It's confusing about loposomal Amphotericin B

When are administering  Liposomal amphotericin B, should we need to cover it from light or not. Is it photo degradable or not???

My opinion:

There is  actually no where in literature with regards to liposomal amphotericin B, they have actually mentioned that you need to cover and protect from light but at the same time they have not mentioned that  there is no  need to cover also. So as for now for liposomal  amphotericin B, there is no need to cover . Whereas  for conventional  amphotericin B there is an absolute requirement to cover it and prevent excess exposure from light. Even you have to protect the IV line tubing from the excessive light exposure

BELSOMRA- a new drug for insomnia

S NO	BELSOMRA
1.	NAME	BELSOMRA
2.	CATEGORY	Medical Neurology
3.	COMPANY	Merck’s
4.	INDICATION DEVELOPED FOR	Insomnia
5.	MECHANISM OF ACTION	Orexin antagonist
6.	MORE DETAILED M.O.A	Induces sleep by blocking binding of two wakefulness neuropeptide Orexin A and Orexin B to their receptor OX1R and OX2R
7.	NOVEL	yes/no
8.	STAGE OF DEVELOPMENT	Phase 3 completed and entering Phase 4
9.	US FDA APPROVAL	yes/no
10.	DATE OF APPROVAL BY FDA	August 13 2014
11.	INDICATION APPROVED FOR BY FDA	-
12.	INDIAN SCIENARIO	-
13.	ANYTHING SPECIAL WITH THIS DRUG	Instead of traditional way of inducing sleepiness, it fight against wakefulness
14.	BACKGROUND KNOWLEDGE REQUIRED	Orexin-A and B are excitatory neuropeptide hormones that promote wakefulness by sending inhibitory signals to the ventrolateral preoptic nucleus, an area of the hypothalamus with a high concentration of GABA-producing neurons.
15.	ISSUES WITH THE DRUG	·       To be cautious on next day driving ·       Sleep pattern does not resemble to that of normal physiological sleep, it favours REM sleep over NREM sleep ·       People who took this drug experienced somnolence
16.

YOU HAVE FOUND A NEW DRUG.HOW TO MOVE ABOUT NOW. DOSE AND DURATION OF TREATMENT FOR THE NEW DRUG.

FIRST SELECT THE BEST ANIMAL MODEL FOR THE DISEASE  IN WHICH YOU HAVE DECIDED TO WORK.

YOU HAVE A NEW DRUG IN YOUR HAND AND IS CONFUSED WHAT IS THE DOSE IN WHICH THE DESIRED EFFECT WILL COME

Lowest dose which show maximum protection or effect is the rule

How to find the best dose/standardization of doses for a new drug in an animal model??

You take multiple criteria for evaluating the disease progress or severity  and then administer the different  probable doses among which you are confused . Your aim is to find what will be your best suitable dose which will have a significant effect in decreasing the disease severity or produce maximum protection effect. 

The thing to note is that you will have the data of effect of the different doses on the same parameter which you wish to check.

This dose at which maximum benefit is seen is the best dose to give for the indication we intend to give.

How to find the duration of the treatment for a new drug in an animal model???

In the dose selected above now your aim is to find the duration of the therapy.You give treatment and then analyze the model at different time interval to find the best time duration in which the drug maximum effect has been obtained. The thing to  note is if you administer the drug more than this time ,some may argue that there will be no detrimental effect. Yes, of course but administering more than this time wont add to any beneficial effect too.

DIFFERENCE BETWEEN PUBMED AND MEDLINE

As early as 1879, US National Library of Medicine started maintaining a bibliography of all the articles in various journals, the name of the compilation was Index Medicus MEDLINE is the electronic version of original raw data that is Index Medicus with the US National Library of Medicine. The database is updated very frequently by them and is robust. The electronic version was initially only with the librarians and the computers used by the librarians was known as MEDLARS.

The MEDLINE was open for public in 1996 through which the public can search it from different location around the world. This is essential  as the super computer database is in USA. The public interface for MEDLINE is known as PUBMED.

