Ultrasound Patch: An innovative technology for rapid treatment and management of ulcers

Venous skin ulcers also known as stasis ulcers or varicose ulcers are chronic wounds caused by the poor blood circulation in the venous valves or veins, usually occurring in the lower part of the legs, between the ankle and the calf. This condition is known venous insufficiency and accounts for roughly 70 % to 90% of leg ulcer cases. These ulcers are often recurring, extremely painful and can take months and years to heal. This condition affects approximately 500,000 Americans annually, and the number is expected to increase as the rate of obesity climbs. It is estimated that the financial burden for the treatment of venous skin ulcers costs US healthcare systems over one billion dollars per year and the monthly treatment costs could be as high as $2,400 a month. Current treatments for venous skin ulcers are either conservative management, such as compression therapy or invasive and expensive surgical procedures, such as skin grafts. Other available treatment options include mechanical treatment and medications. The most standard treatment however involves the infection control, wound dressings and compression therapy in which patients are asked to wear elastic stockings to help improve leg circulation. Nevertheless, all these approaches were not found to be successful in every case and these wounds take often months or sometime years to heal.

Designing Ultrasound patch:

Recently, a team of researchers led by Dr. Peter A. Lewin at Drexel University at Philadelphia have designed a novel non-invasive technique called “Ultrasound Patch” for treating chronic ulcers and wounds. This technique uses patches with a novel ultrasound applicator that can be worn effortlessly like a band-aid. In this alternative therapy, battery-powered patch sends low-frequency and low-intensity ultrasound waves directly to the wound site. The therapeutic benefits of ultrasound for wound healing were established in previous studies, but most of studies were performed with much higher frequencies, around 1-3 megahertz (MHz). Dr. Lewin believed that decreasing the frequency to 20–100 kilohertz (kHz) might work better with a reduced exposure. According to him, one of the biggest challenges in designing this technology was to build a battery-powered patch since most ultrasound transducers require a bulky apparatus which need to be fixed on the wall. Dr. Lewin and colleagues also wanted to create something which is portable and can be easily worn for which the device has to be essentially battery operated. To accomplish this, they designed a transducer that could produce medically pertinent energy levels using minimum voltage. The ultrasound patch in its present form, weighs approximately 100 grams and required two rechargeable AA batteries. It is designed to be worn over the ulcer or the wound and the patient can deliver controlled pulses of ultrasound directly to the wound, while at home. The funding for this study was received from the National Institute of Biomedical Imaging and Bioengineering (NIBIB), a part of the National Institutes of Health.

Clinical studies for testing Ultrasound patch

To determine the optimal frequency and treatment duration of ultrasound patch, the study trial was carried out initially in total 20 patients, divided into four groups. Each group received either 20 kHz for 15 minutes, 20 kHz for 45 minutes 100 kHz for 15 minutes, or 15 minutes of a placebo or control which received no radiation.  According to the researchers, the first group was the one that eventually came out best, where all the five participants completely healed by the time they reached their fourth session. In contrast, the ulcers of the patients in the placebo group worsened over the similar duration. Results suggested that patients who received this low-frequency, low-intensity ultrasound therapy during their weekly follow ups (in addition to the standard compression therapy), showed a net reduction in wound size just after four weeks of the therapy. Whereas, the patients who did not received the ultrasound treatment had an average increase in the wound size. The team’s clinical findings were further confirmed by their in vitro studies where after 24 hours of receiving 20 kHz ultrasound for 15 minutes, mouse fibroblasts cells that play an active role in wound healing showed a 32% increase in cell metabolism and a 40% increase in cell proliferation as compared to the control cells. These findings are yet to be published in the Journal of the Acoustical Society of America.

