Clinical

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David Gschneidner_edit

As Emisphere’s Vice President of Carrier Technology, Dr. Gschneidner is responsible for developing a better understanding of the Eligen® Technology.  Dr. Gschneidner joined Emisphere in 1996 as a Medicinal Chemist and over the years has been involved in the design, synthesis, scale-up and manufacture of Emisphere carriers.  Other responsibilities have included overseeing carrier screening and serving as a technical liaison to Emisphere’s partners. Previously, Dr. Gschneidner worked as research scientist at Cytec and as a post-doctoral fellow at the University of Colorado, Boulder.

Dr. Gschneidner holds a Ph.D. in Organic Chemistry from University of Wisconsin, Madison and a Bachelor of Science in Chemistry from Iowa State University.  Dr. Gschneidner has authored a number of scientific communications, including peer reviewed scientific publications and national conference presentations. He is an inventor on twenty-four U.S. patents.

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Hyperglycemia and metformin use are associated with B-vitamin deficiency and cognitive dysfunction in older adults – Long-term metformin use has been linked for a while to  B12 deficiency in many diabetic individuals.   It is also well known that low B12 levels can result in dementia and other neural damage.  Now a new study has shown a correlation between the use of metformin and both a deficiency of B vitamin and of cognitive decline.

The study involved older adults (> 60 years) with no signs of cognitive issues.  Comparisons were made between normal and hyperglycemic subjects, further divided to those on metformin and not.  Low B12 status (from serum B12, holoTC and homocysteine levels) was found to be linked to metformin usage.  Interestingly, low vitamin B6 levels were also connected to metformin use, but other B vitamins (folate and riboflavin) were not.

Cognitive decline and dementia are known to be a risk associated with diabetes.  Metformin usage has not been shown previously to  be correlated with these conditions.  However, the older adults who were on metformin in this study had a higher likelihood of cognitive dysfunction. Two different well known tests of brain function were used for this assessment.  And, though not expressly shown, this diminishment in cognition could possibly be related to the deficiency found in vitamins B12 and B6 for these individuals.

The bottom line is that long term users of metformin especially those in groups vulnerable to deficiency such as elderly and vegans should have their B6 and B12 levels checked at least twice a year.  If a deficiency is detected, one can then act to normalize levels before any permanent damage is done.  B vitamin supplements may very well work, but if deficiencies persist stronger measures will need to be taken.

 

 

Vitamin B12 and deficiency from the perspective a practicing hematologist – Because the most telltale signs of B12 deficiency affect the blood it is most often  diagnosed by a hematologist (specialist in diseases of the blood).  This is typically seen in immature, larger red cells being observed.  Symptoms (fatigue, shortness of breath, and lightheadedness) are slow to develop, as over time these immature bigger cells become a larger proportion of the blood leading to less efficient transporting of oxygen throughout the body.

However,  B12 deficiency does no always give symptoms related to blood.  For instance, when signs of dementia or neuropathy are observed, B12 deficiency is not usually the first cause to come to mind.   In addition, high levels of folate can sometimes temporarily mask anemia, delaying the diagnosis of B12 deficiency and allowing nerve damage to go undetected.

Vitamin B12 can be measured directly in the blood.  Along with 3 other markers blood tests can be used to diagnose B12 deficiency.  Two of these other tests are for higher levels of homocysteine (Hcy) and methyl malonic acid (MMA).  Due to the absence of B12, the cellular cycles they are part of are interrupted, causing the levels of these compounds to rise.  The last biomarker tested for is the amount of active B12 (holoTC) present.  HoloTC (about 10-30% of the B12 in normal blood) is the form of B12 that can readily enter a cell and thus drive critical cellular processes.  So a measurement of that is lower than the norm can be indicative of B12 deficiency.

A diagnosis of B12 deficiency can readily be countered by supplementing B12, either by IM injection or daily pills.  However, for many B12 will need to be taken regularly for the rest of one’s life (along with periodic blood tests) in order to avoid the consequences of being B12 deficient.

 

 

Vitamin B12 and Homocysteine Levels Predict Different Outcomes in Early Parkinson’s Disease – The occurrence of Parkinson’s Disease (PD) and B12 deficiency both increase significantly as the population ages. Thus the chance of being B12 deficient (or high homocysteine) and having Parkinson’s becomes more probable. No causative connection has been found between the two conditions.  Yet both conditions share some of the same symptoms.

