Thursday, December 31, 2009

Happy New Year

May God Decorate Every Golden Ray of the Sun Reaching You With Health, Wealth, Success and Prosperity for You in the Year "2010".

Wish you a "Very Happy and Memorable New Year".

Tuesday, November 24, 2009

Pre and Post Approval Carcinogenicity Studies

Carcinogenicity studies are needed in adequate number and multiple species of animals before the marketing approval of a drug to evaluate trans-species carcinogenicity. However, for infrequently administered drugs or short duration exposure compounds like anesthetics and radiolabelled imaging agents, these studies are not mandatory. Post-approval carcinogenicity studies must be conducted for the pharmaceutical compounds developed to treat serious diseases. Endogenous peptides or their analogs or protein substances like animal insulin, pituitary-derived growth hormone and calcitonin, which are administered in very low doses, are exempt from pre or post approval carcinogenicity studies. Carcinogenicity studies should essentially be conducted for the analogs if:

  • The dose to be administered is higher than the physiological dose.

  • Significant variation in biological effects as compared to the natural counterpart.

  • There is significant difference in the structure of synthetic compound as compared to natural counterpart.

Animals and doses for carcinogenicity studies:

The strains of animals selected for carcinogenicity studies should not have very high or very low incidence of spontaneous tumors. Rats are the most commonly used and accepted animals for such studies. However, the study may also be conducted on mice if the morbidity and rate of mortality of animals is not high during the period of study. Pre or post approval carcinogenicity studies should be conducted using at-least three dose levels. The highest dose should be sub-lethal and that should not reduce the life span of animals by more than 10% of expected normal life of animals. The lowest dose should be twice the intended therapeutic dose or same as therapeutic dose. The third dose should be intermediate dose between the highest and the lowest dose. An untreated group of animals as well as a vehicle control group should also be included in the study. There should be three groups of animals (50, 20 and 10 animals in each group) for high, intermediate and low dose of a drug. The period of dosing should be 24 months for rats and 18 months for mice. Equal number of animals of each sex should be included in each group of animals.The sacrificed and/or dead animals should be evaluated for neoplasia and histopathological changes in various organs and tissues. The effect on body weight, signs of intoxication and food intake should be recorded periodically. Urine analysis, hematology, biochemistry parameters, organ weights, gross pathology and detailed histopathology should be done for each animal under study. The description, site and dimensions of benign or malignant tumors developed should be recorded along with time of detection and histological typing should be worked out and recorded. Any benign or carcinogenic lesions detected during the post-approval carcinogenicity study should immediately be communicated to the Food and Drug Administration (FDA) or Drug Controller or Drug Research and Development Organization of you zone.

Wednesday, September 9, 2009

Renal impairment and Drug Metabolism

Renal diseases can cause considerable variability in drug response, which may present as enhanced or diminished drug response. Renal diseases (kidney diseases) affect the glomerular blood flow, glomerular filtration, tubular reabsorption and secretion. Renal bioactivation affects the drug metabolism, which causes alterations in drug absorption, bioavailability, distribution, binding of drugs to proteins and renal or non-renal clearance. Accumulation of drug metabolites and exogenous substances may make it necessary for the clinician to adjust the dose of drugs for the renal disease and associated ailments otherwise this variability can lead to either enhanced efficacy or enhanced toxicity depending on the drug characteristics. Renal diseases (renal disorders) may affect both pharmacokinetic and pharmacodynamic characteristics of a drug (as thiopental has been observed to cause prolongation of its anesthetic action and gentamycin to cause increased toxicity).

Dosage adjustment is usually needed if >30% drug is excreted unchanged in urine or is removed by dialysis in patients with renal impairment or renal failure. Impaired and compromised renal function effects the drug elimination and leads to accumulation of drug. The accumulation of drug further depends on the frequency of drug administration and half life of drug. The treating physician needs to know the pharmacokinetics and pattern of accumulation of drugs in renal failure and tentative time to achieve the steady concentration in plasma for the adequate dose adjustments.

Primary influence of renal disease on drug absorption is almost negligible. However, a few secondary influences like vomiting and diarrhoea due to uremia lead to dehydration and further lead to decreased perfusion and absorption of drugs from intramuscular and intestinal sites. Diabetic and uremic gastroparesis leads to altered rates of absorption of short acting drugs like sulfonylureas. Acid base imbalance and alteration in the levels of potassium in serum affects gastrointestinal tract mobility and rate & extent of drug absorption. Commonly used antacids bind and chelate dietary phosphates and lead to hypophosphatemia, also impair the absorption of drugs like iron and ketaconazole which need an acidic pH for optimal absorption. Impaired protein binding may also impair absorption of drugs. Edema caused by nephrotic syndrome or congestive heart failure has been documented to slowdown the drug absorption and cause increased bioavailability of drugs.

Drug Development: Non-Clinical Mutagenicity and Carcinogenicity Studies

The fundamental aim of non-clinical or pre-clinical studies in relation to new chemical entity (NCE) is to generate biological, pharmaceutical and toxicological data to ascertain that NCE would not cause any serious harm to the humans or would not cause cancer and/or genetic disorders through mutations. The limits of toxicological study of a NCE are decided with reference to route and duration of its intended use as a drug. Studies to evaluate carcinogenicity and mutagenicity of a NCE are performed in animals before it is declared as a drug and given to humans. Animal species usually used for carcinogenicity and mutagenicity are rats and mice, as some strains of these animals have very low incidence of spontaneous tumors and sufficient background knowledge about physiological parameters of these animals is available. Guidelines for such studies can be obtained from the regulatory agencies like FDA (USA), DCGI (India) and EMEA (Europe). The NCE is generally administered to the animals by at least two routes, one of which is usually the intended clinical route. The other route is usually intravenous so as to ensure adequate exposure of the animal to the new chemical entity. It is highly desirable to develop sensitive analytical methods for detecting the drug and its metabolites in the body fluids before starting the pre-clinical studies, as this would help in elucidating the toxicokinetics, pharmacokinetics, mutagenicity and carcinogenicity of the NCE. All studies need to be conducted in Good Laboratory Practice (GLP) compliance laboratories.

