SlideShare a Scribd company logo
New Diabetes Drug Invokana Has Major
Treatment - And Market - Potential
A new treatment option will soon be available to people with type 2 diabetes with the FDA’s
approval on Friday of Invokana, a first-in-class medication to lower blood sugar.
Johnson & Johnson’s Invokana (generic name canagliflozin) attacks blood sugar right from the
get go, reducing the amount of sugar absorbed from food into the bloodstream. The body then
flushes the excess sugar out in the urine.
The medical profession – and analysts – have been paying close attention to Invokana because it
lowers blood sugar by a different mechanism than the other diabetes drugs on the market.
(Metformin, which I wrote about last week for its anti-cancer and anti-aging benefits, is one of
the other popular diabetes medications available.)
Controlling blood sugar is the key to preventing the many side effects caused by diabetes, such
as vision loss, nerve damage, kidney damage, and increased risk of heart attack and stroke.
Johnson & Johnson’s application for Invokana cited nine clinical trials involving more than
10,000 patients. The main side effects found were urinary tract infections (UTIs) and yeast
infections caused by large amounts of sugar in the urine. (Women prone to UTIs are familiar
with this problem.) Forbes’ Matthew Herper reports that this problem could limit Invokana’s
sales, according to some analysts’ predictions. People taking Invokana were also found to have
the potential to become dizzy or faint when standing up suddenly, giving the drug the potential to
cause falls, which can be particularly dangerous to the elderly.
Invokana’s action takes place in the kidneys – it blocks an enzyme, sodium-glucose co-
transporter 2, from putting sugar removed by the kidneys back in the bloodstream. Therefore
some members of the FDA’s advisory panel expressed concern that Invokana should not be
taken by people with moderate to severe kidney disease.
Invokana was found in trials to raise cholesterol, both LDL or bad cholesterol and HDL, or
“good” cholesterol. An elevated risk of stroke and heart attack was found in the first 30 days
after starting the medication, but after 30 days Invokana reduced these risks.
Some diabetes drugs, in particular the former “blockbuster” Avandia, have run into trouble
because of increased heart attack risk. Avandia is now restricted to patients who’ve tried and
failed to respond to other medications, and is banned in Europe. The FDA required Johnson &
Johnson to conduct five additional long-term studies of Invokana’s effects on cardiac health,
liver problems, cancer, and pancreatic disease.
Any diabetes drug that works well – and has limited side effects – has major market potential
simply because there are so many people with diabetes.

More Related Content

Similar to New diabetes drug invokana has major treatment

Prescription Drug Dependency Cascade-Research Abstracts
Prescription Drug Dependency Cascade-Research AbstractsPrescription Drug Dependency Cascade-Research Abstracts
Prescription Drug Dependency Cascade-Research AbstractsSuzanne Lennartz
 
IDENTIFYING THE SIDE EFFECTS OF SELF-MEDICATED DICLOFENAC
IDENTIFYING THE SIDE EFFECTS OF SELF-MEDICATED DICLOFENACIDENTIFYING THE SIDE EFFECTS OF SELF-MEDICATED DICLOFENAC
IDENTIFYING THE SIDE EFFECTS OF SELF-MEDICATED DICLOFENACGABRIEL JEREMIAH ORUIKOR
 
Metformin Case Study
Metformin Case StudyMetformin Case Study
Metformin Case StudyTina Jordan
 
R & I declofenac side effects leaflet
R & I declofenac side effects leafletR & I declofenac side effects leaflet
R & I declofenac side effects leafletAaron Saund
 
Diabetes and Drug Treatments Essay.docx
Diabetes and Drug Treatments Essay.docxDiabetes and Drug Treatments Essay.docx
Diabetes and Drug Treatments Essay.docxstudywriters
 
Impact of patient counseling on diabetes mellitus patients in the territory c...
Impact of patient counseling on diabetes mellitus patients in the territory c...Impact of patient counseling on diabetes mellitus patients in the territory c...
Impact of patient counseling on diabetes mellitus patients in the territory c...SriramNagarajan17
 
