Oral agents for Diabetes Mellitus 2

                    Oral agents for Diabetes Mellitus type 2.

                                               PKGhatak, MD  

 

Oral Drug Treatment of Diabetes Type II.

Diabetes-II is also called Adult diabetes; however, fundamentally the Diabetes- II is a different disease from Diabetes -I; the only connection between the two is that glucose utilization is abnormal in both diseases.

Glucose, a hexose sugar, is the principal energy-generating molecule that the human body utilizes. Glucose belongs to the carbohydrate class of food substances. Humans can also use other hexoses and pentose sugars. But under normal conditions, all forms of carbohydrates are converted to Glucose in the human intestine before it is absorbed. The Liver is the chief organ where Glucose is transformed into other sugars and glycogen, a complex carbohydrate for storage.

The Liver, in normal circumstances, converts Fat and Proteins into glucose; this process is called Neoglucogenesis.

Breastfeeding nursing mothers generate Galactose, another hexose sugar, from blood glucose to form milk sugar, Lactose.

To utilize Glucose by the tissue, the glucose molecule must pass through the cell membrane, for which Insulin plays a crucial role.

When Insulin production is altogether absent, the disease is called Diabetes mellitus-I. Whereas, in conditions where insulin production is present but insulin for one reason or another is ineffective in ferrying glucose molecules across the cell membrane, the disease is called Diabetes mellitus II.

Oral agents used in the treatment of Diabetes II.

In recent years, major advances have been made in oral antidiabetic medication. It is now almost standard, after initial attempts to control high blood sugar with a low-carbohydrate and 1500 to 18000 calorie diet, to start with Metformin. Then, if additional medication is necessary, a SG2 transport protein blocker is added.

The drugs are mentioned in order of their utilization in recent years.

Metformin:

Metformin. Brand name – Glucophage. It is a Biguanide. The pharmacological actions of metformin are different from other classes of oral agents. It decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin has an anti-androgenic effect, also improves insulin resistance and helps insulin enter cells. It is a useful drug in polycystic ovary disease.

SGLT-2 Inhibitors:

Canagliflozin, brand name Invokana. Canagliflozin interferes with Sodium-Glocose contraspoters (SGLT-2). SGLT-2 interferes with the reabsorption of sugar from the glomerular filtrate in segment 3 of the proximal tubules, and blood sugar levels fall, and more and more sugar is lost in the urine.

The results in weight loss, significantly reduced HbA1c levels and lower BP, lowers oxygen radicals and inflammatory mediators. Improvement in β-cell glucose sensitivity and insulin secretion is observed. A decrease in tissue glucose disposal and an increase in endogenous glucose production are noted.

Recent reports caution that concurrent use of Rosuvastatin and Canagliflozin may result in rhabdomyolysis and hepatotoxicity.

Dapagliflozn, brand name Farxiga. It is another SGLT-2 inhibitor. In normal conditions, SGLT-2 is responsible for 90 % of the glucose reabsorption in the renal tubules; blocking this transport mechanism results in glucose loss in the urine.

Empagliflozin, brand name Gardiance. It is the 3rd SGLT-2 approved in the USA. The mechanism of action is similar to the other two mentioned above. But it is worth remembering that SGLT-2 is a group of transporter proteins. In humans, there are 8 such SGLT-2  proteins, and each one is specifically abundant in certain organs. Though currently three SGLT-2 inhibitors are available, individual agent mainly prevent one such transporter protein in a specific organ. As a result, the toxicity and side effects are different in these drugs.

Thiazolidinediones:

This group of drugs acts by increasing the activity of Peroxisome proliferators, which increases Insulin sensitivity.

Because of hepatotoxicity and increased incidence of urinary bladder tumors, this drug was withdrawn from India and Germany; later studies cleared this drug, and now available in all countries.

Pioglitazone, brand name Actos. It is a selective agonist of Peroxisome proliferator activated receptor-gamma (PPAR-Y). These receptors are present in adipose tissue, skeletal muscle, and liver.

Rosiglitazone, brand name Avanda. It activates PPAR-y receptors and facilitates glucose and lipid metabolism.

Sulfonylureas:

There are several members in this group; at one time, these were the only effective oral agents. But the use of sulfonylureas have decresed with the arrival of severl new ganets, some of them are mentioned above. This medication works by stimulating the Beta cells of the pancreas by binding with ATP dependent Potassium channels, to incrse production of Insulin.

Common side effects of Sulfonylureas.

Skin rashes from sun exposure, weight gain, episodes of low blood sugar, gastrointestinal upset, nausea, and vomiting. Dark urine and hemolytic anemia in patients with glucose 6 phosphatase deficiency (G6P deficiency). Concomitant administration of other sulfa drugs tilts the free vs protein bound sulfonylurea in favor of the free form, which results in more therapeutic action and hypoglycemic episodes.

Common drugs of this group are-

Chlopropamide, brand name Diabesese.

Glipizide, brand name Glucotrol.

Glyburide, brand name Micronase

Tolazomide, brand name Tolinase.

Tolbutamide, brand name Orinase.

Acetohexamide, brand name Dymelor.