Carcinogenicity studies are needed to be done in adequate number of animals, depending on the regulatory requirements, before obtaining the approval for marketing of a drug. The drugs or compounds on which mutagenicity, carcinogenicity, teratogenicity and reproductive performance related effects need to be elucidated are of following types:

  1. When the drug product is to be used for three months or longer period for at least six months - Carcinogenicity studies are must.
  2. When the drug or compound is to be used frequently or in an intermittent manner in chronic or recurrent conditions like depression, anxiety and allergic rhinitis.
  3. Prolonged exposure due to certain drug delivery systems makes it mandatory to carry out carcinogenicity studies.

Relaxations and Exemptions:

  1. Genotoxic compounds are presumed to be trans-species carcinogens; hence long-term carcinogenicity studies are usually not needed.
  2. Pharmaceuticals administered infrequently or for short duration of exposure (such as anesthetics and radiolabelled imaging agents) are exempted from carcinogenicity studies.
  3. Carcinogenicity testing need not be conducted before market approval for the drugs developed for treating serious diseases.
  4. If the life expectancy in the indicated population is short (less than 3 years), no long-term carcinogenicity studies are not required for the compounds to be administered to these subjects.

Saturday, August 29, 2009

Drug Development: Non-Clinical Toxicity Study

Majority of allopathic drugs are developed from the organic or inorganic chemicals. The most important part of the process of drug development is the decision to take a new chemical entity (NCE) from a non-clinical to clinical phase. A lot of data needs to be generated through non-clinical safety study to evaluate the toxicity level of the NCE before it could be passed on for clinical phase of testing. The fundamental aim of non-clinical or pre-clinical studies is to generate biological, pharmaceutical and toxicological data to ascertain that NCE would not cause any serious harm to the humans. The limits of toxicological study of a NCE are decided with reference to the mode and duration of its use as a drug. Guidelines for such studies can be obtained from the regulatory agencies like FDA (USA), DCGI (India) and EMEA (Europe).

Why toxicity studies are necessary?

All chemical substances are poisons. Even the large doses of common salt (Sodium chloride) are poisonous and may affect our kidneys, heart and liver. Only a right dose differentiates a poison from a remedy. So, it is mandatory to conduct non-clinical or pre-clinical toxicity study for a NCE to generate pharmacological, toxicological and physicochemical data. There may be a dose which is safe and effective for humans otherwise a low dose would not generate any ill effect and a higher dose may produce deleterious effects. Non-clinical or pre-clinical toxicity studies of a NCE are performed in animals before it is declared as a drug and given to humans. Animal species usually used are mice, rats, guinea pigs, dogs and rabbits as lot of background knowledge about biological and physiological parameters of these animals is available.

Major goals of non-clinical toxicity studies:

  1. Generation of data regarding dose response and physiological and biological toxic effects.
  2. Identification of toxicities with respect to target organs if any.
  3. Evaluation of time-dependence of effects or reversibility of toxic effects
    after discontinuation of NCE under study.
  4. Identification of parameters required to be monitored effectively in human beings. Like liver function, renal function or thyroid function studies.
  5. Evaluation of safe starting dose for the first-in human trial, and
  6. Detection, identification and management of consequences of overdoses.

Friday, July 24, 2009

Anti-thyroid Drugs: Precautions in Pregnancy, Lactation and Asthma

The thyroid gland of our body controls the body metabolism through its iodine containing hormones. Normal thyroid gland is not palpable but the enlarged thyroid gland could be felt in front of the neck and may be associated with non-toxic or toxic goitre. Goitrous gland may have normal function or under function (hypothyroidism) or over function hyperthyroidism). The exophthalmic goitre is known as Graves's disease and in this
disease the eye balls protrude due to thyrotoxicosis.

The compounds used as anti-thyroid drugs include carbimazole and propylthiouracil. Anti-thyroid drugs inhibit the formation of thyroxine and triiodothyronine (T3) in the thyroid gland. Propylthiouracil also retard the peripheral conversion of thyroxine into triiodothyronine (T3). The same drugs are also used for the treatment of thyrotoxicosis and preparation for thyroidectomy. Anti-thyroid drugs may suppress the bone marrow so blood cell counts are advisable at regular intervals during the course of treatment. Pregnant and/or lactating patients with thyrotoxicosis need to consult the endocrinologist and to reduce the dose to minimum. Patients with tracheal obstruction or asthma also need extra care during the treatment of hyperthyroidism or thyrotoxicosis. Anti-thyroid drugs may cause nausea, gastro-intestinal upset, thyroid enlargement, agranulocytosis, granulocytopenia ( low count of neutrophils and eosinophils), leucopenia (low count of white blood cells) and thrombocytopenia low count of platelets); that is why regular blood counts are advisable. Self-treatment of hyperthyroidism or thyrotoxicosis is not advisable, as it needs investigative follow up. However, carbimazole oral drug is started with a dose of 15-45mg daily in divided doses depending on the severity of the disease and maintenance dose could be 2.5-25mg daily for 12 months. For thyroidectomy preparation, the dose may be 15-45mg daily in divided doses for 2-4 weeks depending on the severity of the disease.

