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Saturday, January 14, 2017

Treatment of Type II Diabetes Mellitus (T2DM) with Metformin in a nutshell

Metformin is a Biuagnide. It was derived from the herb Galega officinalis (French lilac, also known as Goat’s Rue or Italian Fitch) 

and has been used as a traditional botanical (tea infusion) for over 3,000 years to relieve polyuria (frequent urination) and halitosis (sweet odor on the breath), both are now well known symptoms of diabetes.

  • It was approved for the treatment of hyperglycemia in Britain since the late 1950’s, Canada in the 1970’s and U.S. in 1995.

  • Metformin is the most widely prescribed anti-diabetes drug (over 120 million prescriptions filled yearly worldwide).

Mechanism of action
      Lowers both basal and postprandial plasma glucose. 
      It decreases hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis. Enhances secretion of GLP-1 and peptide YY, which in turn affect systemic mechanisms including reducing hepatic glucose production through glucagon suppression and enhanced glucose-dependent insulin secretion
      Delays intestinal absorption of glucose

    Enhances insulin sensitivity by increasing peripheral glucose uptake and utilization.
      Some other unclear pathway
What is the Waiting Time to Show Effect?
      Usually, dose is gradually increased from 500 mg-1000 mg-1500 mg-1700 mg-2000 mg-2550 mg
      Gradual Increment lessens GI side effects
      May take days together to show its’ full effect, if prescribed in this manner.
      Mostly, effect is seen after 1500 mg/day dose is reached.
Whether Extended Release or Plain tablet?
  •   Extended Release is better tolerated-Maximum dose 2000 mg/day. Metformin should be taken with meals to help reduce stomach or bowel side effects that may occur during the first few weeks of treatment. Swallow the extended-release tablet whole with a full glass of water. Do not crush, break, or chew it.  
  •  Plain tablet-maximum dose-2550 Mg
What are the types of technology of manufacture?
      Dissolution/erosion controlled release
      Diffusion controlled release
      Osmotic controlled release
When to be taken?
If in single dose
  • Morning!
  • Evening!
If, taken in the evening, it works better by suppressing hepatic neoglucogenesis that occurs towards dawn.
What is passing in Stool? What is Ghost Pill?
Some patient see passing out of tablet in stool. They apprehend, the medicine might not be working. Why is passing out in stool?
It is the technology for delayed release of the ingredients and un digested portion comes out in feces.
Important Side Effects!
      Vomiting (Gastritis) and Diarrhea!
      Lactic Acidosis
      Sometimes B12 deficiency: vitamin B-12 concentrations of ≤ 150 pmol/l; Dietary calcium or Vit. B12 supplementation
The mechanism of vitamin B12 deficiency with metformin is undoubtedly due to malabsorption of vitamin B12 at its absorption site in the terminal ileum. Absorption of the vitamin B12-intrinsic factor complex is calcium dependent and metformin interferes with its’ effect on calcium-dependent membrane action in the terminal ileum.
In support of this hypothesis is evidence that dietary calcium supplementation reverses metformin-induced vitamin B12 malabsorption.
Can it be prescribed to Patients of Impaired Kidney Function?
What is Impaired Kidney Function
      Generally, 90-120 ml/minute/1.73 m2 of eGFR is taken as normal value.
       Levels below 60 mL/min/1.73 m2 for 3 or more months are a sign of chronic kidney disease.
      A GFR lower than 15 mL/min/1.73 m2 is a sign of kidney failure and requires immediate medical attention.
      Hence, in addition to the level of serum creatinine (creatinine levels reach 1.4 mg per dL {120 μmol per L) in women or 1.5 mg per dL (130 μmol per L) in men}.
Labeling Change Recommendation-FDA: FDA concluded, from the review of studies published in the medical literature, that metformin can be used safely in patients with mild impairment in kidney function and in some patients with moderate impairment in kidney function.
      eGFR below 30 mL/minute/1.73 m2: Metformin is contraindicated
      eGFR between 30-45 mL/minute/1.73 m2: Starting metformin is not recommended.
      Patients taking metformin whose eGFR later falls below 45 mL/minute/1.73 m2: assess the benefits and risks of continuing treatment. Discontinue metformin, if the patient’s eGFR later falls below 30 mL/minute/1.73 m2.