Future Of Nanomedicine In Diabetes Treatment.pdf
Future Of Nanomedicine In Diabetes Treatment.pdfFuture Of Nanomedicine In Diabetes Treatment.pdf
Future Of Nanomedicine In Diabetes Treatment.pdfPharmacy 7065
 
Diabetes
DiabetesDiabetes
Diabetesnymufti
 
Dr. mc dougall's diabetes challenge
Dr. mc dougall's diabetes challengeDr. mc dougall's diabetes challenge
Dr. mc dougall's diabetes challengeMary-Margaret LaRue
 
Revolutionizing Care for People with Type 2 Diabetes
Revolutionizing Care for People with Type 2 Diabetes Revolutionizing Care for People with Type 2 Diabetes
Revolutionizing Care for People with Type 2 Diabetes Denise Barnard
 
Techno assignment 3 marks
Techno assignment 3 marksTechno assignment 3 marks
Techno assignment 3 marksAsra Hameed
 

Similar to New diabetes drug invokana has major treatment (20)

Diabetes Mellitus
Diabetes MellitusDiabetes Mellitus
Diabetes Mellitus
 
Prescription Drug Dependency Cascade-Research Abstracts
Prescription Drug Dependency Cascade-Research AbstractsPrescription Drug Dependency Cascade-Research Abstracts
Prescription Drug Dependency Cascade-Research Abstracts
 
Serendib tea
Serendib teaSerendib tea
Serendib tea
 
Top medical advances 2016
Top medical advances 2016Top medical advances 2016
Top medical advances 2016
 
Serendib tea
Serendib teaSerendib tea
Serendib tea
 
IDENTIFYING THE SIDE EFFECTS OF SELF-MEDICATED DICLOFENAC
IDENTIFYING THE SIDE EFFECTS OF SELF-MEDICATED DICLOFENACIDENTIFYING THE SIDE EFFECTS OF SELF-MEDICATED DICLOFENAC
IDENTIFYING THE SIDE EFFECTS OF SELF-MEDICATED DICLOFENAC
 
ACE - Inhibitors
ACE - InhibitorsACE - Inhibitors
ACE - Inhibitors
 
Metformin Case Study
Metformin Case StudyMetformin Case Study
Metformin Case Study
 
Diabetes awarness presentation new
Diabetes awarness presentation newDiabetes awarness presentation new
Diabetes awarness presentation new
 
R & I declofenac side effects leaflet
R & I declofenac side effects leafletR & I declofenac side effects leaflet
R & I declofenac side effects leaflet
 
Diabetes and Drug Treatments Essay.docx
Diabetes and Drug Treatments Essay.docxDiabetes and Drug Treatments Essay.docx
Diabetes and Drug Treatments Essay.docx
 
Impact of patient counseling on diabetes mellitus patients in the territory c...
Impact of patient counseling on diabetes mellitus patients in the territory c...Impact of patient counseling on diabetes mellitus patients in the territory c...
Impact of patient counseling on diabetes mellitus patients in the territory c...
 
Future Of Nanomedicine In Diabetes Treatment.pdf
Future Of Nanomedicine In Diabetes Treatment.pdfFuture Of Nanomedicine In Diabetes Treatment.pdf
Future Of Nanomedicine In Diabetes Treatment.pdf
 
Diabetes
DiabetesDiabetes
Diabetes
 
Diabetes
DiabetesDiabetes
Diabetes
 
Dr. mc dougall's diabetes challenge
Dr. mc dougall's diabetes challengeDr. mc dougall's diabetes challenge
Dr. mc dougall's diabetes challenge
 
Interacciones farmacológicas
Interacciones farmacológicasInteracciones farmacológicas
Interacciones farmacológicas
 
diabetes.pdf
diabetes.pdfdiabetes.pdf
diabetes.pdf
 
Revolutionizing Care for People with Type 2 Diabetes
Revolutionizing Care for People with Type 2 Diabetes Revolutionizing Care for People with Type 2 Diabetes
Revolutionizing Care for People with Type 2 Diabetes
 