To know more about thyroid gland and its functions-click here: http://ntips4u.blogspot.com/2009/07/thyroid-gland-and-its-functions.html


 

Thursday, July 23, 2009

Thyroid Drugs: Precautions in Diabetes and Heart Disease

Thyroid drugs are used for treatment of hypothyroidism a condition caused by under function of thyroid gland. These drugs are based on thyroid extract and increase the metabolic rate with a subsequent increase in catabolism. Thyroid gland is associated with the general metabolism of all body tissues. Suboptimal activity of thyroid gland at birth leads to hypo-secretion of thyroid hormones and causes cretinism, impairing the mental and physical growth of an infant or child. The child grows up a mentally retarded dwarf, unless diagnosed and treated with thyroid drugs. Patients affected by under function of thyroid gland or hypothyroidism, develop generalized oedema called myxoedema (swelling of body). In myxoedema metabolic processes slow down with a tendency to gain weight. There is slowness of mind and speech and one feels lethargic.

Thyroid drugs used for hypothyroidism as well as cretinism contain thyroglobulin, thyroxine or liothyronine. Same drugs are also used for thyroid replacement therapy in cases of thyroidectomy. Treatment is started with low initial dose of 50-100 mcg daily, increased 25-50mcg at 3-4 weeks interval and maintenance dose may be 200-300mcg.
Overdosage or too rapid increase may produce signs and symptoms of hyperthyroidism, so self-treatment of hypothyroidism is not advisable. Patients receiving diabetic treatment, anticoagulant therapy, corticosteroid therapy or anti-hypertension therapy may need readjustment of treatment. There are many side effects of thyroid drugs. Patients receiving treatment for hypothyroidism, myxoedema, or cretinism may feel restlessness and have headache, transient diarrhoea, weight loss, anginal pain and palpitations. Overdosage of thyroid drugs in patients with heart disease may lead to serious complications.

To know more about thyroidisms click here: http://ntips4u.blogspot.com/2009/07/signs-and-symptoms-of-thyroid-disorders.html

Thursday, June 18, 2009

Management of Hyperlipidemia

Elevated levels of fatty components in our blood is termed as hyperlipidemia. It is considered as a primary risk factor for coronary heart disease (CHD), stroke and peripheral vascular disease irrespective of the gender of a patient. Hyperlipidemia may complicate the health status in association with the diabetes, hypertension and kidney disease. There exists a strong association between the total cholesterol level and CHD. The cholesterol homeostasis is maintained by the liver and small intestine through very delicate balance of cholesterol input (dietary intake and de-novo synthesis of cholesterol) and elimination by conversion to bile and through fecal excretion. In the liver cells (hepatocytes) low density lipoprotein cholesterol (LDL-C) is produced through the conversion of HMG-Coenzyme-A (HMG-CoA) to mevalonic acid. It is important to note that LDL-C is a bad lipid whereas HDL-C is good. There is need to keep a check on the level of cholesterol in general and LDL-C in particular.

Cardiovascular morbidity and mortality is directly associated with the level of total cholesterol and LDL-C, and inversely with the level of high density lipoprotein cholesterol HDL-C). Cholesterol-enriched and triglyceride-rich lipoproteins, including very low density lipoproteins (VLDL) and intermediate density lipoproteins ((IDL) could also promote atherosclerosis. The elevated level of LDL-C warrants the need of cholesterol lowering therapy, inclusive of life style modification and cholesterol lowering drugs. HMG-CoA reductase inhibitor or statins are the most potent and widely used drugs for treating hypercholesterolemia or hyperlipidemia because of their efficacy in reducing LDL-C to the desired level as recommended by the National Cholesterol Education Program (NCEP). For effective control of hyperlipidemia around 20-55% reduction in the level of LDL-C needs to be achieved by Statins. The hyperlipidemia may be primary (heterozygous familial or non-familial hyperlipidemia) or secondary to some other disorder like renal disease. It has been established now that ezetimibe as monotherapy in association with customized diet, effectively reduces the elevated level of total cholesterol, LDL-C, Apo-B and triglycerides, and increases the level of HDL-C in patients with hypercholesterolemia. Ezetimibe is a selective cholesterol absorption inhibitor and was approved by FDA about 8 years ago. Statins (atorvastatin, lovastatin, pravastatin and simvastatin) are potent, HMG-CoA reductase inhibitors. The combination of ezetimibe and atorvastatin or simvastatin is effective therapy for taming down the elevated levels of total cholesterol and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH). The treatment of hyperlipidemia should be commenced under medical advice and follow-up with biochemical evaluation of lipids in blood.

Important tip: Kill the fat before it kills you.

Saturday, June 13, 2009

Post Exposure Prophylaxis Therapy for HIV

The impact of exposure to human immunodeficiency virus (HIV) depends on two main factors: (1) Nature of exposure and (2) The status of the source patient (the patient to whose blood or body fluids exposure has occurred). There is need to evaluate the source patient within 2 hours of exposure so that post exposure prophylaxis (PEP) could be started. The initiation of PEP should not be delayed more than 72 hours in any case. The baseline HIV testing should also be done for the exposed person before starting post exposure prophylaxis therapy. The post exposure prophylaxis refers to the comprehensive management given to the exposed person to minimize the risk of infection following potential exposure to blood-borne viruses (HIV, HBV and HCV). The risk assessment could only be evaluated through relevant laboratory investigations. Antiretroviral therapy should be started after consultation with the physician and follow up and supportive counseling should be provided to the exposed person at the surveillance centers.


The relative risk of HIV transmission after different routes of exposure has been established as under:


Exposure Route

HIV Transmission

Blood transfusion90-95%
Sexual intercourse-Vaginal1-10%
Sexual intercourse-anal0.05-0.5%
Sexual intercourse-oral0.005-0.01%
Perinatal20-40%
Intravenous drug use0.5-1%
Needle stick injury0.5%
Mucous membrane splash to eyes0.1%

The exposure to blood, semen, vaginal secretions, cerebrospinal fluid, synovial fluid, pleural fluid, pericardial fluid and amniotic fluid is considered risky and infectious. However, exposure to tears, sweat, urine, faeces and saliva is not considered infectious unless these secretions contain blood. The exposure is considered mild if the contact is with the eyes or mucous membranes or there is needle stick injury with small bore needle generally during vaccination or skin testing. The exposure is considered moderate if the mucous membranes or intact skin is exposed to large volume of body fluid or blood of the infected patient. A cut with surgical blade or needle stick injury with blood smeared needle. The exposure is considered severe if the accidental prick is with high bore (> 18G) needle contaminated with blood or a deep wound is caused with surgical knife smeared with blood. Transfusion of infected blood or packed cells.


