DRUG DRUG INTERACTION STUDY OF FAVIPIRAVIR AND DOXYCYCLINE WHEN USED CONCOMITANTLY IN COVID19 POSITIVE PATIENTS

Parameters:

Pharmacodynamic study

Pharmacokinetic study

Bioeuivalence study

Hepatotoxicity study

EFFECT OF MANGIFERIN ON PHARMACOKINETIC, ANTIDIABETIC AND HEPATOTOXICITY OF PIOGLITAZONE IN ALBINO RATS"

 

       

TITLE OF THE TOPIC

“EFFECT OF MANGIFERIN ON PHARMACOKINETIC,   ANTIDIABETIC  AND HEPATOTOXICITY OF PIOGLITAZONE  IN ALBINO RATS"

NEEDS FOR THE STUDY: 

 Pioglitazone  is  an  oral  antidiabetic  drug, which  acts  through  nuclear peroxisome proliferators activated receptor gamma (PPARγ), which activates insulin-responsive genes that  regulate carbohydrates  and  lipid  metabolism. Used in the treatment of type-2 diabetes  mellitus1.  Pioglitazone  is  the  class  of   thiazolidinediones  and  orally  well absorbed  within  two  hours,  is  metabolized by  hepatic  cytochrome  CYP3A4  and  CYP2C82.

            Several examples have been reported in the literature that show herbal drug interaction after the co-administration of herbal phytochemical along with pharmaceutical drug, which may lead to adverse drug interaction. These interactions occur by modulating p450 system, including the induction or inhibition of p450 enzyme and the metabolic clearance of the drug3,4. A typical example is St. Johns wort, widely used for depressive disorders, which is a potent inducer of CYP3A45. It is often evident that diabetic patients often consume herbal preparations along with routinely prescribed antidiabetic agents6. 

           Mangiferin, a xanthone glucoside, is an active phytochemical present in various plants including Mangifera indica Linn. (Family: Anacardiacae, Genus: Mangifera)7. Mangiferin has been reported to possess antioxidant8, antitumor9, antiviral10 and immunomodulatory activities11.  

            Mangiferin has recently been shown  to  have antidiabetic  activity  in KK/Ay mice,  a genetic  model  of  non-insulin-dependent  diabetes mellitus (NIDDM) with hyperinsulinemia12. 

            Mangiferin  have been reported to be potent alpha-glucosidase inhibitors that have been shown  to inhibit increases in serum glucose levels13. Mangiferin also shows modulation of certain P450 enzymes14.

            In this research, we propose to undertake a systemic study on interaction of pioglitazone and mangiferin on pharmacokinetics, antidiabetic and hepatotoxicity effects in non-diabetic and alloxan induced diabetic rats.

REVIEW OF LITERATURE

            Thiazolidinediones  are  synthetic  ligands  for  PPARγ,  which  is expressed  predominantly  in  the  adipose  tissue. These  drugs  are  effectively  used in  the  treatment  of  diabetes  mellitus  type-2. The other members of thiazolidinediones  are  rosiglitazone,  

troglitazone.  Pioglitazone  is  an   oral   anti diabetic  agent  of   Thiazolidinediones  class  

which  acts  through  nuclear peroxisome  proliferators  activated  receptor  gamma(PPARγ).

           Pioglitazone is a chemically (+)-5(-p-(-2-(5-ethyl-2-pyridyl)-ethoxy) benzyl)-2,4-thiazolidinedione has shown to have hypoglycaemic effect in animals models  of  non-insulin dependent diabetic mellitus pioglitazone orally well absorbed within  two  hours, is metabolized  by  hepatic cytochrome  CYP3A4  and  CYP2C815 , by  hydroxylation  and  oxidation;  the  metabolites  also partly convert to glucuronide  or  sulphate  conjugates.    

            The aqueous extract from the bark of mango obtained under the name VIMAG contains polyphenols whose major ingredient is Mangiferin. [C-glucosyl-xanthone (1,3,6,7-tetrahydroxyxantone-c2-β-D-glucoside)]16. 

               Mangiferin rich plants are widely used medicinal plants in India for the treatment of immunodeficiency diseases such as arthritis, diabetes, hepatitis, cardiac and mental disorders17.  Being a polyphenolic antioxidant, Mangiferin has strong antioxidant, anti lipid peroxidative, immunomodulatory, cardiotonic, hypotensive, wound healing, antidegenerative and antidiabetic activity18.