Techno assignment 3 marks
Techno assignment 3 marksTechno assignment 3 marks
Techno assignment 3 marks
 

More from Ashish Garg

10 important drugs discovered by accident
10 important drugs discovered by accident10 important drugs discovered by accident
10 important drugs discovered by accidentAshish Garg
 
General drug categories
General drug categoriesGeneral drug categories
General drug categoriesAshish Garg
 
List of approved drug for marketing in india
List of approved drug for marketing in indiaList of approved drug for marketing in india
List of approved drug for marketing in indiaAshish Garg
 
Enteric coating of pharmaceutical products
Enteric coating of pharmaceutical productsEnteric coating of pharmaceutical products
Enteric coating of pharmaceutical productsAshish Garg
 
Erythrocytes2 090814024428-phpapp02
Erythrocytes2 090814024428-phpapp02Erythrocytes2 090814024428-phpapp02
Erythrocytes2 090814024428-phpapp02Ashish Garg
 

More from Ashish Garg (7)

10 important drugs discovered by accident
10 important drugs discovered by accident10 important drugs discovered by accident
10 important drugs discovered by accident
 
Review article
Review articleReview article
Review article
 
General drug categories
General drug categoriesGeneral drug categories
General drug categories
 
List of approved drug for marketing in india
List of approved drug for marketing in indiaList of approved drug for marketing in india
List of approved drug for marketing in india
 
Voglibose
VogliboseVoglibose
Voglibose
 
Enteric coating of pharmaceutical products
Enteric coating of pharmaceutical productsEnteric coating of pharmaceutical products
Enteric coating of pharmaceutical products
 
Erythrocytes2 090814024428-phpapp02
Erythrocytes2 090814024428-phpapp02Erythrocytes2 090814024428-phpapp02
Erythrocytes2 090814024428-phpapp02
 

Recently uploaded

Arterial health throughout cancer treatment and exercise rehabilitation in wo...
Arterial health throughout cancer treatment and exercise rehabilitation in wo...Arterial health throughout cancer treatment and exercise rehabilitation in wo...
Arterial health throughout cancer treatment and exercise rehabilitation in wo...Catherine Liao
 
Impact of cancers therapies on the loss in cardiac function, myocardial fffic...
Impact of cancers therapies on the loss in cardiac function, myocardial fffic...Impact of cancers therapies on the loss in cardiac function, myocardial fffic...
Impact of cancers therapies on the loss in cardiac function, myocardial fffic...Catherine Liao
 
"Central Hypertension"‚ in China: Towards the nation-wide use of SphygmoCor t...
"Central Hypertension"‚ in China: Towards the nation-wide use of SphygmoCor t..."Central Hypertension"‚ in China: Towards the nation-wide use of SphygmoCor t...
"Central Hypertension"‚ in China: Towards the nation-wide use of SphygmoCor t...Catherine Liao
 
The hemodynamic and autonomic determinants of elevated blood pressure in obes...
The hemodynamic and autonomic determinants of elevated blood pressure in obes...The hemodynamic and autonomic determinants of elevated blood pressure in obes...
The hemodynamic and autonomic determinants of elevated blood pressure in obes...Catherine Liao
 
The Normal Electrocardiogram - Part I of II
The Normal Electrocardiogram - Part I of IIThe Normal Electrocardiogram - Part I of II
The Normal Electrocardiogram - Part I of IIMedicoseAcademics
 
Alcohol_Dr. Jeenal Mistry MD Pharmacology.pdf
Alcohol_Dr. Jeenal Mistry MD Pharmacology.pdfAlcohol_Dr. Jeenal Mistry MD Pharmacology.pdf
Alcohol_Dr. Jeenal Mistry MD Pharmacology.pdfDr Jeenal Mistry
 
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
 
Retinal consideration in cataract surgery
Retinal consideration in cataract surgeryRetinal consideration in cataract surgery
Retinal consideration in cataract surgeryKafrELShiekh University
 
