Promising Therapies in Diabetes Mellitus

Diabetes mellitus (DM) results from defects in insulin secretion (type 1) or insulin resistance (type 2). Insulin is used to manage type 1 DM, and oral hypoglycemic agents are used to manage type 2 DM. These therapies are inconsistent in maintaining glycemic control and cause some severe adverse effects such as undue weight gain and hypoglycemia. New and appropriate therapies are needed to overcome these problems. Drugs that are in the pipeline include oral insulins for type 1 DM and incretin mimetics, incretin enhancers, gastric inhibitory peptides, amylin analogues, peroxisome proliferator-activated receptor-α/γ ligands, sodium-dependent glucose transporter inhibitors, and fructose 1,6-bisphosphatase inhibitors for type 2 DM.

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Top Ten Health Stories of the Year 2010

The year 2010 saw a lot of ‘hustle and bustle’ in the medical circle. Here are the Top 10 stories as viewed by eMedinewS.

1. Overhauling of Medical Council of India: The major story of the year was the arrest of MCI President Dr. Ketan Desai, dissolution of the MCI; appointment of six out of seven Board of Governors; subsequent release of Dr. Ketan Desai on bail, common entrance exam for MBBS; reduction in forensic faculty requirement; increase in retirement age to seventy and the suspense behind 7th seat of Board of Governors etc.
2. Medical Council of India action against Indian Medical Association: MCI took action against the IMA President and Secretary for violation of MCI Ethics on the ground that IMA should not have endorsed Pepsi products. The IMA had to approach High Court to take a stay. The matter is now in the High Court. Is that a start of MCI actions against ethics violations? Will it act against the cut system?
3. Delhi Bug: A huge controversy arose when British Medical Journal broke a story about NDM1 bug being named after New Delhi. The medical circle in India said that it was unfair and was an attempt to sabotage the medical tourism in India. The new bug is a gram negative bacteria showing resistance to all present antibiotics. New Delhi metallo–beta–lactamase (NDM–1) is an enzyme that makes bacteria resistant to a broad range of beta–lactam antibiotics. These include the antibiotics of the carbapenem family, which are a mainstay for the treatment of antibiotic–resistant bacterial infections. The gene for NDM–1 is one member of a large gene family that encodes beta–lactamase enzymes called carbapenemases. Bacteria that produce carbapenemases are often referred to in the news media as “superbugs” because infections caused by them are difficult to treat. Such bacteria are usually only susceptible to polymyxins and tigecycline. NDM–1 was first detected in a Klebsiella pneumoniae isolate from a Swedish patient of Indian origin in 2008. It was later detected in bacteria in India, Pakistan, the United Kingdom, the United States, Canada, Japan and Brazil. The most common bacteria that make this enzyme are Gram negative such as Escherichia coli and K. pneumoniae, but the gene for NDM–1 can spread from one strain of bacteria to another by horizontal gene transfer.
4. H1N1 havoc: H1N1 created great havoc, but ultimately, proved to be a ‘much hyped’ virus with mortality even lower than the regular human flu virus. Most of the hospitals who had started special H1N1 virus wards, now do not have these wards.
5. Chikungunya epidemic: The latest epidemic in the North India was that of Chikungunya with patients presenting with fever, rash and joint pains. It complicated the pre–existing dengue epidemic in the society.
6. Dengue with a difference: This year dengue was different than other years, came with more GI symptoms, pancreas involvement, dengue hepatopathy and lot of skin reactions. The platelet count dropped to less than 10000 but most required no platelet transfusion.
7. Diabetes diagnosis: The year saw a new advancement where A1C is to be used for diagnosis of diabetes and not fasting sugar. An A1C >6.5% means diabetes.
8. New pill for HIV prevention: A new pill is now available for HIV prevention along with condoms. It is to be used before the act and continues for seven days. In a trial involving nearly 2,500 HIV–negative, but high risk, gay men in six countries, researchers found that a combination antiretroviral pill (tenofovir and emtricitabine) reduced the risk of HIV infection by 44%, compared with placebo. When scientists looked more carefully at the study volunteers who took the medication most faithfully, on a daily basis, they found that the risk of contracting HIV was even lower — 73% lower than the placebo group. More studies will need to confirm the benefit of antiretrovirals in the prevention of HIV, and public health experts warn that even if the results hold up, it would not replace the best method of prophylaxis: safe sex and consistent use of condoms. That’s because the way so–called pre–exposure prophylaxis, or PrEP, works is to load up high–risk people with HIV–disabling antiretroviral drugs before exposure to the virus, which allows the medication to hit HIV as early as possible. But the drugs do not work as a vaccine would, by priming the immune system to actually prevent infection.
9. National Programme for Prevention & Control of Cancer, Diabetes, Cardiovascular Diseases and Stroke (NPCDCS) started in the country:At last, Govt. of India, Ministry of Health and Family Welfare has started the above program.
10. New drug for premature ejaculation: The year ended with the launch of an SOS drug for premature ejaculation. This will be breakthrough for the community. Premature ejaculation, the most common sexual problem apart from erectile dysfunction, has been often found to put marriages under strain. While the existing drugs, which are not specific to treat premature ejaculation, need to be taken regularly, the new pill can be popped just a few hours before intercourse. It works by altering levels of serotonin, a chemical in the brain. The drug, dapoxetine, comes from a family of drugs called selective serotonin reuptake inhibitors, which block the reabsorption of the neurotransmitter serotonin.