Advantages and applications of Ultrasound patch

Researchers believe that using ultrasound patch for chronic ulcers will reduce the treatment cost and patient’s discomfort. It aids in speedy recovery of wounds as compared to the conventional approaches and could eventually be used to manage wounds associated with diabetic and pressure ulcers. However, before it widespread applications, studies need to be conducted on the larger-scale for establishing its overall safety and efficacy. The ultrasound patch is light weight and can be easily worn like a band-aid. Another characteristic feature of this patch is an attached monitoring component that uses near infrared spectroscopy (NIRS) to assess the progress of wound healing. NIRS can help to non-invasively assess changes in the wound bed and monitor if the treatment is working in its initial stages, when healing is difficult to spot with the naked eye.  Using this patch will also prevent frequent visits to doctor’s clinic or hospital, which can be at times very difficult for patients with chronic wounds. Currently, studies with larger numbers of patients are underway to confirm the safety and efficacy of this patch before it makes its way into the clinics.

Antibiotic Resistance: Cause and Mechanism

Scope of antibiotic resistance problem:

Antibacterial-resistant strains and species, occasionally referred as “superbugs”, now contribute to the emergence of diseases that were well controlled few decades ago. In a recent report “Antibiotic Resistance Threats in the United States, 2013,” CDC calls this as a critical health threat for the country. According to the report more than 2 million people in the United States get antibiotic resistant infections each year and at least 23,000 of them die annually. Now, this is the situation in a country where drug regulations are quite tough and stringent and physicians are relatively careful in prescribing medications. Imagine the situation in developing countries like India, where antibiotics are available over the counter without medical prescription and more than 80-90% of population use antibiotics without physician’s consultation. In fact they are not even aware of the proper use of the antibiotic course. This is again a huge health challenge that will pose even more serious threat in coming years in treating antibiotic resistant infections. Recently, in a clinic in Mumbai some 160 of the 566 patients tested positive for TB between March and September that were resistant to the most powerful TB medicine. In fact, more than one-quarter of people diagnosed with tuberculosis have a strain that doesn’t respond to the main treatment against the disease. According to WHO and data from Indian government, India has about 100,000 of the 650,000 people in the world with multi-drug-resistance.

 Factors contributing to antibiotic resistance:

Inappropriate treatment and misuse of antibiotics has contributed maximum to the emergence of antibacterial-resistant bacteria.Many antibiotics are frequently prescribed to treat diseases that do not respond to these antibacterial therapies or are likely to resolve without any treatment. Most of the time incorrect or suboptimal doses of antibiotics are prescribed for bacterial infections. Self-prescription of antibiotics is another example of misuse. The most common forms of antibiotic misuse however, include excessive use of prophylactic antibiotics by travelers and also the failure of medical professionals to prescribe the correct dosage of antibiotics based on the patient’s weight and history of prior use. Other misuse comprise of failure to complete the entire prescribed course of the antibiotics, incorrect dosage or failure to rest for sufficient recovery. Other major causes that contribute to antibiotic resistance are excessive use of antibiotics in animal husbandry and food industry and frequent hospitalization for small medical issues where most resistant strains gets a chance to circulated among the community.

To conclude, humans contribute the most to the development and spread of drug resistance by: 1) not using the right drug for a particular infection; 2) not completing the antibiotic duration or 3) using antibiotics when they are not needed.

In addition to the growing threat of antibiotic-resistant bugs, there may be another valid reason doctors should desist from freely prescribing antibiotics. According to a recent paper published online in Science Translational Medicine, certain antibiotics cause mammalian mitochondria to fail, which in turn leads to tissue damage.

 Mechanism of antibiotic resistance:

Antibiotic resistance is a condition where bacteria develop insensitivity to the drugs (antibiotics) that generally cause growth inhibition or cell death at a given concentration.

Resistance can be categorized as:

a) Intrinsic or natural resistance:  Naturally occurring antibiotic resistance is very common, where a bacteria may be simply, inherently resistant to antibiotics. For example, Streptomyces possess genes responsible for conferring resistance to its own antibiotic, or bacteria naturally lack the target sites for the drugs or they naturally have low permeability or lack the efflux pumps or transport system for antibiotics. The genes which confer this resistance are known as the environmental resistome and these genes can be transferred from non-disease-causing bacteria to the disease causing bacter, leading to clinically significant antibiotic resistance.

b) Acquired resistance: Here a naturally susceptible microorganism acquires ways not to get affected by the drug. Bacteria can develop resistance to antibiotics due to mutations in chromosomal genes or mobile genetic elements e.g., plasmids, transposons carrying antibiotic resistance genes.