Alpha-Glucosidase Inhibitors:

Alpha-Glucosidase Inhibitors work by delaying carbohydrate digestion and absorption, thereby lowering the postprandial glucose load.

Significant side effects of alpha-glucosidase inhibitors include bone marrow depression. Liver enzyme elevation and increased incidence of Pneumocystoides intestinalis infection and intestinal obstruction.

Two agents are available in this group: they are -

Acarbose, brand name Precose.

Miglitol, brand name Glyset.

Edited May 13, 2025

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Immunocytes & Immunomodulators

                         Immunocytes & Immunomodulators

                                     PKGhatak, MD

Newton's first law of motion states that every action has an equal and opposite reaction. Our body is also governed by a similar law, for every function, there are the Stimulators and Suppressors mediated through proteins. Advances in molecular biology have led to the unlocking of secrets of the mechanisms by which the body detects and eliminates disease causing agents and cancer. This branch of therapeutics is called Immunotherapy and the agents are known as Immunomodulators.

Immunocytes produce proteins which act like keys and fit perfectly to a specific receptor present on the surface of the effector cells and initiate reactions and the response can be either stimulation or suppression of immune reactions. The immunocytes communicate constantly with each other and react in response to secreted proteins.

In the end, the Immunoglobulins are produced by Plasma cells. Immunoglobulins neutralize foreign agents and the natural killer cells (NK) and phagocytic cells engulf foreign substances and remove accumulated debris.

The immunoglobulins are many; written as IgM, IgG, IgA, IgD and IgE. The IgG is subdivided into many fractions. Both IgM and IgG are present in plasma, IgA is most abundant in the enterocytes of GI tract, genitourinary tract and in tears. IgD is bound to lymphocytes B (B cells). IgE appears in plasma, it is active against multicellular foreign organisms and parasites and is associated with allergy.

Immunocytes:

A group of cells - the White Blood Cells (WBC), Macrophages, Plasma cells and Dendritic cells are collectively called Immunocytes.

B-lymphocytes (B-cells)

Among the WBCs the Lymphocytes play a crucial role. Lymphocytes are divided into B-lymphocytes (B stands for bursa Fabricius of birds) and T-lymphocytes (T for Thymus) according to their origin. Both B-lymphocytes and T-lymphocytes are subdivided again into many numerical numbers according to the presence of surface CD (cluster designation) and are grouped as stimulators and suppressors.

During the maturation process, the B-lymphocyte travels to the thymus, spleen and lymph nodes. B-lymphocytes are activated by dendritic cells by presenting them with an antigen and the activated B-cells in lymph nodes act as temporary memory cells and the rest of the B-cells return to the bone marrow to become permanent Memory cells.

T-lymphocytes (T-cells).
T-lymphocytes originated in the embryonic Thymus gland. A subgroup of T-cells is natural killer cells (NK cells). T-lymphocytes perform a multitude of immunological functions along with B-cells.

Dendritic cells.

Dendritic cells are known as antigen presenting cells. In the skin, they are called Langerhans cells. In addition to skin, these cells are present in the nose, respiratory tract, stomach and intestine. Immature dendritic cells are present in peripheral blood. Dendritic cells attack foreign antigens and also diseased body cells and take a bite out of them and then process the antigen and finally hand over the antigen to plasma cells for antibody production. Also, the dendritic cells supply B-cells with antigens, and B-cells become memory cells.

Plasma cells.

Plasma cells originate in the spleen and lymph nodes from activated B-cells. Then the activated B-cells move to the bone marrow and reside there permanently. Plasma cells have large cytoplasm and an eccentrically located nucleus with coarse chromatin. Plasma cells are the chief producers of Immunoglobulins. Initial production of immunoglobulin is IgM specific to an antigen, then after a week or so, the IgM production slows down and the plasma cells start to produce IgG antibodies in response to the same antigen.

Macrophages (large eaters).

Macrophages are derived from monocytes of the blood. This transformation takes place as the monocytes extravasate the blood vessels in response to cytokines. Macrophages present in all tissues and assume different shapes are called histiocytes in connective tissue, Kupffer cells in the liver, osteoclasts in bone, microglia cells in the brain, etc. Macrophages exhibit amoeboid movement. Macrophages encircle foreign substances like bacteria or virus particles or decaying cells and digest them and help clear the field of cellular debris, prerequisite for repair.

Eosinophils.

Eosinophils originate in the bone marrow and are present in blood and all places except in the skin, lungs and esophagus. Eosinophils respond to multicellular organisms and parasites. Eosinophils are involved in anaphylaxis, asthma and atopic dermatitis, hay fever, and also produce many cytokines.

Basophils. Basophils produce heparin, histamine, serotonin, and IL-D4. Basophils have IgE receptors on the cell surface. After binding with the antigen, the conjugates initiate allergy and chronic inflammation to parasites. Like eosinophils, basophils are responsible for anaphylaxis, allergy and hay fever.
  