New molecular entities (NMEs) approved in 2010

• Asenapine (Saphris, Merck & Co., Inc.)
• Bepotastine (Bepreve, ISTA Pharmaceuticals)
• Dronedarone (Multaq, Sanofi-aventis)
• Liraglutide (Victoza, Novo Nordisk)
• Tocilizumab (Actemra, Genentech)
• Ustekinumab (Stelara, Centocor Ortho Biotech)
• For details see http://www.medscape.com/viewarticle/731720

• New Drug Review 2010

  Jack DeRuiter, PhD; Pamela L. Holston, RPh, BS, BA
  Posted: 11/10/2010; US Pharmacist © 2010 Jobson Publishing

Onabotulinumtoxin A for Migraine

The US Food and Drug Administration (FDA) has approved onabotulinumtoxinA (Botox; Allergan Inc) for headache prophylaxis in patients with adult chronic migraine who suffer headaches on 15 or more days per month, each lasting more than 4 hours.

    To treat chronic migraine, onabotulinumtoxinA is given approximately every 12 weeks as multiple injections around the head and neck. The recommended dose is 155 units (1 mL) divided across 7 head and neck muscles, administered at intervals of at least 12 weeks.

The most common adverse reactions reported by patients being treated with onabotulinumtoxinA for chronic migraine were neck pain (9%) and headache (5%).

Marketed as Botox and Botox Cosmetic, onabotulinumtoxinA has a boxed warning that the effects of the botulinum toxin may spread from the area of injection to other areas of the body, causing symptoms similar to those of botulism.Symptoms include swallowing and breathing difficulties that can be life-threatening.

 Source: FDA New Drug Web site (www.fda.gov)

Oral Insulin

1) The FDA has approved Oral-lyn, an insulin spray treatment for type I and type II diabetes, for its Investigational New Drug program.


The spray delivers prandial insulin orally through a device similar to an asthma inhaler, which sprays it on the inside of the cheek, rather than via injection.

Researchers have spent much time looking for alternative means of dispensing insulin to diabetics, and the IND program allows patients with serious or life-threatening conditions, and without suitable alternative treatment, to access drugs otherwise available only to those in a clinical trial.



2) Oramed has developed a tablet form of insulin in which the hormone's protein structure is supposedly protected by special adjuvants from destruction by gastric juice. The firm just reported positive results from a Phase 2A clinical trial with Type I diabetics.

What is translational Pharmacology?