You should also know that there are other interfaces by which you can operate the raw data of National Library of Medicine , they are EBSCO and ISI

That is the same source of information “MEDLINE” can be read via Pubmed , EBCSO and ISI

ANAEROBIC ACTIVITY OF CEFOPERAZONE SULBACTAM

ANAEROBIC ACTIVITY OF CEFOPERAZONE SULBACTAM

Sulbactam is added with Cefoperazone in order to increase the anaerobic activity of Cefoperazone. Individually sulbactam has shown activity against anaerobic bacteria including those producing beta lactamases

Antagonistic activity between the Cefoperazone and sulbactam has not been noted.(1)
In a study done for assessing the anaerobic activity of sulbactam in combination with Cefoperazone against Bacteroides fragilis it was found that out of 42 % of Bacteroides fragilis which was found initially resistant to Cefoperazone alone, 94% among them were converted to susceptible on the addition of sulbactam.(1) Out of all the strains of Bacteroides fragilis studied 67% was susceptible to Cefoperazone sulbactam and 27%was moderately susceptible.(1)

One more invitro study where the activity of the Cefoprazone alone and in combination with sulbactam was compared , it was shown that Cefoprazone sulbactam has anaerobic activity and inhibited 90-100% of all bacteria but Cefoperazone has activity of 63%. The percent susceptible against Bacteroides fragilis group is 99 to 100% for cefoperazone-sulbactam and for Cefoperazone, 49%.(2)

In one more study where 374 selected beta-lactamase-producing gram-negative anaerobes (including 22 cefoxitin-resistant strains and 36 strains refractory to the enhancing effect of beta-lactamase inhibitors) and 20 beta-lactamase-negative strains were tested against antimicrobials. The organisms included in the study consists of 217 Bacteroides fragilis group strains, 137 non-B. fragilis group Bacteroides spp., and 40 fusobacteria. (3)

The study showed that in Bacteroides fragilis group 95% were susceptible to cefoperazone-sulbactam. For the beta-lactamase-positive non-B. fragilis group Bacteroides spp., greater than or equal to 94% were susceptible cefoperazone-sulbactam. . For the beta-lactamase-positive fusobacteria, greater than or equal to 97% were susceptible cefoperazone-sulbactam.(3)

DRAWBACK:
Cefoperazone-sulbactam lacked activity against some cefoxitin-resistant B. fragilis group strains but had excellent activity against other organisms.

CONCLUSION:
Adddition of Metronidazole to Cefoperazone -sulbactam routinely is not needed. As Cefoperazone -sulbactam itself will cover most of anaerobe, addition of Metronidazole will add to unnecessary cost of treatment to the patient without any increase in benefit and also will lead to development of resistance to the Cefoperazone-sulbactam.

REFERENCES
1. D'Amato RF, Hochstein L, Frankel H. In vitro activity of cefoperazone/sulbactam and other antimicrobials against anaerobic bacteria. Diagnostic microbiology and infectious disease. 1990 Jan-Feb;13(1):51-5. PubMed PMID: 2331850. Epub 1990/01/01. eng.
2. Wexler HM, Finegold SM. In vitro activity of cefoperazone plus sulbactam compared with that of other antimicrobial agents against anaerobic bacteria. Antimicrobial agents and chemotherapy. 1988 Mar;32(3):403-6. PubMed PMID: 3364960. Pubmed Central PMCID: PMC172186. Epub 1988/03/01. eng.
3. Appelbaum PC, Spangler SK, Jacobs MR. Susceptibilities of 394 Bacteroides fragilis, non-B. fragilis group Bacteroides species, and Fusobacterium species to newer antimicrobial agents. Antimicrobial agents and chemotherapy. 1991 Jun;35(6):1214-8. PubMed PMID: 1929264. Pubmed Central PMCID: PMC284313. Epub 1991/06/01. eng

TCS - PGI SYMPOSIUM PART 2

1.    CD 38+ is the characterisation of Pluripotent stem cells. All cells have this positive.

2.    If CD 34+ then it is committed stem cells. 

MESENCHYMAL STEM CELLS FROM THE UMBLICAL CORD: A USEFUL SOURCE

Stem cells have self-renewal and differentiation capacity.