Cytokines:

These are products of immunocytes, cytokines are also produced by some non-immunocytes, like endothelial cells, fibroblasts and stromal cells. There are several cytokines and are named according to the substrate they act on, e.g., Interferons, Interleukins (ILs), Lymphokines, and TNF (tissue necrosis factor). Cytokines are peptides, secreted in minute amounts, measured in picograms (1 pico = 0.001 nano) are very potent but the range is limited to cells of origin or nearby cells only. Cytokines may be inactivated by small molecules which form a covalent bond with the active site of cytokine and are known by a suffix "tinib" e.g., Acalabrutinib.  Cytokine must attach to its specific receptors on the surface of effector cells and requires a perfect fit as a key fit with the lock in order to initiate the production of an enzyme (- kinase). Because cytokines are antigenic, specific antibodies can be produced in animals or in cell cultures against cytokines and cytokine receptors for therapeutic use.

Therapeutic Use of Immunocytes and Antibodies:

Monoclonal antibodies (mAbs).

Monoclonal antibodies are produced by the activated plasma cells, and these antibodies attack a specific antigen. The antigens may be a biological substance like viruses and bacteria. Antigen can be cytokines, cell surface receptors and also a lab-engineered hybrid antigen. 

In the laboratory these monoclonal antibodies are produced and purified for transfusion the patients.

Medical conditions where mAbs are in use are expanding, particularly in the treatment of malignancy. Some of the well-known conditions of mAbs use are malignant melanoma, rheumatoid arthritis, Crohn's disease, and multiple sclerosis.

The currently available mAbs are – for TNF- Infliximab, etanercept, adalimumab, golimumab. For T-cell inhibition - abatacept. For B-cell inhibition - rituximab, belimumab. For IL-1 receptor inhibitor - anakinra. IL-6 receptor inhibitor- tocilizumab, sarilumab. For IL-6 cytokine – cetuximab.

Checkpoint inhibition: 

Cell population at any moment is a balance between new cell formation and programmed cell deaths. Cell deaths are performed by an enzyme called Caspase. PD1 protein on T-cell prevents cell death. Cancer cells copies PD-L1 proteins and prevent T-cell directed cancer cell death.  

PD-1/PD-L1 monoclonal antibodies.

Cancer cells of the breast, stomach and other organs express PD-L1 legends on their surface. T-cells are attracted to cancer cells and bind with cancer cells, thereby making T-cells inactive. And thus, cancer cells escape NK cells and continue to grow.

Monoclonal antibodies PD-1/PD-L1 are Atezolizumab, Avelumab, Nivolumab and pembrolizumab. 

CART Therapy:

Chimeric Antigen Receptor T -cell therapy involves patient's T-cells made to recognize and kill cancer cells by genetically modifying T-cells to express CAR receptors on their surface, against a specific tumor antigen. Then these genetically altered cells are grown in large numbers in the laboratory then transfused back to the patient. This therapy is most effective in the treatment of relapsed leukemias and multiple myeloma

EGF (Epidermal Growth Factor) and HER2 Receptor (human epidermal growth factor receptor2).

Epidermal Growth Factor (EGF) is a protein that binds with EGF Receptors on the cell surface initiates cell proliferation, and differentiation and prolongs cell survival. It works through the Tyrosine-kinase system.
Antibodies to EGF.
Currently, available mAbs that bind to EGF are Gefitinib, Erlotinib, and Afatinib.

Antibodies to HER2.

Cancer of some breasts, stomach and other solid organs is treated with the HER2 mAbs, e.g., Trastuzumab and Pertuzumab,

VEGRF.

The vascular epidermal growth factors can be blocked by antibodies, e.g., Bevacizumab and ranibizumab

VEGRFRmAbs (Vascular epidermal growth factor receptor monoclonal antibodies.) Ramucirumab is available.

Polyclonal Antibodies (pAbs).

There are two ways to produce pAbs. One is from donated blood pools, isolating and purifying the antibodies, and the second method is to inject multiple antigens into a suitable animal and collect the antibodies. Animal origin pAbs are used in the treatment of snake bites, jellyfish toxins, spider bites, etc.

The pAbs are the mainstay of treatment of the immune thrombocytopenic purpura (ITP). RhD negative mothers, pregnant with a second child tested positive for the RhD, are treated with pAbs to prevent hydrops foetalis in newborns.

The pAbs are also produced in labs. Human T-cells are injected in horses or any other suitable lab animals. After several days, blood is collected and the antibody containing immunoglobulins is purified. The pAbs so engineered are mainly used in acute rejections following kidney transplants. It is also a useful way to treat diseases of uncertain etiology where runaway immune reactions threaten life, as is happening in covid-19. Previously such pAbs were used in Ebola. MRSA infections. It is useful in Digitalis toxicity, Kawasaki disease and recent incidents of COVID-19 Kawasaki syndrome. Guillain-Barre syndrome is treated with mAbs along with plasmapheresis. Similarly, Myasthenic crisis responds to a similar intervention.

Medications that can modify cell growth and production of tissue damaging factors:

Disease Modifying Drugs (DMD):

Human immunity has two components - the inborn or Innate immune system. Innate immune response to a foreign invading agent takes place within hours.  Adaptive Immune system response usually takes weeks to months. This adaptive system consists of 3 parts, namely antibodies, B-cells and T-cells.

Autoimmune diseases are treated with drugs that are in use for a long time. Most of the drugs are well known - like prednisone, cyclophosphamide, cyclosporine, methotrexate, azathioprine, gold compounds, sulfadiazine, etc.