The prescription of post exposure prophylaxis depends on the category of exposure. For mild exposure, basic regimen or 2-drug combination is generally prescribed depending on the status of the source of exposure. If the exposure source is HIV+ but asymptomatic, consider 2-drug PEP and if the source is HIV+ and clinically symptomatic, immediately start 2-drug PEP. In case of moderate exposure to HIV+ but asymptomatic source, start 2-drug PEP. If the source is found HIV+ and clinically symptomatic in case of moderate exposure, start expanded regimen which is 3-drug combination. In case of severe exposure to an HIV+ but asymptomatic or clinically symptomatic source, immediately start 3-drug combination. PEP regimens prescribed by health centers are: (1) 2-drug regimen: Zidovudine (AZT) + Lamivudine (3TC) or Stavudine (d4T) + Lamivudine (3TC). (2) 3-drug regimen: Zidovudine (AZT) + Stavudine (d4T) + Lamivudine (3TC). Expert opinion is must before starting PEP therapy.

Friday, June 12, 2009

Antimicrobial Agents and Drug Resistant Bacteria

There are about a dozen antimicrobial agents (AMA) and an equal number of bacterial types or species which are resistant to one or the other afore said antimicrobial agent or antibiotic. A list of these antimicrobial agents or antibiotics and corresponding resistant bacteria has been cited in the table-1 below. Antimicrobial susceptibility testing (AMST) against these antimicrobial agents or antibiotics with reference to corresponding bacteria could be discontinued to save time and money.


Table-1: Antimicrobial agents or antibiotics and resistant bacteria


Antimicrobial agentResistant Bacteria
AminoglycosidesAnaerobic bacteria, Enterococci and Streptococci
AmpicillinKlebsiella species
AztreonamGram-positive bacteria
VancomycinGram-negative bacteria
Sulphonamides, trimethoprimProteus aeruginosa
Tetracycline, chloramphenicolP. aeruginosa
All cephalosporinsEnterococci
AminoglycosidesEnterococci
ImipenemStenotrophomonas maltophilia
MetronidazoleAerobic bacteria

Sunday, May 31, 2009

Why Antimicrobial Susceptibility Testing is important?

There is a long list of antimicrobial agents (AMA) available commercially but any one AMA may have variable bactericidal action against different pathogenic bacteria. Antimicrobial susceptibility testing is way of determining action of an antimicrobial agent (antibiotic) against any isolated pathogenic bacteria in a given case. The presumptive identification of a bacterial infection is made by Gram staining of samples obtained from infected sites with sterile precautions. Later the organisms (bacteria) are grown on artificial media in the laboratory and definitive identification is made for antibiotic sensitivity or antimicrobial susceptibility testing. For a legitimate report on antimicrobial susceptibility test, the physician as well as the microbiologist should keep the following points in mind:


  • Specimen should be collected/obtained before initiation of any tentative antibiotic/antimicrobial therapy.

  • Specimen should not be contaminated with indigenous microbial flora.

  • Clinical note of the treating physician should accompany the request for antimicrobial susceptibility testing.

Antimicrobial susceptibility testing is of utmost importance as it culminates the following objectives:


  • It provides guidance to the clinicians in getting definitive information in the selection of most appropriate antibiotics/AMA against the infectious agents.

  • It directs the line of treatment towards the limited spectrum and least expensive antibiotics/AMA to which the isolated pathogen would respond.

  • It predicts about the outcome of the treatment with the specified antibiotic/AMA. The implication of the result 'susceptible' or 'sensitive' is that there would be high probability of treatment of infection with the specified antibiotic/AMA. A 'moderately susceptible/sensitive' result indicates a need for high dose of the drug would be required for treatment and a 'resistant' result indicates that the treatment with the pointed out antibiotic/AMA would not be possible.

Saturday, May 30, 2009

Antimicrobial Chemotherapy

Antimicrobial chemotherapy or antibiotic therapy assists our body in the fight against the intruding infectious organisms, mainly bacteria. Majority of bacteria are non-pathogenic and many types of these have symbiotic existence in our body. The pathogenic species of bacteria have been found sensitive to a variety of antibiotics; however, some of these have become resistant to antibiotics. Despite the advancement in diagnostic facilities and availability of a large number of antibiotics, still a patient may die due to infection of drug resistant bacteria. Suboptimal and inappropriate use of antibiotics has probably led to the development of resistance to antibiotics in bacteria. Only a well equipped Microbiology Laboratory can determine the antimicrobial susceptibility of clinically significant bacteria isolated from biological specimens like blood, urine, stool, pus, sputum or other body fluids. Advice on the most appropriate antimicrobial agent (antibiotic) must be obtained form the laboratory before starting antibiotic therapy against offending bacteria. The clinician should use reputed brands of antibiotics and report back to the drug manufacturing company and the testing laboratory for recording the trend of resistance and resistance pattern.