Rather than going through the well worked phrases of science that goes ‘from bench to bedside’ or from ‘mouse to man’, a more accurate definition might be ‘the application of biomedical research (pre-clinical and clinical), conducted to support drug development, which aids in the identification of the appropriate patient for treatment (patient selection), the correct dose and schedule to be tested in the clinic (dosing regimen) and the best disease in which to test a potential agent (disease segment)’. A challenge to say, let alone do, but it is fast becoming one of the most exciting research areas for pharmacologists to work in, as they get to see the translation of their hypotheses into the clinic for testing. 

Translational pharmacology (TP) can answer some simple questions once a drug candidate has emerged from a screening cascade. These include: 

   

• What disease might this agent work in? By testing in a number of pre-clinical models of human disease and working out whether this is predictive of disease in man some direction can be provided pre-clinically. 

• What dosing schedule can we test in the clinic for maximum therapeutic benefit with minimum toxicity, based upon the scientific profile of the molecule and data from pre-clinical models? 

• Can we use pharmacodynamic ‘biomarker(s)’ (measures of biological effect in man) to determine whether the compound blocks or stimulates the target receptor or enzyme in man as it does in animals (commonly known as proof of mechanism)? What effect does modulating the target have on the cellular phenotype that we might be trying to modulate (known as proof of principle, or proof of biology)? Does induction of this phenotypic change result in therapeutic benefit to the patient, and at what dose does this occur in the patients (proof of concept)? 

• Can we identify patients from within a disease population who might benefit from the agent, either by a gene mutational change or an over/under-expression of the protein target receptor or enzyme as examples? 

• If an agent is being developed as second or third in the market place (usually termed a ‘best in class’ agent), what differentiating pharmacology might this compound require in order to encourage regulatory agencies, physicians, and patients to test it? 

  Frankly speaking, TP is only a journey, not a specific scientific technique.

source: Netrum

Phase 0 - Microdosing strategy in clinical trials

Drug development is an activity that is long, complex and expensive. In 2004, attrition in the drug development paradigm prompted the US Food and Drug Administration (FDA) to introduce its ‘Critical Path’ document, which highlighted the serious discordance between major scientific advances and limited drug development process. One issue addressed was that of microdosing. The concept of microdosing involves the use of extremely low, nonpharmacologically active doses of a drug to define the pharmacokinetic profile of the medication in human subjects. Microdosing, thus, appears as a new viable concept in the ‘toolbox’ of the drug development activity. It appears that microdosing strategy could complement standard animal-to-human scaling, redefining the existing concept of phase I clinical research. In future, when research methods and technology involved in Phase 0 studies become more sophisticated, human microdosing may be applied to a number of drugs developed subsequently.

Steps of New drug discovery & development

 1. Search for the Active Site/ Target (Biological Development Phase)

   * Identifying appropriate drug "targets," such as single genes or proteins.
   * The targets are rigorously "validated," meaning proven to be involved in the disease state.
2. Search and Optimization of Active Compound (Chemical Research Phase)
    # Identification of hit molecules (hits)
discovering or inventing compounds that can alter the disease-causing mechanism, whether a single protein or a complex pathway of proteins, to bring it back into line with normal function.
* Random screening (e.g. Cyclosporine)
* Serendipity (e.g. Methotrexate)
* Molecular modification of known drug (e.g. Cephalosporins)
* Rational drug designing (e.g. ACE Inhibitors)
* Designing of a Prodrug or Active metabolite (e.g. Levodopa)
    #Identification of lead series (leads)
      set of related molecules that share common structural features and have some variation of activity if structure    is modified
      -- Optimize Lead Compound
Compounds are altered in ways that
* increase their potential efficacy
* minimize any potential side effects
3. Testing of the Active Compound (Pre-clinical Phase)
* Pharmacological testing (screening)
* Preliminary toxicilogical testing
* Pharmacokinetic testing
* Chemical and Pharmaceutical development
4. Clinical Trials
5. Approval Process