The two major mechanisms of how antibiotic resistance is acquired are:

Genetic resistance: It occurs via chromosomal mutations or acquisition of antibiotic resistance genes on plasmids or transposons.

Phenotypic resistance: Phenotypic resistance can be acquired without any genetic alteration. Mostly it is achieved due to changes in the bacterial physiological state. Bacteria can become non-susceptible to antibiotics when not growing such as in stationary phase, biofilms, persisters and in the dormant state. Example: Salicylate-induced resistance in E. coli, Staphylococci and M. tuberculosis.

In genetic resistance category, following are the five major mechanisms of antibiotic drug resistance, which occurs due to chromosomal mutations:

1. Reduced permeability or uptake (e.g. outer membrane porin mutation in Neisseria gonorrhoeae)

2. Enhanced efflux (membrane bound protein helps in extrusion of antibiotics out of bacterial cell; Efflux of drug in Streptococcus pyogenes, Streptococcus pneumoniae)

3. Enzymatic inactivation (beta-lactamases cleave beta-lactam antibiotics and cause resistance)

4. Alteration or over expression of the drug target (resistance to rifampin and vancomycin)

5. Loss of enzymes involved in drug activation (as in isoniazid resistance-KatG, pyrazinamide resistance-PncA)

Examples of transfer of resistance genes through plasmid are; Sulfa drug resistance and Streptomycin resistance genes, strA and strB while the transfer of resistance gene through transposon occurs via conjugative transposons in Salmonella and Vibro cholera.

In the next post, I will discuss few important examples of antibiotic resistance in clinically relevant microbes.

Antibiotics: Wonder drugs or a threat to public health?

What are antibiotics?

Antibiotics, also known as antibacterials, are category of medications which kills or slow down the bacterial growth. Penicillin was the first antibiotic, discovered by Sir Alexander Fleming in 1928, but it was not until the early 1940s that its true potential was recognized before it came into widespread use. In 1942, the term antibiotic was first used by Selman Waksman. In earlier days, antibiotics were often referred as “wonder drugs” because they cured several bacterial diseases that were once fatal. With antibiotic use, the number of deaths caused by bacterial infections like meningitis, pneumonia, tuberculosis, and scarlet fever were drastically reduced.  Discovery of antibiotics have revolutionized human development in a highly significant way. Other than vaccines, few medical discoveries had such a huge impact on healthcare delivery. Major complicated surgeries, transplants, advances in neonatal medicine, and advances in chemotherapy for cancer patients would not be possible without antibiotics.

Antibiotics classification:

Antibiotics are broadly classified based on their mechanism of action, structure, source or origin of the antibacterial agent or their biological activity. With the recent advances in medicinal chemistry, most antibiotics available nowadays are semisynthetic derivative of various natural compounds (penicillins, Cephalosporins and Ampicillin). Very few antibiotics like aminoglycosides (Streptomycin, Gentamicin, and Neomycin) are isolated from living organisms while many other antibiotics, Sulfonamides,Quinolones, Moxifloxacin and Norfloxacin are chemically synthesized. Based on the biological activity of the microorganisms, antibiotics are classified as bactericidal agents (which kill bacteria) and bacteriostatic agents (which slow down or impede bacterial growth). Microorganisms are known to develop resistance faster to the natural antimicrobials since they have been pre-exposed to these compounds in nature. Therefore semisynthetic drugs were developed for increased efficacy and less toxicity. Synthetic drugs possess an added advantage that bacteria are not exposed to these compounds until they are released systemically. They are designed to have even improved effectiveness with decreased toxicity.

Antibiotics are also classified based upon their range of effectiveness. Broad-spectrum drugs are effective against many types of microbes (gram-positive and gram-negative) and tend to have higher toxicity to the host. Narrow-spectrum drugs are effective against a limited group of microbes (either gram-positive or gram-negative) and exhibit lower toxicity to the host. Based on the chemical structure, antibiotics are classified into two categories: β-lactams and aminoglycosides. All the above mentioned classes of antibiotics are further divided according to their targets or mode of action in the bacteria. Following are the five important antibiotic targets in bacteria.