Biological drugs are at present favored over traditional chemical compounds, though used together, results are much better.

Some common uses of MAbs:

Rheumatoid arthritis. Overactive TNF is controlled by Etanercept containing a fusion protein IgG that binds with TNF alpha. Infliximab is a chimeric mAbs used for the same purpose. Adalimumab is a humanized mAbs also binds with TNF alpha.

IL-6(interleukin-6), an IL-6 receptor blocker, Tocilizumab, is used in solid organ rejection.
IL-2 receptor blockers are used in metastatic melanoma and renal cell carcinoma.

Psoriasis and Psoriatic arthritis.  Anti TNF therapy with mAbs in psoriasis and psoriatic arthritis responds well.

Polymyositis and dermatomyositis. B-cell mAbs, Rituximab, is used with success.

IgG4 related disease has a varied presentation. Rituximab is used with conventional DMD. 

Wegener Granulomatosis / Granulomatosis with polyangiitis. It is associated with antineutrophil cytoplasmic antibodies (ANCA). Anti B-cell mAbs, rituximab, with prednisone are commonly used.
In asthma, Omalizumab, an IgE inhibitor, is used.

Antiviral mAbs. 
Bavituximab, a serine mAb used in Hepatitis C.
Palivizumab, a RSV virus mAb, is used in respiratory syncytial virus bronchiolitis and pneumonia.
Anakinra and Tocilizumab, IL-1 and IL-6 receptor inhibitors respectively, are at present undergoing trials in COVID-19 pneumonia and multi organ failure.

Use of mAbs in hematologic cancers
Rituximab, a CD B20 chimeric mAb used in non-Hodgkin's lymphoma.
Alemtuzumab, a CD52 on B-cell & T-cells used in B cell leukemia. 
Gemtuzumab, a myeloid cell antigen CD33 humanized mAb used in relapsed myeloid leukemia.

 Clinical Use of Monoclonal Antibodies:

Recently, mAbs are approved for the treatment of neurological diseases. 

Multiple Sclerosis (MS). MS is an autoimmune disease resulting in damage to myelin sheath from cytokines overproduction. Glatiramer acetate binds with CD4B-cells and CD4T cells and decreases cytokines production.

Natalizumab, an alpha 4 integrin mAb, binds with immunocytes and prevents them from crossing the blood brain barrier.
Rituximab, an anti-CD20 mAb, lowers complement and cytokines.
Ocrelizumab acts in the same manner.
Alemtuzumab binds with TCD52. Fingolimod is an analog to sphingosine. It binds with sphingosine receptors on T-cells and B-cells and limits cytokine production.

Migraine.
The etiology of migraine is not fully understood but migraine pain is due to the release, at the end of the nerve terminals, a preformed calcitonin gene related protein (CGRP) at the junction of nerve terminals and smooth muscles in the intracranial vessels. CGRP protein binds with CGRP receptors (CGRPR) present on the blood vessels and results in a release of pain causing substance P. Examples are -  Erenumab.
Frenanezumab and Galcanezumab are mAbs that neutralize CGRP ligand and Galcanezumab use limits the incidence of migraine attacks and shortens the duration of migraine.

Adverse effects:
 Disease modifying drugs are an effective treatment for autoimmune diseases and cancers. Biologic modifying agents are used in increasing numbers. However, biological substances have serious side effects. Infection with atypical organisms, atypical mycobacteria, fungal infections and the recurrence of previous viral illnesses - particularly Hepatitis B and C and cytomegalovirus are problematic. Reactivation of old TB and varicella are not unusual. In long-term follow-up of biological DMD shows an increased incidence of lymphoma and leukemia.

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Edited march 2026.

Stem Cells & Stem Cell Transplantation

Stem Cells and Stem Cell Transplantation.

                      PKGhatak,MD

 

Stem Cells and Stem Cell Transplantation.

The total number of cells in a human body is unknown. It is estimated that an adult average person has 34 trillion cells, about 200 different cell types. The cells perform a multitude of functions. However, one group of cells is assigned only one bodily function, take for example - liver cells are assigned protein manufacturing, whereas, kidney cells filter blood and discard the waste product as urine. Each cell has 23 pairs of chromosomes, (sperm and ovum just one copy), and the genes of the chromosomes carry the blueprints of cellular functions. The question then arises, who decides the type of function a cell should perform and who is watching over. Why not one day the liver cells start producing urine like kidney cells. Molecular biologists and bioengineers are gradually unlocking those secrets and applying their knowledge in creating new exciting chapters in human biology.

In every organ, there are primitive cells that have retained the embryonic property, namely, the capacity to produce several lines of cells. Stem cells are also distinct in another way from mature cells- they can replicate themselves and produce mature cells at the same time.  These cells are the mother of all cells and jack of all trades and are called Stem Cells.

We have three distinct types of stem cells.

1. Embryonic Stem Cells are also called Pluripotent Stem Cells. They can turn out any line of cells.
2.The second type of stem cell - the Induced Embryonic Stem Cell. Scientists make them in laboratories from Adult Stem cells (not to be confused with the cells from an adult person). Induced embryonic stem cells function the same way as regular embryonic stem cells.