  • Before starting metformin, obtain the patient’s eGFR (glomerular filtration rate estimating equation).
  • It is recommended to have the eGFR estimated in patients of T2DM before starting of Metformin or metformin in combination; also periodically measure, while on the medication.
      Obtain an eGFR at least annually in all patients taking metformin. In patients at increased risk for the development of renal impairment such as the elderly, renal function should be assessed more frequently.
      Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/minute/1.73 m2; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart metformin, if renal function is stable.
Other Uses!
      PCOS (Polycystic Ovary Syndrome)
      Cancer (Breast, Colon, Lung, Pancreas and Prostate)!
It is believed that systemic effect of metformin manifested by the reduction of circulating level of insulin and insulin-like growth factor 1 (IGF-1) might be associated with anticancer action.
Old is Gold

Saturday, December 24, 2016

After supper walk a mile to burn more Fat!

The old saying, “after lunch rest a while, after supper walk a mile’ may hold good; a recent research, published in the Science Daily, suggests. 
The use of lipids/fats and glucose in muscle depends on the circadian rhythm and may have a role in metabolic disorders like obesity and diabetes. 
The research team performed a number of functional genomics studies that established the link between HDAC3 (Histone Deacetylase3) and the circadian clock. 
In normal mice, when the mouse is awake, the clock in the muscle anticipates a feeding cycle and uses HDAC3 to turn off many metabolic genes. This leads the muscles to use more carbohydrate. When the animal is about to go to sleep and anticipates a fasting cycle, the clock removes HDAC3. This leads the muscles to use more lipid. 
Although these studies were done in mice, the researchers speculate that human muscles most likely will follow the same cycle. The study opens the possibility of promoting body fat burning by increasing exercise activity during the periods in which muscles use lipid, which is at night for people. 
The master clock in the SCN (Suprachiasmatic Nucleus in Hypothalamus) drives circadian rhythms of behavior including the sleep-wake cycle and feeding patterns.
Overview of biological circadian clock in huma...
Overview of biological circadian clock in humans. Biological clock affects the daily rhythm of many physiological processes. This diagram depicts the circadian patterns typical of someone who rises early in morning, eats lunch around noon, and sleeps at night (10 p.m.). Although circadian rhythms tend to be synchronized with cycles of light and dark, other factors - such as ambient temperature, meal times, stress and exercise - can influence the timing as well. (Photo credit: Wikipedia)
Circadian rhythms are generated at the cellular level by a self-sustained molecular clock. Exposure to alternating cycles of light and darkness synchronizes the SCN clock, thereby aligning behavior with the solar cycle.
The SCN regulates rhythmic synthesis of endocrine factors, including the release of glucocorticoids, which can potentially synchronize peripheral clocks. Through its effects on feeding cycles, the SCN can also coordinate the timing of peripheral cellular oscillators.
In general, the primary function of clock control of processes is to prepare the cell/tissue for a predictable event before its onset; through regulation of metabolism, circadian clocks likely allow anticipation of daily fluctuations in energy demand and/or nutrient availability (e.g. increased physical activity during the awake phase).
Common behavioral/environmental risk factors for cardiometabolic diseases (e.g. food intake, physical activity, lighting, etc.) are known to influence circadian clocks in a tissue-specific manner, leading to the suggestion that circadian misalignment contributes toward obesity, diabetes mellitus, and cardiovascular disease. 
Losing body fat would be easier by exercising lightly and fasting at night. "It's not a bad idea to take a walk after dinner."


Monday, December 19, 2016

Endometriosis of the Cesarean Section scar

A young lady and mother of a child complained of pain in the right side of lower abdomen for more than 7 years. Apparently, it began about 1 year after the cesarean section delivery of her child. It has nothing to do with the timing of food, and her bowel and bladder habits were normal.
She was examined by many experts and her ultrasonogram of abdomen was showing a cyst in the ovary (Right). She was examined by me. I inquired about the suture materials used during the previous cesarean se4ction. I presumed it to be due to the use of non-absorbable suture material, like polypropelene, the knot of which sometimes gives rise to pain. However, as she could not exactly say about the use of the suture material, I too suspected it to be due to the ovarian cyst.
English: localisation of endometriosis Deutsch...
English: localisation of endometriosis Deutsch: Lokalisation der Endometriose (Photo credit: Wikipedia)
The cyst along with the innocent appendix was removed in a higher centre. But, she continued to experience the same pain and approached me again. This time, I could make out a tender sub-cutaneous nodule in the right lower abdominal wall. Again, I thought it to be a foreign body granuloma arising out of use of some non-absorbable suture material. Ultrasound was ordered for the abdominal wall. It suggested that there is a well defined solid sub-cutaneous nodule. I thought it to be some benign tumour of the fascia or again foreign body granuloma. The nodule was subjected to FNAC examination. It came out to be non-specific inflammation. It was presumed to be a foreign body granuloma.
It was planned for excisional biopsy. Intra-operatively, it was found that the nodule was a part and partial of the rectus sheath. The nodule was excised and fascial defect repaired. The HP study came out to be endometriosis.
Though, endometriosis is rare after a cesarean section, is a reality. This happens due to implantation of endometrial tissue from uterus during the cesarean section. Typically, endometriosis becomes painful, towards the time of periods, but this feature was not there in the present case.
Hence, painful and tender sub-cutaneous nodule in the scar of previous cesarean section should be suspected to be endometriosis.  