Tuesday, April 21, 2009

AIDS and HIV Vaccines

AIDS or acquired immunodeficiency Syndrome is caused by human immunodeficiency virus (HIV). The World Health Organization (WHO) is an International Organization associated with the community health programs throughout the world and it is the reward of concerted efforts that the diseases like smallpox and polio have completely been eradicated through vaccination. Now the worldwide focus is on the development of an effective vaccine to control the spread of AIDS and providing prophylaxis to health professionals. An ideal HIV vaccine would be the one which could mount a good humoral and cell mediated immune response both locally and systemically. HIV is an enveloped virus that contains two copies of genomic ribonucleic acid (RNA). There is a glycoprotein of 120 kD molecular weight commonly known as gp120, through which the virus binds to the cellular receptors at the surface of T-helper lymphocytes or CD4+ cells. The binding of virus to the CD4 receptor in association with chemokine co-receptor causes a dynamic change in gp120 and further activates trans-membrane protein gp41. These changes cause fusion of HIV envelope to the cell membrane of CD4+ cell and further make way for the entry of virus into the cytoplasm of CD4+ cell, replicate there, destroy cell and infect new cells.


Experimental studies in animals have shown that a considerable amount of T-cell response can be induced with HIV vaccines thereby limiting the viral RNA levels in plasma and minimizing the destruction of CD4+ T-cells. The survival of CD4+ T-cells through vaccination might help control infection and prolong disease-free survival of immunized person. The HIV vaccine capable of controlling the viral replication may also reduce the secondary transmission since the progression of secondary transmission is directly related to the plasma viral load. The oldest procedure of vaccine development has been tried wherein live attenuated viruses are used as vaccine but could not be put to the practice in case of HIV vaccine due to danger of infection if the virus particle were not completely killed or attenuated. Novel strategies are being used wherein certain immunogenic viral peptides (non-infectious and genetically engineered) have been tried and put to clinical trials. HIV vaccines developed on the guidelines of viral vectors containing vaccines and DNA vaccines are under way of active clinical trials. The vaccine war is going on against HIV.

Saturday, April 18, 2009

Anti-Retroviral Drugs for Treatment and Prophylaxis

There are over a dozen anti-retroviral drugs duly approved for treatment of HIV-1 infection and for optimal prophylaxis against the virus. Anti-retroviral drugs include HIV-1 protease inhibitors, non nucleoside reverse transcriptase inhibitors (NNRTIs) and fusion inhibitors (HIV entry inhibitors). At present combination drug therapy is used to thrash the dynamics of HIV-1 replication. The four main classes of anti viral agents are: (1) Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs and NtRTIs), (2) Non nucleoside reverse transcriptase inhibitors (NNRTIs), (3) Protease inhibitors (PIs) and (4) HIV entry inhibitors.


Nucleoside reverse transcriptase inhibitors (NRTIs) available are: Zidovudine (AZT/ZDV), Stavudine (d4T), Lamivudine (3TC), Didanosine (ddI), Zalcitabine (ddC), Abacavir (ABC) and Emtricitabine (FTC).


Nucleotide reverse transcriptase inhibitor (NtRTI) available is: Tenofovir (TDF).


Non nucleoside reverse transcriptase inhibitors (NNRTIs) available are: Nevirapine (NVP), Efavirenz (EFV), Delavirdine (DLV) and Etravirine.


Protease inhibitors (PIs) available are: Saquinavir (SQV), Ritonavir (RTV), Nelfinavir (NFV), Amprenavir (APV), Indinavir (INV), Lopinavir/Ritonavir (LPV), Fosamprenavir (FPV), Atazanavir (ATV) and Tipranavir (TPV).


HIV entry inhibitors (Fusion inhibitors) available are: Enfuviritide (T-20) and CCR5 entry inhibitors.


Acquired immunodeficiency Syndrome or AIDS is caused by human immunodeficiency virus (HIV). HIV is an enveloped virus that contains two copies of genomic ribonucleic acid (RNA). There is a glycoprotein of 120 kD molecular weight commonly known as gp120, through which the viruses bind to the cellular receptors at the surface of T-helper lymphocytes or CD4+ cells. The binding of virus to the CD4 receptor in association with chemokine co-receptor causes a dynamic change in gp120 and further activates trans-membrane protein gp41. These changes cause fusion of HIV envelope to the cell membrane of CD4+ cell and further make way for the entry of virus into the cytoplasm of CD4+ cell. The main receptors used by HIV-1 are chemokine receptors CCR5 and CXCR4. It has been resolved through the assessment of amino acid sequences of different HIV-1 strains that there are five variable (V1-V5) and four constant (C1-C4) regions in gp120. The expression of CCR5 or CXCR4 on the surface of CD4+ target cells (T-helper lymphocytes) defines their susceptibility to infection by corresponding HIV-1 strain. The use of specific receptors by viruses for infecting the target cells determines the virus cell tropism. The dual tropic viral strains can use both the receptors at the surface of CD4+ target cells. It is well established now that R5 viruses remain present in approximately 50-60% of individuals who progress to AIDS, whereas remaining 40-50% of individuals switch to X4 viruses with the progression of the disease and show a decline in the count of CD4+ target cells. The mutations in viruses confer them resistance to CCR5 treatment in the absence of co-receptor switch. HIV entry inhibitor compounds have been gaining importance as therapeutic agents for the treatment and post exposure prophylaxis against HIV infection. The aim of HIV therapy is to suppress the viral infection to achieve the disease free prolonged survival and this can not be achieved with monotherapy only due to complex life cycle of HIV.


HAART Therapy


The most effective HIV therapy is the highly active anti-retroviral therapy (HAART) wherein anti-retroviral agents are administered in combination of different drug classes. Generally HAART is any combination regimen designed to achieve the goal of complete virus suppression and these regimens comprise a minimum of three drugs. NNRTI based regimen comprises two NRTI or NtRTIs plus one NNRTI. PI based regimen comprises two NRTI or NtRTIs plus one or more PIs. Monotherapy is restricted to the prevention of perinatal transmission of HIV. Zidovudine (ZDV or AZT) and nevirapine (NVP) are generally used drugs for the monotherapy. The indications for HAART are history of AIDS-defining illness with CD4+ cell counts <350/µl or pregnant women without consideration for CD4+ cell count. Persons with HIV-associated nephropathy and persons co-infected with hepatitis virus-B (HBV) are considered fit cases for initiation of HAART.