3. And the third group is the Adult Stem Cells. They are present in all tissues, organs and peripheral blood. But each adult stem cell is limited to generate just one line of cells. These cells are named according to their place of origin, for example - Mesenchymal stem cells originated in embryonic mesoderm, and Hematologic stem cells originated in the bone marrow. 

Additional sources:

A. There is an additional source of stem cells from cord's blood and blood in the placenta. Cord stem cells are able to cross the blood brain barrier. Another advantage of cord stem cells is that they do not produce significant adverse immune responses in recipients.

B. Scientists are capable of engineering the Embryonic stem cells to become Progenitor cells then turn them to precursors to adult stem cells and finally to mature cells. They can reverse the process and make the Embryonic stem cells from the adult stem cells. Scientists also know how to coax the bone marrow and other tissues to release stem cells in the peripheral blood. 

C. Scientists can clone human embryonic stem cells in the laboratory from an unfertilized egg, they first remove the nuclear material and replace it with the nuclear material from a cell of a patient waiting for stem cell transplant. This engineered egg cell then advanced to a Blastocyst and was guided to become an embryonic stem cell and finally into adult stem cells.

                                                            Transplantation:

The sold organ transplants began with a cadaver kidney transplant in 1950 in France. In 1954 a kidney transplant was successfully performed in Boston, MA using a kidney from a living donor.

In 1956 a Bone marrow transplant was performed in New York. A leukemia patient received a bone marrow transplant from his twin brother. These successes encouraged bone marrow transplantation. Now it has become a standard therapy in Leukemia and related conditions.

Bone marrow transplants for non-cancerous blood conditions are a natural extension of that success.

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Some confusing terminology.

Allo -means the other person or not genetically identical. Auto - means from one location to another in the same person. Autologous- means tissue obtained from the same person. Syngeneic - means biologically similar or identical. Homeostatic - means inert like bone and cartilage.

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Basic Consideration for stem cell transplant.

Stem cell transplantation is not risk free. In allogeneic transplants, the donor ABO blood group and HLA tissue group must match with recipients' and thus the availability of donors becomes a big hurdle. Several life-threatening complications, both prior and post transplants, must be avoided. Immune reactions may lead to graft failure and graft versus the host disease as seen in solid organ transplants. 
 [ It should be kept in mind that stem cells are modified in the laboratory to match a particular organ or tissue requiring a transplant. ]

Bone marrow  failure is the most often reason for for stem cell transplantation in Non - malignant condition. and the second group is chemotherapy and radiation therapy induced bone marrow depression.

 A. Stem cell Transplantation for Non-malignant diseases:

 1. Aplastic Anemia.   In aplastic anemia, the Hematopoietic stem cells fail to produce adequate numbers of Red Blood cells (RBC), WBC (white blood cells) and Platelets. Anemia becomes very profound.

2. Other conditions lead to Aplastic anemia. - Radiation injury to bone marrow as documented in atomic bombs survivors in Japan.

3. Accidents in atomic power plants result in the leakage of radioactive gases and water into the environment.

4. Excessive radiation exposure to techs and doctors in the radiology department of hospitals.

 5. .Intentional or accidental poising with radioactive agents. 

6.Thalassemias, paroxysmal nocturnal hemoglobinuria.

7. Sickle cell anemia. Heavy metal poisoning, exposure to benzene and gasoline byproducts.

8.Viral infections - it includes HIV, all hepatitis viruses, specially, Hep B and Hep C. Epstein-Barr virus, Parvoviruses, Cytomegalovirus.
Recent COVID-19 pandemic some sick patients were found to have depleted beneficial immune cells and mesenchymal stem cell transplantation to replace immune cells is undergoing trial in some centers.
9. Diseases like Lupus, Rheumatoid arthritis.
10.Drugs - many drugs are known to produce bone marrow depression, these drugs are numerous, starting from chloramphenicol to phenylbutazone. 
11. Several congenital immunodeficient diseases - Fanconi anemia, Diamond-Blacklane syndrome, Schwachman Diamond syndrome.

Since the patient's own hematopoietic stem cells are nonfunctional, a bone marrow transplant, either from a matched donor or matched cord blood (Allogenic) stem cell transplant is performed. This procedure is called Allogenic hematopoietic stem cell transplantation.

 Experimental Stem cell transplantation.

1.Neurological diseases:  Stem cell transplant, initially, was enthusiastically welcomed as the lifesaver for Parkinson's disease. Alzheimer disease. Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Spinal cord injuries, and Strokes. Neurogenic stem cells and Cord Blood stem cells were used. But long term results were disappointing. At present stem cell transplantation in neurodegenerative diseases is considered experimental. Similarly, spinal cord injury cases are abandoned. 

2. Heart diseases:  Damaged heart muscles can be repaired by injecting mesenchymal stem cells directly into damaged muscles in experimental animals. A few years later similar stem cell transplants were performed in the post MI heart failure patients. Stem cells were given IV. Heart specific adult stem cells and mesenchymal stem cells were used. Now, such procedures are considered experimental because of frequent complications.

 3. Liver diseases: Stem cell transplants are performed on varieties of liver diseases, the most frequent among them are Alcoholic cirrhosis, Non-alcoholic cirrhosis, Alpha 1 antitrypsin deficiency, Autoimmune liver diseases, Galactosemia, Hemochromatosis. Wilson's disease, Gilbert syndrome. The initial enthusiasm now has subsided because of frequent failures. It is relegated as experimental. 