Totipotent cells-	Early embryo
Pluripotent cells	Blastocyst
Multipotent stem cells	Adult stem cells

1.     Embryonic stem cells- objectionable

2.     Foetal stem cells- ok but still some problem

3.     Mesenchymal stem cells- can renew into neural tissue also?

4.     MSC derived from old age people have reduced capacity of proliferation.

5.     HYPOTHESIS PROPOSED: UNIVERSAL STEM CELLS BY ALLOTRANSPLANTATION WITHOUT REQUIREMENT OF IMMUNO SUPRESSION.

6.     MSC are hypo immunogenic and also alter the immune response and modulate the T cells phenotype

Having low level of MHC II and lack of MHC I

MSC downregulate the T cell response.

These immune regulatory property encourage them to be used in lot of AUTOIMMUNE DISORDER and can be used for allogenic transplants.

7.     MSC has an enormous proliferating capacity and this is very important in making them enlarge very fast.

8.     Sources of MSC

Umbilical cord matrix, Umbilical cord blood, Placenta, Amniotic fluid (Neonatal MSC)

Other sources Bone marrow, Adipose tissue. (Adult MSC)

9.     Neonatal MSC are useful as age related changes which occur in the adult MSC will not occur over here.

10.  Plasticity, homing are some of the property required for both Neonatal as well as Adult stem cells.

11.  Wharton’s jelly is the source of the MSC in the umbilical cord.

12.  Explants method

Take the umbilical cord – Mice into small pieces

 Keep in the plate, the MSC will adhere to the basement of the plate and will grow         enormously.

13.  Another is Digestion method

14.  MSC also have safety issue and but some study research said that does not have any malignant transformation potential.

15.  There is an ocean full of pearls and we need to search the pearls for the good.

2 R’S OF MESENCHYMAL STEM CELLS-REPAIR AND REGENERATION

1.     E. Donnnall Thomas 1990

2.     Yamanaka -2012 Noble prize

3.     Artificial trachea- lancet 20087

4.     Artificial urethra-2011

5.     MSC are used in more than 76% of the trial.

6.     Earlier paracrine factor was thought to be responsible for causing proliferation of the stem cell injected area.

Transdifferentiate

Exosomes are released from the MSC- they have some receptor will go and add to the recipient cells and help them to regenerate.

7.     Dendritic derived Exosomes in severe cancer- Trial going on.

8.     MSC have many healthy mitochondria which get transferred from the MSC to the dying cells. This is documented.

9.     5 azacytidine is the commonly used for the characterisation of MSC into the cardiac cells.

10.  TGF beta also characterise the MSC into cardiac cells.

11.  FGF-2 helps in transformation to neural tissue. Something else are also there.

12.  Take a nerve cut it and then connect the cut by keeping a tissue

13.  Bench to bedside. Ocular Surface Reconstruction. EX vivo transfer of limbal corneal stem cells

14.  Vitiligo- Tissue specific stem cells – for the treatment of the vitiligo.

15.  STEM CELL AND TISSUE ENGINEERING

CORNEAL DEFECT

LONG BONE DEFECT

16.  MSC are used for IBD where it has immunomodualtory capacity and the same MSC are used in Regenerative capacity. So is it the environment which determines the effect by which MSC will behave.

TCS-PGI SYMPOSIUM

TCS-PGI SYMPOSIUM

Reporting from the symposium. Important excerpts from the symposium

DATA IN SUPPORT OF THE CLINICAL USE OF ADIPOSE DERIVED MSC: GROWTH, STORAGE, FUNCTION AND SAFETY

WILLIAM A FAUBION MD

ALLAN B DIETZ Ph.D.