1. Inhibitors of cell wall synthesis (-cillins)

2. Inhibitors of protein synthesis (-mycins)

3. Inhibitors of membrane function (Polymyxin)

4. Anti-metabolites (Sulfa drugs)

5. Inhibitors of nucleic acid synthesis (Nalidixic acid, Rifampicin)

 The deluge of antibiotic resistance bacteria:

“The first rule of antibiotics is try not to use them, and the second rule is try not to use too many of them”, a quote by Paul L. Marino. Well, after an era of plentiful antibiotics, presently, the situation is alarming due to the ever increasing number of antibiotic resistant strains. In early years, new antibiotics were developed faster than bacteria developed resistance to them. But the bugs have caught up fast now. In the 1950s and 60s, many new classes of antibiotics were discovered. However, in 1980s and 1990s, scientists have only managed to make improvements within different classes of antibiotics.

 The emerging resistance of bacteria to antibacterial drugs is becoming a continuous threat to human health. Bacterial resistance to penicillin was observed within 2 years of its introduction in mid 1940s. Rapidly emerging resistance to ciprofloxacin and various anti-tuberculosis drugs indicates that it is microbe’s world and they are ready to adapt. Since, microbes congregate in large numbers to induce infection, generate rapidly and mutate efficiently, developing resistance is not a matter of “if” but of ‘when”. To overcome any assault, bacteria possess efficient defense system present within DNA or chromosomes or extrachromosomal elements called plasmid. The bacteria have advantage that these plasmids carrying resistance gene with them can easily shuttle between bacterial cells and humans.

Now, no longer limited to the hospitals, antibiotic resistance with Neisseria gonorrhea and Streptococcus pneumoniae is becoming a household and a community setting phenomenon. The use of surface antibacterials in common households, self-medication and unregulated sales of antibiotic in many countries are further aggravating the problem. According to a CDC report by the end of 20th century, approximately 30 % of S. pneumoniae (causative agent of meningitis, otitis media and pneumonia) were no longer found to be sensitive against penicillin. Similarly, treatment failures were observed in patients because of the resistant strains of, Shigella, Salmonella typhi, Staphylococcus, Mycobacteria tuberculosis, Klebsiella pneumoniae, Clostridium difficle and S. pneumoniae. Drug-resistant bacteria can be acquired in community settings like, daycares, schools and other crowded places. Other risk factors are antibiotic use and consumption of food products treated with antibiotics. Increased use of quinolones in poultry and farm animals has been associated with the increased prevalence of human infection with quinolone-resistant Salmonella and Campylobacter.  Besides, the established pathogens, relatively recent appearance of opportunistic organisms, intrinsically resistant to many drugs are making the matter worse. With a larger number of immunocompromised patients, these organisms have become ‘specialized’ pathogens—typically attacking only the most vulnerable patients. Examples of such opportunistic pathogens are Enterococci, the coagulase-negative Staphylococci, Pseudomonas aeruginosa and Acinetobacter baumanii. Therefore, it is the high time to think and act to reverse this trend of antibiotic resistance by medical professionals by creating awareness among communities on the proper use of antibiotics and discouraging self-medications. In the next series, I will discuss the factors responsible for antibiotic resistance and its detailed mechanism.

 