Monday, August 22, 2016

Dengue (DEEngee) in Nutshell



Sunday, June 19, 2016

Once Daily Combination Drug Linagliptin and Metformin approved by FDA for T2DM

The FDA has approved once-daily Jentadueto XR (linagliptin and metformin hydrochloride extended-release) tablets from Eli Lilly and Boehringer Ingelheim for the treatment of type 2 diabetes (T2D) in adults.
English: The blue circle is the global symbol ...
English: The blue circle is the global symbol for diabetes, introduced by the International Diabetes Federation with the aim of giving diabetes a common identity, supporting existing efforts to raise awareness of diabetes and placing the diabetes epidemic firmly in the public spotlight. (Photo credit: Wikipedia)

Indications: Jentadueto XR is a dipeptidyl peptidase-4 (DPP-4) inhibitor and biguanide combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D mellitus when treatment with both linagliptin and metformin is appropriate.

Dosage and administration: Individualize the starting dose of Jentadueto XR based on the patient’s current regimen. Do not exceed a total daily dose of linagliptin 5 mg and metformin 2000 mg. Give once daily with a meal.

Adverse reactions: The most common side effects include stuffy or runny nose, sore throat, and diarrhoea.


Sunday, May 8, 2016

2016 American Diabetes Association (ADA) Guideline for Primary Care of Diabetes

The American Diabetes Association (ADA) published the 2016 Standards of Medical Care in Diabetes (Standards) to provide clinicians, patients, researchers, payers, and other interested parties with the components of diabetes care, general treatment goals, and tools to evaluate the quality of care. The ADA Professional Practice Committee revised recommendations based on new evidence to include 8 key areas important to primary care providers, including:
Diagnosis – 
1. remains an A1c >6.5%, 
2. fasting plasma glucose >126; or 
3. an oral glucose tolerance 2 hr. result >200 mg/dL, or
4.  a random glucose >200mg/dL and classic symptoms of hyperglycemia.
English: Overview of the most significant poss...
English: Overview of the most significant possible symptoms of diabetes. See Wikipedia:Diabetes#Signs_and_symptoms for references. Model: Mikael Häggström. To discuss image, please see Template talk:Häggström diagrams (Photo credit: Wikipedia)
Glycemic targets - The HbA1c goal for most non-pregnant adults is less than 7%; more stringent HbA1c goals (such as <6.5%) may be recommended for patients without co-morbidities and who have a short duration of diabetes, and less stringent  A1c goals are appropriate for older patients with significant comorbid illness.
Hypoglycemia – severe or frequent hypoglycemia is an indication to modify treatment regimens.
Medical management – intervention should always include lifestyle modification with diet and exercise. If lifestyle modification is not sufficient to reach target A1c goals, then metformin should be added at or soon after diagnosis. If A1c is over target for longer than 3 months, then a second agent should be added. The second agent could be from the class of: sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, sodium–glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, or basal insulin.
Cardiovascular risk factor management - blood pressure treatment goal is <140/90 mm Hg, and an ACE or an ARB should be used as part of BP management. Statins are recommended for most persons with diabetes age 40 or older.
These recommendations highlight individualized care to manage the disease, prevent, or delay complications, and improve outcomes.
Citation: Chamberlain JJ, Rhinehart AS, Shaefer CF, Neuman A. Diagnosis and management of diabetes: Synopsis of the 2016 American Diabetes Association standards of medical care in diabetes. Ann Inter Med. 2016;164:542-552. doi:10.7326/M15-3016.
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