AIDS and HIV Entry Inhibitors’ Target Action

Acquired immunodeficiency Syndrome or AIDS is caused by human immunodeficiency virus (HIV). HIV is an enveloped virus that contains two copies of genomic ribonucleic acid (RNA). There is a glycoprotein of 120 kD molecular weight commonly known as gp120, through which the virus binds to the cellular receptors at the surface of T-helper lymphocytes or CD4+ cells. The binding of virus to the CD4 receptor in association with chemokine co-receptor causes a dynamic change in gp120 and further activates trans-membrane protein gp41. These changes cause fusion of HIV envelope to the cell membrane of CD4+ cell and further make way for the entry of virus into the cytoplasm of CD4+ cell. The virus entry inhibitors sabotage the ability of gp41 to mediate fusion of viral and cellular envelopes. HIV entry inhibitor drugs are of first choice after exposure to virus and are newer drugs in the scenario of HIV therapy. Currently, most regimens of HIV therapy are combinations of inhibitors of two viral enzymes: reverse transcriptase and protease. HIV entry inhibitors are of great interest because of their activity against multi-drug resistant viruses.

The brief mechanism of HIV entry into T-helper lymphocytes or CD4+ cells has been cited above. The main receptors used by HIV-1 are chemokine receptors CCR5 and CXCR4. It has been resolved through the assessment of amino acid sequences of different HIV-1 strains that there are five variable (V1-V5) and four constant (C1-C4) regions in gp120. The expression of CCR5 or CXCR4 on the surface of CD4+ target cells (T-helper lymphocytes) defines their susceptibility to infection by corresponding HIV-1 strain. The use of specific receptors by viruses for infecting the target cells determines the virus cell tropism. The dual tropic viral strains can use both the receptors at the surface of CD4+ target cells. The HIV entry inhibitor compounds could be targeting the inhibition at different stages of virus entry such as:


  1. The attachment inhibitor: Sulfated polysaccharides or polyanions such as dextran sulfate (dextran-2-sulfate or D2S) and heparin have been shown to inhibit binding of V3 loop antibodies to HIV-1 gp120 in-vitro.

  2. Inhibitors of gp120-CD4 interaction: The currently available inhibitors of gp120-CD4 interaction are PRI 542 (CD4 - IgG2), TNX 355, and BMS 488043 antibodies/molecules. PRI 542 (CD4 - IgG2) is a tetravalent antibody and has passed clinical trials. TNX 355 is a monoclonal antibody (humanized) against the domain-2 of human CD4. BMS 488043 is a small molecule and blocks the entry of virus by preventing the binding of gp120 to CD4 receptors on CD4+ target cells.

  3. Co-receptor Antagonists: Some new molecules have been tried as antagonists to CXCR4 and CCR5 but abandoned due to cardiac abnormalities and heart conduction abnormalities like prolonged QT intervals. CCR5 is the co-receptor mainly used by HIV for its transmission; so many drugs have been enlisted for targeting CCR5.

It is well established now that R5 viruses remain present in approximately 50-60% of individuals who progress to AIDS, whereas remaining 40-50% of individuals switch to X4 viruses with the progression of the disease and show a decline in the count of CD4+ target cells. The mutations in viruses confer them resistance to CCR5 treatment in the absence of co-receptor switch. HIV entry inhibitor compounds have been gaining importance as therapeutic agents for the treatment and post exposure prophylaxis against HIV.

Friday, March 20, 2009

Evolution of Antimalarial Drugs

The effectiveness of the antimalarial drugs may differ with the species and stage of parasite and the parasite load in the liver and blood circulation. The malaria is an intracellular protozoan infection, endemic in tropical and subtropical countries. Four species of the protozoal parasite Plasmodium cause all infections in human beings and these are: Plasmodium vivax, Plasmodium malariae, Plasmodium ovale and Plasmodium falciparum. The parasites are inoculated into the human host by blood sucking female anopheline mosquitoes. The sporozoites from the infected mosquito reach the liver and develop into tissue schizonts. These tissue schizonts then rupture, form free merozoites and invade erythrocytes or red blood cells (RBCs) and develop as erythrocytic schizonts and lead to rupture of RBCs. Antimalarial drugs have undergone a great deal of evolution and at present there are many classifications of antimalarial drugs depending on the stages of malarial parasites in the liver and erythrocytes, on the bases of chemical groups or clinical effectiveness of the drugs.


If we look at the chemical groups of antimalarial drugs the Cinchona alkaloid or Quinine and Quinidine were the very first drugs and there after 4-aminoquinoline (Chloroquine and Amodiaquine), 8-aminoquinoline (Primaquine and Bulaquine), Quinoline-Methanol (Mefloquine) and Biguanides (Proguanil and Chlorproguanil) were developed. Diaminopyrimidines (Pyrimethamine), Sulfonamides (Sulfadoxine and Dapsone), Tetracyclines (Tetracycline and Doxycycline) and Aminoalcohols (Halofantrine and Lumefantrine) are other effective antimalarial drugs. Chloroquine has been used extensively for the treatment and prevention of malaria. It has considerable efficacy for the treatment of Plasmodium vivax, Plasmodium malariae and Plasmodium ovale infections, however, widespread resistance has been seen against Plasmodium falciparum infection. Artemisinin, Artemether, Artemotil and Atovaquone could be called newer antimalarial drugs. Artemisinin or Qinghaosu is a sesquiterpene lactone extracted from the leaves of Artemisia annua known as Sweet Wormwood in China. The extract of the leaves of Artemisia annua or Sweet Wormwood has been used in China for over a thousand years for the treatment of fever. Antifolate combinations like sulfadoxine pyrimethamine and sulfalene pyrimethamine are more safe drugs but are known to have longer elimination half life.