            According to review of literature on pioglitazone for interaction with other classes of drugs have affected the pharmacokinetics as well as pharmacodynamics19. Recently effect of rifampicin on the pharmacokinetics study of pioglitazone is seen20. Prior administration of quercetin increases the bioavailability of pioglitazone  in    rats21. Plasma  concentration   of 

Pioglitazone is elevated by gemfibrozil22. Pioglitazone along with simvastatin or atorvastatin causes adverse events23.

             However, there is no experimental evidence presently available in the literature with regards the effect of mangiferin along with pioglitazone as an antidiabetic. Hence, the present study is carried out in an attempt to do systemic study on pharmacokinetics, antidiabetic and hepatotoxicity activity in alloxan induced diabetes in rats.

OBJECTIVES OF STUDY 

            The objectives of  the  present  study  are :

To induce diabetes in rats by intra-peritoneal administration of alloxan (150mg/kg) and to investigate the hypoglycaemic activity of pioglitazone at various doses in diabetic rats.

To investigate the hypoglycaemic activity of pioglitazone administered along with Mangiferin in rats.

To investigate the hypoglycaemic activity of mangiferin

To determine the plasma concentration of pioglitazone at various time intervals after oral administration in rats.

To determine the plasma concentration of pioglitazone along with mangiferin at various time intervals after oral administration in rats.

Hepatotoxicity estimation of the enzyme levels (AST, ALT) after treating with individual drug and the combination.

To carry out the histopathology of the liver.

Materials and methods :

SOURCE OF DATA

            The source of data for this study is based on laboratory experiments on animals. Also the data obtained from the literature will be the source of data.

METHOD OF COLLECTION OF DATA:

(Including sampling procedure if any)

 MATERIALS:

 Drugs used are Pioglitazone and Mangiferin.

 (Chemicals required are alloxan, ammonium acetate (HPLC grade), Hydrochloric acid (HPLC grade), chloroform (HPLC grade), Methanol (HPLC grade), Acetonitrile (HPLC grade) DMSO (HPLC grade).

PHARMACOKINETIC  STUDY IN RATS

             This  study  is  carried  according  to  previous  methods  mentioned  in  the literature24 . Pharmacokinetic studies will be done in the rats.  The  animals  will  be divided  into  two  groups  containing  six  animals  each.  First  group  will  receive Pioglitazone alone while the other group will receive the  combination  of  Pioglitazone  and  Mangiferin  by  oral  route  and  blood samples are drawn at regular intervals from retro-orbital plexus puncture and collected  in  heparinized   glass  tubes, which  is  then  centrifuged at  3000 rpm  for  15  minutes. From  this 0.5 ml  of  the  plasma  is  added  to  0.10  ml  glass  tubes  containing  internal  standard, 100µl  of  1N  hydrochloric  acid  and 4ml  of chloroform.  After vigorous stirring for 2 minute, the aqueous phase is separated by centrifugation (3000rpm for 15 minutes) and discarded.

            The remaining organic phase is evaporated to dryness and dry residue is reconstituted with 100 micro 1 of 50% methanol. From this 30µl aliquot is injected into the HPLC system and the eluent is monitored by ultra violet detection at 269 nm.

ANTIDIABETIC ACTIVITY IN RATS 

             Antidiabetic  activity  will be  done  in  rats,  receives an  intra-peritoneal injection  of  alloxan  150 mg/kg  of single  dose 25.  After  48  hrs  they  will  be confirmed  diabetic  by  estimating  the  blood  glucose  level. Animals showing fasting blood   glucose   level>250 mg/dl   will   be   considered   as   diabetic. Animals were divided into four group   containing six animals each. The  first group  will  receive  citrated  buffer  alone  and  serve  as  the  control.  Where as,  the second  and  third  group  will  receive pioglitazone  and  mangiferin  individually and  final  fourth  group  will receive  only  the  combination of  pioglitazone  and mangiferin.

            After  a  week  of  treatment  the  blood  sample  were  obtained  by  retro  orbital plexus  in  order  to  measure  the  blood  glucose  level.  The   blood glucose level will be estimated by standardized glucometer.

HEPETOTOXICITY STUDY

             Hepatotoxicity studies will be conducted in rats by   chronic model.  Animals were 

divided into four groups containing six animals each. The  first  group will serve  as  a  control  where  as  the  second  and  third  group  will  receive Pioglitazone  and  Mangiferin  

individually.  The fourth   will receive a combination of Pioglitazone and Mangiferin.  After  a  week  of  treatment  with the   drug  the  rats  were  sacrificed  by  decapitation  and  estimated  the  levels of enzymes (AST,ALT)  at  regular  time  interval  and  histopathology  study  of  liver for  Pioglitazone  with  or  without  Mangiferin will  be  carried  out.    

   

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