How B12 and homocysteine (a biomarker for low B12) levels can affect individuals with early Parkinson’s disease is the subject of the Christine article.  The first issue of note is that due to the similarity in the symptoms, B12 deficiency or elevated homocysteine levels can often be overlooked in these PD patients.  Not recognizing the presence of these problems could lead to a more rapid decline in mobility and/or cognitive abilities.

Early PD patients were followed for up to 24 months and their declines in both mobility and cognitive skills were measured periodically.  Comparisons were made between those with normal B12 and homocysteine baseline levels to those with who either had low B12 or high homocysteine or both.  Interestingly, low B12 at baseline predicted a more rapid decline in mobility, while elevated homocysteine foreshadowed a potentially swifter cognitive decline.  This suggests that supplementation with B12 (and folic acid for elevated homocysteine) for these individuals could result in a slower decline in mobility or cognitive abilities.  The authors believe that B12 and homocysteine levels need to be checked for patients with Parkinson’s to ensure that the true cause of all the symptoms are recognized. One other recommendation is that a study should be initiated to determine if proper supplementation to normalize B12 and/or homocysteine would result in slowing the decline for these early PD patients.

 

 

Primer:  Vitamin B12 deficiency – The Green, et al article explains B12 deficiency in terms of risk factors, prevalence, mechanisms of occurrence, symptoms, diagnosis, prevention and management.  Focusing on the management of low B12 levels one needs to understand that this vitamin deficiency has two primary causes:  1) lack of sources of enough B12 in the diet (especially prevalent in certain 3rd world countries) and 2) problems with absorbing B12.

The remedy for the first is to ensure that B12 is part of one’s regular diet.  In this situation oral supplements are usually an appropriate solution.  However, when absorption is the issue, it is necessary to move onto a course of action whereby there is certainty that plenty of B12 is getting into bloodstream so that levels can rise to and stay in the normal range (>220 pmol/L).

Restoring B12 to back to the normal range can be done by either intramuscular injection or oral supplementation, but the success of the treatment needs to be monitored by checking the cobalamin in the blood, as well as by homocysteine and methyl malonic acid biomarker levels. High levels of these two biomarkers are an indication of B12 deficiency.   Staying with the treatment that consistently provides B12 in the normal range along with lower levels of homocysteine and methyl malonic acid is the key to avoiding the debilitating symptoms that occur if the amount of B12 sink back to deficient values.

 

 

Proton pump inhibitors, H2-receptor antagonists, metformin, and B12 deficiency:  clinical implications – Studies have clearly shown that long-term use of the drugs cited in the title do reduce systemic B12 levels.

Proton pump inhibitors (PPI’s) such as omeprazole (Prilosec) and H2-receptor antagonists such as cimetidine (Tagamet) reduce the amount of acid produced in the stomach.  This same acid is needed to free B12 (cobalamin) from the food that is eaten, so without the acid there is less of the vitamin to absorb later in the intestine.  Metformin is believed to effect the binding of B12 to intrinsic factor, the enzyme that facilitates absorption of the cobalamin.  In general, ceasing the use of these drugs allows B12 levels to return to previous levels.

The question the Miller paper is seeking to explore is whether or not supplementation or closer monitoring of these individuals who take these drugs for years is required.  The worry is that for those with low B12 levels the use of these drugs could push them into deficiency where clinical symptoms may begin to appear.  The author’s conclusion is that it would be a good idea to assess the patient’s B12 status (measuring B12 levels and biomarker levels) before and during the years of treatment with these drugs.  Secondly, studies should be carried out to see if taking B12 on a regular basis would lead to better outcomes for individuals using these drugs long term.

 

 

Current concepts in the diagnosis of cobalamin deficiency – Vitamin B12 (cobalamin) deficiency symptoms generally fall into two categories:  neurologic (related to the nerves) and haematologic (related to blood cells). Symptoms range from numbness – most often in the feet or hands, problems in walking, impaired dexterity, dementia, lack of energy, diarrhea, psychosis and depression.

The Green and Kinsella article highlights some of the difficulties in making the correct diagnosis of B12 deficiency.  For one, the symptoms observed are not unique to low B12 levels and, secondly, the measurement of cobalamin in the blood does not always tell the full story.  This is because only a portion of cobalamin is active (transcobalamin II, also called holotranscobalamin) and able to be taken up the body’s cells to perform its job as a coenzyme in two essential metabolic pathways.

The authors propose a procedure for doctors to follow to make the proper diagnosis, primarily by looking at cobalamin levels, biomarkers of B12 deficiency (homocysteine and methylmalonic acid) and antibodies to intrinsic factor (an enzyme used to facilitate B12 absorption).