4. Wound repair: The skin is rich in mesenchymal stem cells. These stem cells are used in various types of wounds to speed up the healing and repair of ligaments, cartilage and bones.

 5. Juvenile Diabetes: Juvenile diabetes is due to autoantibodies attacking the Beta cells of the pancreas, resulting in Insulin deficiency. Engineered beta cells are transplanted and done. Initial results are encouraging. 

Malignant condition:

 A. Patients with Hematological Malignancies are good candidates for stem cells transplants:
Acute Myeloblastic leukemia (AML), Acute Lymphoblastic Leukemia (ALL) and Chronic Myelocytic Leukemia (CML) happen due to the translocation of genes known as the Philadelphia chromosome.  Allogeneic hematopoietic stem cell (from a donor) transplantation produces good results and promises a cure. Donor stem cells are needed because the malignancy involves the hematopoietic stem cells of patients.

B. Multiple Myeloma: The disease is a malignancy of the Plasma cells.  Autologous hematopoietic stem cell (stem cells harvested from the patient) is done. It is considered curative therapy.

C. Lymphoma, Lymphosarcoma, Mantle cell lymphoma, Non-Hodgkin Lymphoma, myelodysplastic syndrome is treated with Autologous hematopoietic stem cell transplants following initial chemoradiation, in cases of recurrence.

D. Ewing Sarcoma: This childhood bone sarcoma is due to a translocation of genes between chromosomes 11 and 22. After a relapse following chemo-radiation therapy Autologous hematopoietic stem cell transplantation is generally performed.

D. Solid organ malignancy:

  At one time it was thought to be an answer to advanced solid organ cancers. The hematopoietic stem cells are harvested from the bone marrow of the patient first in the preparation for stem cell transplant, then the patients are subjected to a very high dose of chemotherapy agents followed by whole body radiation and the head, to eliminate every possible cancer cells. Then Autologous stem cell transplant is performed.
The results are not very encouraging at present; this is relegated to the experimental status.

[ Malignancy of the solid organs treated with chemotherapy and radiotherapy often causes severe bone marrow depression. Allogeneic hematopoietic stem cell transplants are performed to replace them.]


Perils of Stem cell Transplantation:

1.The transplant may fail to take hold and ultimately fail.
When patients' immune system is severely depressed the patients become very vulnerable to infection by every kind of infectious agent, including reactivation of previous virus illnesses and tuberculosis. 2. 2. After a transplant, it takes time for the body to replenish the immune system and the patient still remains vulnerable to infection. 
3. Rejection of graft (stem cells) by the recipient.
4. Graft versus Host disease: Here the graft tissue (transplanted stem cells) attacks the host's cells and damages various organs and tissues.

These anticipated complications are well known to the transplant centers and proper treatment protocols are in use. It should not be a major concern to needy patients.

Ethical issues. It began in earnest when cloned of human stem cells were produced in the laboratory. At present the clone stem cells are not used in transplants. Stem cells are obtained from the patient's peripheral blood or from their bone marrow and also from donors. But still, it generates debates among the concerned population.
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Covid-19 Vaccine

                          Coronavirus Vaccine

                                              PKGhatak,MD

Coronavirus Vaccine.

There are several coronaviruses, but most of them are harmless to humans. The coronaviruses that cause human illnesses are mentioned below

The common cold:

80% of the common cold is due to Rhinoviruses. Various other viruses are also responsible for the common cold, among them are several coronaviruses. No effective vaccine for the common cold is on the horizon.

Influenza:

There are many similarities between influenza and COVID-19, including the viral structure. Though the influenza virus belongs to the Orthomyxovirus family. The yearly vaccine contains several strains of influenza viruses that are needed to protect against emerging mutants of the Influenza virus. The vaccines are made either in cell culture or in eggs, then killed, and the antigens are extracted. Influenza viruses undergo frequent mutations and the vaccine has to be modified every year. The immunity lasts only one year.

MERS (Middle Eastern Respiratory Syndrome):

MERS is due to a coronavirus. Between 2012 and 2019, about 2,500 people were infected with the MERS virus and 858 deaths were recorded. 80% of deaths took place in Saudi Arabia. No MERS vaccine has been produced to date.

SARS:

A local epidemic broke out in Guangdong province in China in 2002 – 2003. The virus had killed 778 people in 29 nations and infected 8,000 people. The virus is called SARS-CoV-1 and the disease SARS (severe acquired respiratory syndrome). A worldwide search for a vaccine was launched. But 18 years have passed without significant success.

COVID-19.

In December 2019, another coronavirus, SARS-CoV-2, began a murderous march. It began in Wuhan City of Hubei province of China. As of this date, this virus has killed 200,000 people and infected 3 million people worldwide, sparing only a few isolated islands.

Steps in vaccine development

Previous experience with the development of vaccines for coronavirus diseases is not particularly encouraging. No one can say when such a vaccine will be found. Finding a vaccine quickly can't be predicted.