In terms of clinical effect on various stages of malarial parasites, the effectiveness of antimalarial drugs is contested for prophylaxis and anti-parasite activity. Effective suppressive prophylaxis has been documented with chloroquine, mefloquine, proguanil and doxycycline as these are schizonticidal drugs. Proguanil and primaquine are best known for causal prophylaxis as these drugs effectively kill the hepatic stages of the parasite. Quinine, chloroquine, primaquine and artemisnins are established gametocidal drugs also. Sulfonamides (sulfadoxine and dapsone) and aminoalcohols (halofantrine and lumefantrine) are also used in the treatment of malaria but are more toxic drugs. The drug toxicity may lead to acute hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Consult your physician for the diagnosis and treatment of malaria.

Wednesday, March 18, 2009

What Could Lead to Drug Addiction ?

Experimentation with psychotropic drugs for fun and elated feelings could activate certain receptors of our brain to such an extent that one would feel depressed without taking a particular drug. When a person starts taking a psychotropic drug, he/she enjoys the drug's euphoric effects. Repeated desire for elevated mood and a kick makes one addict for ever. The drug addiction is mostly unintentional as a person who begins with casual use of a drug does not know that the substance could become his/her daily desire. The drug associated altered neurophysiology leads to drug dependence. The drug related release of neurotransmitters may alter the ultrastructural architecture of neurons at a later stage. Some drugs may lock into some neurons and act like a pump and extensively stimulate the neurons to release more and more neurotransmitters. There exists a natural balance of neurotransmitters under the normal conditions of neurophysiology, but certain drugs may block reabsorption or reuptake of neurotransmitters, leading to behavioral changes altered physiology. The drug adiction is a complex brain disease. Despite the fact that the high effects of a drug are short term phenomenon, one finds it difficult to quit the habit. The compulsive and uncontrollable craving for a psychotropic drug leads to such a behavioral change that one would ignore all the moral values of the life and society to acquire a drug. The habitual use of a neurostimulator or psychotropic drug severely affects the neurophysiology and leads to drug addiction.

Effect of Drugs on Brain

The neurostimulators or psychotropic drugs bind to the receptors in the brain and start an unnatural chain of reactions causing electrical changes and stimulate neurons to release large amounts of drug associated neurotransmitters. Some drugs may lock into the neuron and act like pump. The locked in psychotropic drugs extensively stimulate the neurons to release more and more neurotransmitters. There exists a natural biobalance of neurotransmitters under the normal conditions of neurophysiology, but certain drugs may block reabsorption or reuptake of neurotransmitters, leading to behavioral changes. The drug addiction is a complex brain disease. There could be compulsive and uncontrollable craving for drugs. The compulsive desire for drugs may lead to such a behavioral change when one ignores all the moral values of the life and society to acquire a drug. The habitual use of a drug severely affects the neurophysiology and leads to addiction.

Saturday, February 28, 2009

Whom to Report Adverse Drug Reactions?

Adverse Drug Reaction (ADR) is defined as any unintended and undesired effect of a duly prescribed drug which occurs at a dose used in humans for prophylactic, therapeutic or diagnostic purposes. All drugs taken externally or internally produce some undesirable effects along with their beneficial effects. Adverse events that occur as a result of drug use may range from local reaction, respiratory distress, renal lesions/damage or liver function impairment to serious life threatening condition. The liver and kidney are the organs which bear the brunt of majority of adverse drug reactions (ADRs) as these are associated with the drug metabolism and clearing from the body. The nature of the beneficial effects of a drug is predictable, but the nature of adverse reaction could be predictable to some extent otherwise unpredictable. The term drug here means any substance or product used to modify or explore physiological system and pathological states for the benefit of the patient/recipient. The health products considered to be drugs include vaccines, food supplements, blood and blood products, herbals, traditional or complementary medicines, pace maker devices and implants. Mismatched blood would cause transfusion reaction with life threatening implications. Blood products like platelet rich plasma (PRP) which is normally infused in patients suffering from Dengue virus infection may lead to the development of antibodies against human leukocyte antigens (HLAs) as platelets carry Major Histocompatibilty Complex, class-I (MHC class-I) antigens i.e. HLA-A, HLA-B, & HLA-C antigens at their surface and these antibodies may lead to lyses of platelets and thrombocytopenia (decreased platelet count) at a later stage.

How and Whom to Report ADR?

Independent reporting can be undertaken by any one who is prescribing a drug, administering a drug or consuming a duly prescribed drug. This type of reporting is called Reporting or Spontaneous Reporting. One should be ready with the following information while reporting ADR: Patient"s short name, age, sex, height, weight, trade name of drug, manufacturer, date of manufacture, date of expiry, mode of administration, type of reaction, duration of administration, route of use, date of reaction, date of recovery and associated medication etc. Adverse Drug Reaction should be reported to the Pharmacovigilance Center. There are National, Zonal, Regional and Peripheral Pharmacovigilance Centers in all the countries. The matter can also be reported to the Drug Controller General of the Country or reported directly to the United States FDA. For reporting the ADR or adverse events to the International Regulatory Authority like US FDA one can use online reporting facility at the website http://www.fda.gov/medwatch/ . Go to the FDA-Medwatch website and visit the link-Medical Product Reporting for reporting adverse drug reaction or adverse events.