Presentació "Advancing Emergency Medicine Education through Virtual Reality"
Presentació "Advancing Emergency Medicine Education through Virtual Reality"Presentació "Advancing Emergency Medicine Education through Virtual Reality"
Presentació "Advancing Emergency Medicine Education through Virtual Reality"Badalona Serveis Assistencials
 
TEST BANK For Timby's Introductory Medical-Surgical Nursing, 13th American Ed...
TEST BANK For Timby's Introductory Medical-Surgical Nursing, 13th American Ed...TEST BANK For Timby's Introductory Medical-Surgical Nursing, 13th American Ed...
TEST BANK For Timby's Introductory Medical-Surgical Nursing, 13th American Ed...kevinkariuki227
 
Ocular injury ppt Upendra pal optometrist upums saifai etawah
Ocular injury  ppt  Upendra pal  optometrist upums saifai etawahOcular injury  ppt  Upendra pal  optometrist upums saifai etawah
Ocular injury ppt Upendra pal optometrist upums saifai etawahpal078100
 
Temporal, Infratemporal & Pterygopalatine BY Dr.RIG.pptx
Temporal, Infratemporal & Pterygopalatine BY Dr.RIG.pptxTemporal, Infratemporal & Pterygopalatine BY Dr.RIG.pptx
Temporal, Infratemporal & Pterygopalatine BY Dr.RIG.pptxDr. Rabia Inam Gandapore
 
DECIPHERING COMMON ECG FINDINGS IN ED.pptx
DECIPHERING COMMON ECG FINDINGS IN ED.pptxDECIPHERING COMMON ECG FINDINGS IN ED.pptx
DECIPHERING COMMON ECG FINDINGS IN ED.pptxdrwaque
 
Hemodialysis: Chapter 3, Dialysis Water Unit - Dr.Gawad
Hemodialysis: Chapter 3, Dialysis Water Unit - Dr.GawadHemodialysis: Chapter 3, Dialysis Water Unit - Dr.Gawad
Hemodialysis: Chapter 3, Dialysis Water Unit - Dr.GawadNephroTube - Dr.Gawad
 
HOT NEW PRODUCT! BIG SALES FAST SHIPPING NOW FROM CHINA!! EU KU DB BK substit...
HOT NEW PRODUCT! BIG SALES FAST SHIPPING NOW FROM CHINA!! EU KU DB BK substit...HOT NEW PRODUCT! BIG SALES FAST SHIPPING NOW FROM CHINA!! EU KU DB BK substit...
HOT NEW PRODUCT! BIG SALES FAST SHIPPING NOW FROM CHINA!! EU KU DB BK substit...GL Anaacs
 
For Better Surat #ℂall #Girl Service ❤85270-49040❤ Surat #ℂall #Girls
For Better Surat #ℂall #Girl Service ❤85270-49040❤ Surat #ℂall #GirlsFor Better Surat #ℂall #Girl Service ❤85270-49040❤ Surat #ℂall #Girls
For Better Surat #ℂall #Girl Service ❤85270-49040❤ Surat #ℂall #GirlsSavita Shen $i11
 
TEST BANK For Williams' Essentials of Nutrition and Diet Therapy, 13th Editio...
TEST BANK For Williams' Essentials of Nutrition and Diet Therapy, 13th Editio...TEST BANK For Williams' Essentials of Nutrition and Diet Therapy, 13th Editio...
TEST BANK For Williams' Essentials of Nutrition and Diet Therapy, 13th Editio...kevinkariuki227
 
Why invest into infodemic management in health emergencies
Why invest into infodemic management in health emergenciesWhy invest into infodemic management in health emergencies
Why invest into infodemic management in health emergenciesTina Purnat
 
CURRENT HEALTH PROBLEMS AND ITS SOLUTION BY AYURVEDA.pptx
CURRENT HEALTH PROBLEMS AND ITS SOLUTION BY AYURVEDA.pptxCURRENT HEALTH PROBLEMS AND ITS SOLUTION BY AYURVEDA.pptx
CURRENT HEALTH PROBLEMS AND ITS SOLUTION BY AYURVEDA.pptxDr KHALID B.M
 