Pharmacogenomics: A study of personalized drug therapy

With the increasing advancement of technology and research progress, modern medicine has found cure for several diseases which were considered to be incurable few decades ago e.g. cardiovascular diseases, various cancers, tuberculosis, malaria and infectious diseases. However, till date no single drug is shown to be 100% efficacious for treating a certain diseased condition without exhibiting adverse drug effects. It is now a well recognized fact that each patient respond differently to a given drug treatment for a similar disease. With a particular drug, desirable therapeutic effects could be obtained in few patients where as others may have modest or no therapeutic response. Besides, many patients might experience an adverse effect that also varies from mild to severe and life-threatening. Studies have shown that with a similar dose, plasma concentration of a certain drug might vary up to a difference of 600 fold among two individuals of same weight. Such inter-individual variations occurring in response to a drug might be a consequence of complex interaction between various genetic and environmental factors. Genetic factors are known to account for approximately 15-30% inter-individual variability in drug disposition and response, but for certain drugs it could also account for 95% variations. For the majority of the drugs, these differences are largely ascribed to the polymorphic genes encoding drug metabolizing enzymes, receptors or transporters. These polymorphic genes mainly influence important pharmacokinetic characteristics of the drug metabolism e.g. drug absorption, distribution, metabolism and elimination.

Origin of pharmacogenomics:

The first report of an inherited difference in response to a foreign chemical or xenobiotic was inability to taste phenylthiocarbamide. Another example which showed that drug response is determined by genetic factors which can alter the pharmacokinetics and pharmacodynamics of medications, evolved in late 1950s, when an inherited deficiency of glucose-6-phosphate dehydrogenase was shown to cause severe hemolysis in some patients when exposed to the antimalarial drug primaquine. This discovery elucidated why hemolysis was reported mainly in African-Americans, where this deficiency is common, and rarely observed in Caucasians. Other established evidences of inter-individual variations observed in response to suxamethonium (succinylcholine), isoniazid, and debrisoquine were also linked with a genetic connection. The discovery that prolonged paralysis following the administration of succinylcholine was the result of a variant of the butyryl-cholinesterase enzyme, and peripheral neuropathy occurring in a large number of patients treated with antituberculosis drug isoniazid was an outcome of genetic diversity in the enzyme N-acetyltransferase 2 (NAT2) are excellent examples of “classical” pharmacogenetic traits altering amino acid sequence.

These observations of highly variable drug response, which began in the early 1950s, led to beginning of a new scientific discipline known as pharmacogenetics. Vogel in 1959 was the first to use the term pharmacogenetics but it was not until 1962, when in a booy by Kalow, pharmacogenetics was defined as the study of heredity and the response to drugs.

Pharmacogenomics in new era:

The term pharmacogenomics was later introduced to reflect the recent transition from genetics to genomics and the use of genome-wide approaches to identify the genes that contribute to a specific disease or a drug response. The term pharmacogenomics and pharmacogenetics are many times used interchangeably. Pharmacogenomics is an emerging discipline that aimed at studying genetic differences in drug disposition or drug targets to drug response. With the availability of more sophisticated molecular tools for detection of genetic polymorphisms, advances in bioinformatics and functional genomics, pharmacogenomic based studies are generating data which is used in identifying the genes responsible for a specific disease or the drug response. There is emerging data from various human genome projects on drug metabolizing genes that is rapidly elucidated and translated into more rational drug therapy towards a personalized medicine approach. Many physicians are now reconsidering whether “One Drug for All” approach is ideal while prescribing medicines to treat a certain condition in different individuals. Various studies have now reported genotype- phenotype association studies with reference to many diseases where respective drug metabolizing genes and receptors are highly polymorphic. In the last decade, FDA has increasingly acknowledged the importance of biomarkers and formulated new recommendations on pharmacogenomic diagnostic tests and data submission.

Applications and challenges of Pharmacogenomics:

Personalized medicine is at times deemed to be a future phenomenon; however it is already making a marked difference on patient treatments especially in various cancers. Molecular or genetic testing is now available for colon, multiple myeloma, leukemia, prostrate and breast cancer patients, hepatitits C and cardiovascular diseases where one can identify their genetic profile and based on that it can be predicted whether patients are likely to benefit from new drug treatments simultaneously minimizing adverse drug reactions. Recently, at MD Anderson Cancer Center, “Institute for Personalized Therpay” was created particularly to implement personalized cancer therapy for improving patient outcomes and reducing treatment costs.