Important: Regulatory approval to market drug is usually based on the results of controlled clinical trials, as such, these short term studies in a specific population may not be sufficient to explore the ill effects of a particular drug. The ADR monitoring begins with the earliest administration of a drug to man and continues throughout, as long as a drug is on prescription list of clinicians. Long term surveillance studies are also being undertaken to evaluate effectiveness and safety of a drug in various subpopulations such as, children, elderly patients and patients with associated ailments like impaired liver function, kidney disease and diabetes. In order to highlight the ADR events, the pharmacovigilance is important. The ADR events include the events due to non-compliance, drug interactions with co-administered drugs and drug over dosages and adverse effect of the drug per se. As per the data available to-date, about 6% of Emergency visits are related to ADRs and about 0.1% of these could be life threatening.

Can we prevent Adverse Drug Reactions?

Yes, a lot of these ADRs are preventable, most probably those resulting from mere ignorance of route of administration or non-compliance. There are ADR cases wherein patients have swallowed the tablets prescribed for intra vaginal infection.

Thursday, February 26, 2009

Neurostimulators or Fashion drugs: Worrisome Scenario

The neurostimulator materials have been known to mankind in the one form or the other, from the time immemorial. The alcohol in the form of wine has been known for ages. Now, synthetic chemicals are the core source of majority of drugs for various ailments. The stimulatory action of most of the drugs is being exploited by many to earn a quick buck. The scenario is worrisome the world over. The diversion of pharmaceutical products like ephedrine, pseudoephedrine and morphine for the production of amphetamine type stimulants (ATS)is a matter of grave concern and should be checked effectively by the governments of various countries. Pharmaceutical preparations like pethidine, codeine-based cough syrups, ephedrine and pseudoephedrine should be sold on the production of valid prescription only to avoid misuse as neurostimulators or fashion drugs. The Internet Pharmacies should be issued strict guidelines on narcotics. The manufacture of synthetic drugs like methamphetamine should be done in the government owned drug houses only. It is our duty to educate our siblings, children, students and friends, about the health hazards of narcotics. Effective policing and administrative measures at the National and International Level are the needs of the hour to check the smuggling of traditional narcotics like heroin. Avoid experimentation with fashion drugs for health and longevity.

Hazards of Over Compliance of Drugs

There are substantial health benefits to the patients if the drug compliance by them is 100 percent. The good communication skills of the attending physician could be helpful to overcome the chances of over compliance by a considerable number of patients. Patients need to be briefed about the side effects of over doses as well as the extra doses of the drugs prescribed to them. The intake of over doses or extra doses of any prescribed drug is called over compliance. Inspite of best efforts by the prescribing doctors, about 20% patients may even take more drugs than the prescribed dose to get cured quickly and earlier, but this can be harmful and lead to serious toxicity or a variety of side effects.


Just remember, all drugs are poisonous chemicals and if taken in excess these may affect our health in many wrong ways. Even an indicative dose of an anti-allergic causes drowsiness and if taken in excess it may lead to impairment of judgment while driving. Take an example of common salt, excessive intake of it may induce vomiting and raise the blood pressure. Over use of antibiotics may disturb the normal flora of our intestine and suppress the blood formation in the bone marrow. Over compliance of steroids is known for suppressing the immune system of our body. An over dose of insulin may lead to serious hypoglycemia (low level of glucose in blood) in a diabetic patient. Overuse of some drugs may lead to serious health hazards including organ failure. Be wise and never take over dose of any drug.

Tuesday, February 24, 2009

Steps to Improve the Drug Compliance

The doctor prescribing the treatment could play a vital role to instill confidence in the patient for proper drug compliance as well as improving it. Sharing of knowledge about the disease and drugs could motivate the patient for timely intake of drugs. The patient and his /her family members should be explained the schedule of the treatment regimen. The following tips could be beneficial for improving the drug compliance:


  1. Educate the patient about the dosage, timings and mode of administration of a drug.

  2. Un-necessary investigations should be avoided during the course of treatment.

  3. Written material or audiovisual aids about the drug information should be made available to the patient for proper compliance.

  4. The physician/surgeon should be extra generous to the elderly patients.

  5. The treatment related cost-benefit issues should be discussed with the patient or his/her family members.

  6. The patient should be encouraged to maintain a periodic record of his/her weight, diet, blood pressure and blood sugar level if so required.

  7. The doctor should write prescriptions legibly to avoid any mistaken dispensing.

  8. The doctor should prescribe rationally and accurately to win the faith of his/her patient.

  9. The importance and consequences of a missed dose should be explained to the patient.

Ten Causes of Poor Drug Compliance

There could be following reasons for the poor drug compliance:


  1. Deliberate intention with a sense of suspicion about the side effects of the drugs.

  2. Lack of understanding about the disease and associated complications if treatment is disrupted.

  3. Over busy schedule of daily engagements at the place of work.

  4. High and unaffordable cost of medicines.

  5. Forgetfulness leading to unintentional missed doses.

  6. High cost of investigations required for monitoring of the effects and side effects of a treatment regimen.

  7. Longer schedule or life time medication may become boring for the patient, leading to poor drug compliance.

  8. Lack of motivation in case of patients suffering from chronic diseases and psychological disorders.

  9. Lack of cooperation from the family members.

  10. Cumbersome drug intake schedule when multiple drugs are prescribed to the patients with multiple health ailments.

Sunday, February 22, 2009

Drug Compliance

The health ailments are as old as mankind. The food articles, herbs and roots of some plants had been used as drugs for thousands of years and there existed a schedule for patients' compliance. The drug compliance refers to the willingness of a patient to follow the health related advice to take drugs/medicines as advised prescribed and to attend the follow up appointments. The drug compliance is must for the assessment of the effect of a treatment. The failure of a treatment may depend on the failure of a drug/medicine itself or due to poor compliance.

The problem is more prevalent in well educated people as compared to least educated class. Patients' commitment to drug compliance is a major health issue with outcomes restricted to the status of drug resistance, failure of a treatment, morbidity and mortality. The patients' adherence to treatment schedule or drug compliance is must for better health outcomes.