The POPPY STUDY (Preconception to post-partum cardiovascular function in prim...
The POPPY STUDY (Preconception to post-partum cardiovascular function in prim...The POPPY STUDY (Preconception to post-partum cardiovascular function in prim...
The POPPY STUDY (Preconception to post-partum cardiovascular function in prim...Catherine Liao
 

Recently uploaded (20)

Arterial health throughout cancer treatment and exercise rehabilitation in wo...
Arterial health throughout cancer treatment and exercise rehabilitation in wo...Arterial health throughout cancer treatment and exercise rehabilitation in wo...
Arterial health throughout cancer treatment and exercise rehabilitation in wo...
 
Impact of cancers therapies on the loss in cardiac function, myocardial fffic...
Impact of cancers therapies on the loss in cardiac function, myocardial fffic...Impact of cancers therapies on the loss in cardiac function, myocardial fffic...
Impact of cancers therapies on the loss in cardiac function, myocardial fffic...
 
"Central Hypertension"‚ in China: Towards the nation-wide use of SphygmoCor t...
"Central Hypertension"‚ in China: Towards the nation-wide use of SphygmoCor t..."Central Hypertension"‚ in China: Towards the nation-wide use of SphygmoCor t...
"Central Hypertension"‚ in China: Towards the nation-wide use of SphygmoCor t...
 
The hemodynamic and autonomic determinants of elevated blood pressure in obes...
The hemodynamic and autonomic determinants of elevated blood pressure in obes...The hemodynamic and autonomic determinants of elevated blood pressure in obes...
The hemodynamic and autonomic determinants of elevated blood pressure in obes...
 
The Normal Electrocardiogram - Part I of II
The Normal Electrocardiogram - Part I of IIThe Normal Electrocardiogram - Part I of II
The Normal Electrocardiogram - Part I of II
 
Alcohol_Dr. Jeenal Mistry MD Pharmacology.pdf
Alcohol_Dr. Jeenal Mistry MD Pharmacology.pdfAlcohol_Dr. Jeenal Mistry MD Pharmacology.pdf
Alcohol_Dr. Jeenal Mistry MD Pharmacology.pdf
 
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...
 
Retinal consideration in cataract surgery
Retinal consideration in cataract surgeryRetinal consideration in cataract surgery
Retinal consideration in cataract surgery
 
Presentació "Advancing Emergency Medicine Education through Virtual Reality"
Presentació "Advancing Emergency Medicine Education through Virtual Reality"Presentació "Advancing Emergency Medicine Education through Virtual Reality"
Presentació "Advancing Emergency Medicine Education through Virtual Reality"
 
TEST BANK For Timby's Introductory Medical-Surgical Nursing, 13th American Ed...
TEST BANK For Timby's Introductory Medical-Surgical Nursing, 13th American Ed...TEST BANK For Timby's Introductory Medical-Surgical Nursing, 13th American Ed...
TEST BANK For Timby's Introductory Medical-Surgical Nursing, 13th American Ed...
 
Ocular injury ppt Upendra pal optometrist upums saifai etawah
Ocular injury  ppt  Upendra pal  optometrist upums saifai etawahOcular injury  ppt  Upendra pal  optometrist upums saifai etawah
Ocular injury ppt Upendra pal optometrist upums saifai etawah
 
Temporal, Infratemporal & Pterygopalatine BY Dr.RIG.pptx
Temporal, Infratemporal & Pterygopalatine BY Dr.RIG.pptxTemporal, Infratemporal & Pterygopalatine BY Dr.RIG.pptx
Temporal, Infratemporal & Pterygopalatine BY Dr.RIG.pptx
 
DECIPHERING COMMON ECG FINDINGS IN ED.pptx
DECIPHERING COMMON ECG FINDINGS IN ED.pptxDECIPHERING COMMON ECG FINDINGS IN ED.pptx
DECIPHERING COMMON ECG FINDINGS IN ED.pptx
 