1.     GLP certified Phase 1 trial on the Adipose MSC on the undertaken currently.

2.     There are variety of products for which these Adipose MSC can be used like ALS, MSA, ARAS, Anal fistula, Crohn disease.

3.     Cells therapy are drugs. So it should be as much stable, reproducible and safe.

4.     They have patented a technology known as 5%PLTmax for developing stem cells which can be used with the properties which was mentioned in point 3.

5.     MSC can differentiate into Bone, Cartilage.

6.     The stem cells maintain their viability even when passed through various needles, and the population doubling is independent and not affected by frozen. This was proved.

7.     Safety issue? Tumour, how will it migrate, is it efficacious in the disease specified

8.     For testing the malignant transformation SCID mice is used, as the immunity should not interfere with the malignant transformation.

9.     On very high concentration of MSC, then also tumour did not form but increase collagen was formed

10.  The same high concentration MSC was injected intrathecal, intrarenal. These high concentration was purposefully injected to see for the potential of malignant transformation.

11.  For safety you have to test biometrics (measure the weight), all major organ pathology, study the behaviour and you have administered the MSC as mentioned in the point 9 and 10.

12.  Other important points to note in this preclinical study is that more than 70 animals used, 3 species, different route of injection

13.  EXCITING POINT: In ovarian tumour the stem cell is used as a Trojan war horse which carries the oncolytic virus to the ovarian cancer

14.  CONCLUSION: Don’t put the product in the patient untill all the technology is clearly understood. When a survey was undertaken, patient was preferring autologous over allogenate.

STEM CELLS IN POST SURGICAL GASTROINTESTINAL LEAK

NAVTEJ S BUTTAR MD

1.     Over 10 lakh gastrointestinal surgeries are done per year. So gastrointestinal leak is a common programme and there needs to be new good treatment for the same.

2.     Over Macro and Micro level changes are responsible for the gastrointestinal fistula.

3.     The micro level changes which are responsible is inflammation and Macro level changes are Age, obesity.

4.     Currently drain are used. Scaffold for filling the space is an important factor.

5.     This stem cells will not be used for fresh 2-3 day fistula, over these we use OTSC placement. These stem cells are mainly used for old fistula very difficult to treat.

6.     IDEA CAME FROM: Graham’s idea of using fat for the closure of the ulcer is used hear for the closure of the big fistula in the gut.

7.     With this idea of using adipose tissue for closing, the same logic was used for giving Matrix loaded SMC for closing the large fistula which are resistant to other treatment.

8.     STEMMIX TRIAL IN POST SURGICAL FISTULA is undertaken currently in the world.

AUTOLOGOUS MSC THERAPY OF PERIANAL FISTULIZING CROHN DISEASE

WILLIAM A FAUBION MD

1.     Form a treatment and research team around a patient problem. The inputs which these two teams will give a lot of translational potential.

2.     PROBLEM ATATEMENT: 1 perianal fistula occurred in 33 % of Crohns disease

60% of the patient does not respond to medical therapy. Available treatment is ineffective. Morbidity is significantly

3.     CURRENT THERAPY: Treatment of patient with Fibrin glue was one of the novel approaches but it is ineffective.

4.     Stem cells used for perianal fistula around the world.

5.     So this trial consists of

Seton placement, control of sepsis

After 6 weeks the Seton are removed the Mesenchymal loaded fistula plug is replaced in the place and fixed to fill it.

6.     Healing per drainage cessation was used for assessing the effectiveness of the treatment and Likert scale was used for evaluating it.

7.     Out of 9 patients who were evaluated untill now 8 patients have resolved and the problem recurred. But in one patient there is recurrence.

8.     EXCITING POINTS: In Bioengineering there are a list of compounds which can be used in humans what are those. These are important to use in research.