Personalized medicine might guarantee many medical innovations but its implementation is associated with several challenges regarding public policy, social and ethical issues. Individual may not opt or participate in the genetic research as they feel it might breach their right for privacy and confidentiality. To tackle these challenges, “2008 Genetic Information Nondiscrimination Act” was designed to shield individuals from genetic discrimination. Apart from this, other existing concerns are: ownership of genetic materials, medical record privacy, clinical trial ethics, and patient’s knowledge on the consequences of storing genetic materials and phenotypic data. These concerns must be addressed for the satisfaction of all the stakeholders, especially the patients on reaching a common consensus as how to manage pharmacogenomics applications into clinical practices.

Scientists as Entrepreneurs: Recognizing their potential and commercializing the passion for science

Science and business, many of us thinks do not fit together and some even refers it as a huge culture clash. We imagine a scientist to be working in the lab with test tubes or operating some instruments! But yes, these days as I mentioned in my earlier post, they are coming out of their comfort zone and exploring careers outside academia. And why should not they? We saw entrepreneur legends like Richard and Maurice McDonald or Steve Jobs who do not hold a college degree but established the businesses, now even kids are familiar with.With a PhD, one has the capability to think independently and differently. Well, without getting into the controversy of the degrees one possesses, the point here is any individual with inherent self-confidence and willingness to take risks has a chance of becoming a successful entrepreneur. Till decades ago, scientists generated an idea, executed the research, and disseminated their results largely through publications or patents. Many scientists essentially comprehend that their discoveries could translate into important, very profitable entrepreneurial enterprises but actually never dared to take risks. But now that paradigm has shifted. Today, young researchers and scientists are recognizing their passion and taking their work beyond publications and patents and commercializing resulting technologies. But simply making a discovery or patenting an invention or a technique is not only the prerequisite for a start-up company. Bringing an idea or invention to commercialization and establishing a successful company requires altogether a different set of skills and knowledge than doing the actual science.

Government support for science entrepreneurs:

To help scientists get the necessary skills, National Science Foundation Innovation Corps (USA), American Chemical Society (USA), National Science & Technology Entrepreneurship Development, Technology Business Incubator supported by Department of Science and Technology (India), Department of Biotechnology (India), entrepreneur centers within many business schools and other groups are stepping up with financial aid and training courses and other resources. Plenty of online resources and websites “The Silicon Alley Entrepreneurs Club (SAEC)”, Kauffman Foundation, American Chemical Society initiative called “Entrepreneurial Resources Center” are headed and maintained by successful scientists turn entrepreneurs to provide support to budding entrepreneurs. Similarly, government and universities are encouraging scientists and researchers in academic settings to take up initiatives to sell what their mind thinks are innovative or they discover something in the lab for that matter. But, before scientists can take advantage of the government assistance, it is important that they critically assess their personal goals and the state of their innovation or technology they intent to market.

Challenges of scientists turning entrepreneurs:

Scientists trained in laboratories typically have a passion for science and not business. Decision of a scientist turning an entrepreneur requires acquiring new skills and taking risks for a significant transition into a new career path. Increased time demands, finding the right people to partner with in the start-up, worrying about venture capital, and giving up absolute control and ownership of the technology are few limitations which scientists aren’t so comfortable with.

Before starting anything, scientists need to ask a core set of questions about what they want to commercialize: Is there a growing market need? If yes, does the technology provide the solution to that need? Does anyone else have a better cost-effective solution? And finally, can enough capital be generated to cover the cost of bringing the technology to market and appealing the investors to invest?

Beyond these market-based limitations, scientists need to know a series of reality-check questions. How close is their technology successful in reaching market? If one still have a lot of unanswered questions and research to do, it is better to stay in the lab and wait a little more to achieve that confidence. Scientists also need to mull over whether they have a rational plan in place to effectively commercialize their idea or technology and how much it is going to cost! Addressing these questions is even more complicated for therapeutic innovations in life sciences or medical research because of the regulatory hurdles (Clearing clinical trials and other ethical issues) which needs to be well thought-out. And, perhaps most importantly, scientists must appraise if they have a perfect team in place with all the expertise needed to take the technology successfully to market. Explicitly, scientists will need to associate with business and legal professionals to launch the ambitious start-up. And last but not the least; the route to venture capital should be the prime thing, scientists really need to have in place. Good luck!