophagus for elimination.  Any nasal medication must be absorbed quickly or be washed into the stomach.  When we breathe, air enters through the nares, past the vestibule and into a large nasal cavity.  The empty space contains specialized folds, called conchae, which increase the surface area and create turbulence to help warm the air on the way to the lungs.  Most nasal sprays for the treatment of rhinitis target the inferior and middle conchae. The rich vasculature in the area provides access to systemic circulation, but effects are limited due to nasal mucus.  To target the CNS however, specialized INB sprays target the superior concha to directly access the olfactory bulb.  Comprised of millions of nerve endings, the olfactory bulb sends out those nerve endings through the holes in the cribriform plate to test the air for smells and provides a pathway from the nasal cavity to the brain.  As such, the nasal cavity is a rare location with open access to the nervous system.  INB drugs can bypass the difficult BBB treat CNS disorders.⁵

Reaching the Brain through the Nose

To reach our goal, INB drugs do not target the vasculature, but rather the top of the nasal cavity – olfactory bulb and cribriform.  If absorbed systematically, the drug would still have to pass through the BBB reducing the neuronal availability and potentially cause toxicity.  INB drugs avoid systemic circulation by entering the brain through the more permeable epithelial membrane above the superior concha.  Any INB drug reaches the CNS through two main pathways.  The epithelial pathway uses paracellular transport around the olfactory epithelium, across the cribriform plate and into the subarchnoid space.  The CSF carries the drug particle throughout the brain or clears into the systemic circulation.⁶  Using the epithelial pathway requires a small, hydrophilic molecule.  An olfactory pathway uses the nerve endings to internalize the drug and ferry it to the olfactory bulb and into the olfactory region of the brain.  These molecules must trigger endocytosis to promote transport.

While easier to reach than through the blood, the nasal cavity still possesses a number of factors that can affect absorption.  As stated before, small molecular weight drugs are ideal as absorption is limited at 1000 daltons.  The secretion and removal of mucus can affect absorption clearing drug from the site of absorption.  Few enzymes exist in the area, but degradation remains a concern for drug stability, especially for proteins.  Finally, rhinitis can alter absorption.⁵  Still, the nasal cavity remains a valid alternative to administer drugs to the CNS, especially if the drug is orally ineffective, blocked by the BBB, or requires a rapid onset of action.  Several modifications can protect from these protections and improve INB delivery.

To improve uptake through the olfactory bulb, either the drug or the formulation can be modified.  Prodrugs take advantage of local enzymes and increase lipophilicity.  Excipients transiently open up mucosal pores to increase absorptions.  Chitosan is a natural polysaccharide that binds to the mucosal membrane and loosens the tight junctions between epithelial cells allowing more drug to enter.⁵  PLGA nanoparticles can increase absorption by attaching a lectin ligand, triggering receptor-mediated endocytosis.⁷  Currently, several drugs are being designed and studied to use these methods to treat a variety of CNS disorders.  Mouse models show an increase in brain distribution through INB relative to normal intravenous administration, opening the door to potential treatments for Alzheimer’s disease and autism.

Potential Treatments through INB

Alzheimer’s patients face a dark diagnosis with little positive light.  Chi Zhang and his group in Shanghi hope to make the outlook a little brighter.  Basic fibroblast growth factor (bFGF) simulates the growth of neurons, but remains blocked by the BBB.  Intravascular delivery of the peptide shows that only 1% reaches the brain.  INB offers an alternative route but must overcome mucusal clearance and protein degradation.  Incorporating bFGF into PEG-PLGA nanoparticles coated with Solanum tuberosum lectin, Zhang’s group showed increased residence time, CNS concentration of bFGF in Alzheimer-model rats and corresponding improvement in memory tests.  Direct bFGF administration to the brain through the nose decreases plasma concentrations resulting in fewer toxicities.⁷

Each day, more children receive diagnoses of autism spectrum disorders, but few treatments exist.  Evdokia Anagnostou and her Toronto-based lab want to administer intranasal oxytocin as a potential cure.  Children with ASD have poor social skills, tend to perform repetitive behaviors, and have reduced levels of oxytocin in the blood.  Medical oxytocin could hopefully ameliorate many autism symptoms.  Because oxytocin degrades in the intestines by chymotrypsin, it cannot be given orally.  Intravascular injection of oxytocin shows positive effects, but is too invasive for children.  INB produced better CNS distribution with easier administration.  While early in the process, children treated with INB oxytocin showed promising improvements in autism-related behaviors.⁸