9.     Mesenchymal stem cells have immunomodualtory properties.

Breastfeeding may expose infants to toxic chemicals

Breastfeeding may expose infants to toxic chemicals

                   A recent research report conducted by Harvard has shown that a particular type of Chemical which is used to make pipes and other material resistant to the water is transferred to the young babies through breast milk. The study appeared online on August 20, 2015 in Environmental Science & Technology. The chemical name is PFAS. So on thinking what the effect of this is chemical on the Human body? It is well documented that PFAS is associated with reproductive toxicity, endocrine disruption and immune system dysfunction.

                   On seeing the type of research being conducted by which this is proved, it is by assessing the cause- effect relation. That is as the duration by which the mother breast fed increases, the level of the PFAS in the infant increases. As soon as the mother stopped breast fed, the level decreased. In partially breastfed patients, the level of the PFAS increased proportionately and not to the extent of fully breast fed infants.

                  But the authors are not  saying to stop breast feeding. The thing to note is that there is no legislation regulating the level of these chemicals in the water.

In rat model , the pathology of head injury can be divided into 2 types.

Caspofungin dosage

Day 1 loading dose: 70 mg IV infused over 1 hr (as a single dose)

Maintenance: 50 mg IV OD infused over 1 hr

Continue antifungal therapy for at least 14 days after last positive culture

It is hepatic eliminated . So no dose modification essential in impaired renal clearance

It has shown to be in equal efficacious to Amphotericin B but not superior to Amphotericin B

Least prices found in market:

Casfung from Glenmark (Critica) [Caspofungin]

Strength             Volume Presentation      Price*  

Casfung 50mg   1            Casfung INJ        8920.00  

Casfung 70mg   1            Casfung INJ        8920.00  

Casporan from Ranbaxy [Caspofungin]

Strength             Volume Presentation      Price*  

Casporan 50mg 1            Casporan INJ     7980.00  

Casporan 70mg 1            Casporan INJ     7980.00   

FUTURE OF TREATMENT IN MEDICINE (FOTIM):

                    A new series will start in this blog where I will try to highlight the latest researches in the field of drug discovery , drug development and in medicine.This will throw light on what the future is waiting ahead of us. I hope this will be exciting and will be entertaining too.
                       The series name will be FOTIM which will be a acronym for Future Of Treatment In Medicine.

So to start with, here is the first blog in this series

            GUESS THE  SIDE EFFECT OF THE DRUG IN A PETRI DISH:

                                  Ha ha . Yes it is true. There is a research going on to create miniature heart , lung , liver,skin, kidney in a petridish with every organ just less than 1 cm side by side. You have to then drop the drug over it so that the drug will react on it and you can then guess what is the possible side effect you are going to get with the drug. Exciting right!!!




 

PREPARING A PLATFORM:

                                               If you want to do any clinical project , an important step is  creating a proforma.

WHY IS PROFORMA REQUIRED

1. It will help in easily filling up the required details
2. we wont forget the important information need to be collected in our research.
3. It helps in easy interpretation of our data by the other observer
4. EQUIVALITY OF ALL THE DATA, HELPS IN PERFORMING OUR ANANLYSIS EASILY

SO WHAT ALL SHOULD A PROFORMA CONTAIN:

1. Demographic info of the patients.
2. HISTORY if required.
3. Investigation to be collected. Should be exhaustive. better in tabular column. with the date in one column and it helps in easily adding our data to the sheet.
4. Detail about the drugs given including indication, requirement, dosage, route, rate of infusion, indication

THE KNOWLEDGE OF EXCEL:

             
                                               EXCEL here refers to the Microsoft Excel programme. In order to compute our data for research and also in order to do a lot of Pharmacokinetic evaluation excel will come as a handy help for us.

                               Excel will also help to organise many works in our profession and will also help us to manage the budget of our research. I will strongly recommend you to go for the original version of Excel.
                                In order to learn the excel I will suggest the following idea

1. Try to solve and see yourself in excel. Let it be wrong by this way you will learn the fastest.
2. Look out for the videos for Excel learning in the YouTube
3. Join any workshop of the Pharmacokinetic evaluation.