What are the track records of Viral vaccine development:

Bacteria, one of the infectious agents, were first identified by Robert Koch in the 1800s, and he was also able to grow bacteria in agar in his laboratory.

In 1858, Louis Pasteur demonstrated that sterilization prevented fermentation of grapes into wine, a process that killed the yeast responsible for fermentation, and after that, the Spontaneous generation theory was thrown out.

In 1885, Louis Pasteur successfully treated a 9-year-old boy with Rabies with a vaccine he developed by repeatedly passing the rabies virus in the rabbit brain, thereby weakening its virulence but retaining its antigenicity.. He developed this method of attenuation of viruses between 1881 and 1885.

But he was not the first person to develop a vaccine to treat a viral illness. That distinction goes to Edward Jenner. In 1796, he took a sample of cowpox pus (Vaccinia is the name of the virus) and inoculated an 8-year-old boy and a few months later, inoculated him with the live smallpox virus (the virus is called Variola). The boy remained well and had no ill effects. It was slowly accepted in the medical community and subsequently, the vaccination was adopted by all advanced countries.

 Smallpox has been totally eliminated from the world by the tireless work of the WHO and others. The success of Jenner is an exception to the general rule. Cowpox and smallpox are related viruses and, fortunately, they carry the same antigen and the vaccine for cowpox also protects against smallpox. It must be mentioned that live viruses are not safe to introduce into the human body.

 Currently, the smallpox vaccine is made using a weakened virus grown in cell culture.

To honor Edward Jenner for his gift to humanity, Louis Pasteur called his invention the vaccine.

Other examples of success stories:
 

Take, for example, the Yellow Fever Vaccine.
In 1793, Philadelphia, Pennsylvania, saw a yellow fever epidemic that killed 5,000 people out of a population of only 50,000 at that time. In a panic, the city was practically abandoned.

Yellow fever killed more soldiers in the Spanish-American War of 1868 than in combat. During the construction of the Panama Canal in 1912, several thousand died. Dr. Max Theiler produced a vaccine after a continuous 30 years of trial from a weakened strain of the virus by 30 passages in the mouse brain.

Polio vaccine:

Salk's intramuscular polio vaccine is a product of a weakened strain of poliovirus, grown in monkey kidney cells and inactivated by formalin. It became available in 1954. It took him several years to develop a safe polio vaccine.

Sabin Oral Polio vaccine contains 3 strains of the polio virus, made safe by repeated passage through a primate and cultured in primate cells.

Failure stories:

HIV/AIDS:

HIV jumped from chimpanzees to humans in 1920. In the 1980s, it began to spread from Africa to other countries and became a great health risk for people all over the world. It has now been 30 years since the HIV/AIDS infection began. Fortunately, many safe and effective antiviral drugs can keep patients alive. Research began worldwide in the 1980s for an effective vaccine.  But no vaccine has been produced so far.

Dengue fever:

Though a vaccine was marketed in 2019 within a reasonably short period, however, the vaccine had to be withdrawn because, in post-vaccine patients who were re-infected with dengue, the symptoms were much more severe than in people who were not vaccinated.

The anthology of vaccines is full of stories of successes and failures. Many dedicated researchers and scientists put in countless hours of hard work and sleepless nights behind each vaccine production. The outcome of any research in the arena of biological systems is very unpredictable. In vaccine research, no one can dictate to the researchers to come up with a successful product in 5 months when, in actuality, it takes years, if not a lifetime.

Moderna Boston group.

They are using an engineered messenger RNA (mRNA). It induces viral protein in humans. That triggers antibody production. It is important to note that there is no previous mRNA vaccine produced by anyone that is approved for human use.

Chinese company Sinovac vaccine.

They are using an inactivated COVID-19 virus. This vaccine is safe for humans. The Chinese government has started inoculating its military personnel with this vaccine.

A recent report from India regarding antibody response to the COVID-19 virus infection or post-vaccine response shows that 14 % had no antibodies in blood when tested. The investigators commented that the timing of tests is important because the antibody levels fall in 2 to 3 weeks' time. So, the absence of antibodies does not mean that 14 % did not have antibodies at all.

  From Iceland, an opposite result is published. They used 6 different antibody tests, including two Pan Immunoglobulin (IgG, IgM, IgA) assays to document antibodies in COVID-19 recovered patients. Also, they used Quantitative Polymerase Chain Reaction(q-PCR) assays to identify COVID-19-infected patients. In their study, antibodies remain in the blood for 4 months. And 91 % of patients had antibodies for up to 4 months. The viral particle tests by PCR have fewer false-positive or false-negative results. Quantitative PCR eliminates positive test results. It appears Iceland investigators placed emphasis on finding antibodies by 6 tests and limited virus-positive tests by qualifying the quantity of virus present.

edited  June 2025.

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Mechanical Ventilators

                         Mechanical Ventilators

                                           PKGhatak, MD

 

Mechanical Ventilators:

Every person today has heard "Ventilators”. The ventilator has become the most sought after breathing machine by hospitals around the world inundated with COVID-19 patients requiring assistance in breathing just to keep them alive.

Today's Intensive Care Unit of hospitals is a reminder of 1930s hospitals filled with Polio patients on Iron Lung – a rigid box supporting breathing by applying Negative Pressure on the torso, only the head and foot patients were sticking out of the box.