Conclusion

Getting medication into the brain remains a difficult task as many molecules fail to reach the desired destination.  The BBB protects the neurons but makes treatment more difficult.  As the population grows and ages, more patients will be diagnosed with neurodegenerative diseases, like Alzheimer’s.  A targeted nasal spray to the olfactory bulb could potentially deliver therapeutic compounds for a variety of CNS disorders.  INB is a rapid acting route that avoids the restrictive BBB and potentially toxic systemic side effects.  More studies must determine the safety of this route on a larger scale and show more examples of efficacy.  We should learn more about local side effects of penetration enhancers on an important protective membrane or sensitivity in the nasal cavity leading to rhinitis.  Overall, INB offers a safer, less invasive route of administration directly to the brain and can potentially help the patients with the frightening diseases of the CNS.

References

1.     Patel M, Goyal B, Bhadada S, Bhatt J, Amin A. Getting into the brain: Approaches to enhance brain drug delivery. CNS Drugs. 2009;1:35-58.

2.     Illum L. Nasal drug delivery: New developments and strategies. DDT. 2002;7(23):1184-1189.

3.     Merkus F, van den Berg P. Can nasal drug delivery bypass the blood-brain barrier? questioning the direct transport theory. Drugs R D. 2007;8(3):133-144.

4.     Goldsmith M, Abramovitz L, Peer D. Precision nanomedicine in neurodegenerative disease. Asc Nano. 2014;8(3):1958-1965.

5.     Tayebati S, Nwankwo I, Amenta F. Intranasal drug delivery to the central nervous system: Present status and future outlook. Curr Pharm Design. 2013;19:510-526.

6.     Illum L. Nasal drug delivery - possibilities, problems and solutions. J Controlled Release. 2003;87(187):198.

7.     Zhang C, Chen J, Feng C, et al. Intranasal nanoparticles of basic fibroblast growth factor for brain delivery to treat alzheimer's disease. Int J Pham. 2014;461:192-202.

8.     Anagnostou E, et al. Intranasal oxytocin in the treatment of autism spectrum disorders: A review of literature and early safety and efficacy data in youth. Brain Res. 2014.

Tamiflu and Drug Trial Transparency

Ben Goldacre, British writer and blogger, looked into a growing scandal and the actual governmental cost of making pharmaceutical decisions based on very little information.  He wrote the book Bad Pharma and became a leader in the European push to open up the transparency of clinical trials.  

In 2009 facing a potential flu pandemic, the British government stockpiled (LB) 500 million worth of Tamiflu to cover 80% of their population.  Roche, the makers of Tamiflu, claimed that their drug reduces the serious complications, including pneumonia, from the flu and the number of hospitalizations.  A 2008 Cochrane review gave the green light to Tamiflu after reviewing the available evidence.  Their evidence?  All positive implications of Tamiflu stemmed from one article funded by the industry that summarized ten other summaries, eight of which had not been published.  With big money and high hopes riding on the national , Cochrane initiated a new review and the evidence began to swing in the opposite direction.

Cochrane reviewers contacted the writers of the summary to look at their data, but unfortunately their files were missing.  Turning to Roche, the company offered to help, but put in roadblocks along the way.  Initially, they required a secret confidentiality agreement about the data they hand over.  Then Roche claimed another group was conducting a review elsewhere.  Finally, the company sent some excerpts of research documents, but far less than necessary to complete a thorough review of Tamiflu.  Roche began attacking the credibility of the reviewers and complaining that journalists had been included in their correspondence.  Five years later, after growing scrutiny, Roche relented and provided their data.

Even before receiving Roche’s data, Cochrane had noticed several problems with the clinical studies conducted on Tamiflu.  “Double-blind studies” used a different color placebo or large Phase Three trials were never even published.  With the full data, the Cochrane Review issued its opinion on Tamiflu.  It failed.  Tamiflu does not significantly reduce the number of hospitalizations or the cases of pneumonia.  While it may reduce the duration of your flu by a few hours, Tamiflu can produce serious side-effects.  Remember that the UK bought enough to cover their population in the case of a pandemic.  Cochrane applied the incidences of side effects to a million patients – 11,000 psychiatric cases, 31,000 headaches, and 45,000 people vomiting. 


Clinical transparency is important.  Many medical decisions are based on only a fraction of the appropriate data.  Doctors and pharmacists believe they make recommendations about medications on evidence.  That evidence only applies to what is publicly available.  The Cochrane group ran around and jumped through hoops to get the information needed to make a decision.  Companies will not provide more information than required.  And there are billions of reasons why.