A leap forward:

In the early 1940s, Jet ventilation was introduced and Bennett and Bird. A mechanical device produced "Intermittent Positive pressure Breathing". (IPPB) 

The introduction of ICU (intensive care units) in hospitals virtually eliminated Iron Lung machines and a new era of Non-Invasive IPPB came into medical practice. In 1954, Salk's polio vaccine was given to school children and eventually wiped out polio and the need for ventilators fell way down.

Then came the Pressure control to Volume control ventilators and Non-invasive to Invasive ventilation. 


The chest wall moves outwards during inspiration. The lungs follow the chest wall outward. This causes the pressure inside of the lungs to fall below the atmospheric pressure and the air rushes into the lungs from outside. The recoil of the elastic tissues of the lungs and the chest wall brings the lungs back to their initial state in expiration. In mechanical ventilation, the reverse pressure difference takes place. The chest wall and lungs remain in a passive state. Air is forced into the lungs by a positive pressure (more than the atmospheric pressure) that makes the lungs and chest wall move outwards. That is not something the delicate lung structures can withstand without damage for just a few hours. Damage to the lung by mechanical ventilation is called barotrauma.

The progressive forward march of innovations in mechanical ventilators continued. From an Open Circuit to Closed Circuit to Double Circuits ventilators came next. Manual control of airway pressure, breath volume (tidal volume), adjustments of the duration of inspiration and expiration ratio, and Positive End Exploratory Pressure (PEEP) controls were induced by Puritan Bennett in their MA 1 ventilators.

Patient trigger ventilators came next. Intermittent Mandatory Ventilation (IMV), then Synchronized IMV (SIMV) were possible in new ventilators.

3^rd Generation of ICU ventilators:

Ventilators with Microprocessors were available. All aspects of ventilation came in Puritan Bennett 7200 ventilators with a display of pressure loop which eased operating complexities.

4^th Generation of Ventilators:

Much smaller size models were easier to operate during the transport of patients on ventilators, home use, and use in stable patients.

Non-Invasive ventilation came back in popularity.

Mechanical ventilation in the ICU and the emergency room (ER) meant the placement of an Endotracheal tube in patients. It is a traumatic experience for patients.

The endotracheal tube has to be secured in place by tapes to the mouth or nose. Even then, the tube has a tendency to slip down into the right bronchus, particularly when patients needed to be turned on their sides or out of bed for any reason.

The tube can be left in the trachea for only 5 days without causing local damage to soft tissues. A tracheotomy (an opening in the trachea) is needed to keep the endotracheal tube in place for a longer time.

All of these can be avoided if Non-Invasive Ventilation provides as good an outcome as can be obtained by Invasive ventilation. Recent developments in basic science made non-invasive ventilation gain its rightful place.

Common problems with ventilators:

It is a complex machine. It has several dials like the tidal volume, minute volume, pressures (in, out, peep, end-exp), oxygen concentration, carbon dioxide in expired breath, humidity, temperature, etc. There are as many alarms and lights as adjustment dials.

One should not expect a nurse or a doctor, who has not previously operated on a complex and very sensitive machine, to handle it without adequate training. 

A more advanced ventilator " Adaptive Support Ventilator was introduced" to ease operation. When the patient's height, weight and desired tidal volume, maximum airway pressure, etc. are entered, then the machine automatically delivers the correct volume. 

But new does not always mean better. More automation implies more complexities and may not translate to better performance.

What are the adverse effects of mechanical ventilation:

1. Accidental disconnection of tubes from the machine may produce catastrophic events.

2. There are so many ventilators going on at the same time in the ICU, that there is hardly any moment without an alarm bell ringing. Nurses get immune to warnings and mistakes happen.

3, Under ventilation:

Under ventilation and loss of volume (atelectasis) of the left lung from the endotracheal tube sliding down into the right bronchus.

4. Rupture of lung and pneumothorax.

When one lung has near normal elasticity the other is not (due to the more involvement of one lung over the other), the more compliant lung gets more volume due to lower resistance, causing rupture of the lung from excess volume or pressure.

5. Injuries to delicate structures of the lung. 

When the lungs become very stiff, from accumulated products of inflammation a higher pressure is required to ventilate, producing damage to the alveoli.

6. Aspiration Pneumonia:

An inflatable balloon is positioned below the vocal cord in order to retain the tube in the correct place. But accumulated secretion trickles down the tube into the lungs and causes aspiration pneumonia.

7. Infection:

It is an unfortunately common problem in the ICU. It is known as pneumonia associated with ventilation.

8. Damage to the vocal cord:

This should not happen but does happen.

Today's ventilators are far cry from earlier days, these machines now can perform amazing maneuvers - not only can breathe for patients but also sigh, change the rate of breathing, hold breath for a specific period of time, and warm or cool temperature as required. Also, it can change oxygen concentration, and increase airway resistance during exhalation.

The mechanical ventilator is a life saving device for patients with respiratory failure. It can keep the patients alive for a short or a long period of time and even permanently with expert help and suitable machines.

It is a complex machine and expensive. Ventilators can't be turned out of factories on short notice. To properly operate a ventilator, one has to be trained properly and it takes time.

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