Hemodialysis: Chapter 3, Dialysis Water Unit - Dr.Gawad
Hemodialysis: Chapter 3, Dialysis Water Unit - Dr.GawadHemodialysis: Chapter 3, Dialysis Water Unit - Dr.Gawad
Hemodialysis: Chapter 3, Dialysis Water Unit - Dr.Gawad
 
HOT NEW PRODUCT! BIG SALES FAST SHIPPING NOW FROM CHINA!! EU KU DB BK substit...
HOT NEW PRODUCT! BIG SALES FAST SHIPPING NOW FROM CHINA!! EU KU DB BK substit...HOT NEW PRODUCT! BIG SALES FAST SHIPPING NOW FROM CHINA!! EU KU DB BK substit...
HOT NEW PRODUCT! BIG SALES FAST SHIPPING NOW FROM CHINA!! EU KU DB BK substit...
 
For Better Surat #ℂall #Girl Service ❤85270-49040❤ Surat #ℂall #Girls
For Better Surat #ℂall #Girl Service ❤85270-49040❤ Surat #ℂall #GirlsFor Better Surat #ℂall #Girl Service ❤85270-49040❤ Surat #ℂall #Girls
For Better Surat #ℂall #Girl Service ❤85270-49040❤ Surat #ℂall #Girls
 
TEST BANK For Williams' Essentials of Nutrition and Diet Therapy, 13th Editio...
TEST BANK For Williams' Essentials of Nutrition and Diet Therapy, 13th Editio...TEST BANK For Williams' Essentials of Nutrition and Diet Therapy, 13th Editio...
TEST BANK For Williams' Essentials of Nutrition and Diet Therapy, 13th Editio...
 
Why invest into infodemic management in health emergencies
Why invest into infodemic management in health emergenciesWhy invest into infodemic management in health emergencies
Why invest into infodemic management in health emergencies
 
CURRENT HEALTH PROBLEMS AND ITS SOLUTION BY AYURVEDA.pptx
CURRENT HEALTH PROBLEMS AND ITS SOLUTION BY AYURVEDA.pptxCURRENT HEALTH PROBLEMS AND ITS SOLUTION BY AYURVEDA.pptx
CURRENT HEALTH PROBLEMS AND ITS SOLUTION BY AYURVEDA.pptx
 
The POPPY STUDY (Preconception to post-partum cardiovascular function in prim...
The POPPY STUDY (Preconception to post-partum cardiovascular function in prim...The POPPY STUDY (Preconception to post-partum cardiovascular function in prim...
The POPPY STUDY (Preconception to post-partum cardiovascular function in prim...
 

New diabetes drug invokana has major treatment

  • 1. New Diabetes Drug Invokana Has Major Treatment - And Market - Potential A new treatment option will soon be available to people with type 2 diabetes with the FDA’s approval on Friday of Invokana, a first-in-class medication to lower blood sugar. Johnson & Johnson’s Invokana (generic name canagliflozin) attacks blood sugar right from the get go, reducing the amount of sugar absorbed from food into the bloodstream. The body then flushes the excess sugar out in the urine. The medical profession – and analysts – have been paying close attention to Invokana because it lowers blood sugar by a different mechanism than the other diabetes drugs on the market. (Metformin, which I wrote about last week for its anti-cancer and anti-aging benefits, is one of the other popular diabetes medications available.) Controlling blood sugar is the key to preventing the many side effects caused by diabetes, such as vision loss, nerve damage, kidney damage, and increased risk of heart attack and stroke. Johnson & Johnson’s application for Invokana cited nine clinical trials involving more than 10,000 patients. The main side effects found were urinary tract infections (UTIs) and yeast infections caused by large amounts of sugar in the urine. (Women prone to UTIs are familiar with this problem.) Forbes’ Matthew Herper reports that this problem could limit Invokana’s sales, according to some analysts’ predictions. People taking Invokana were also found to have the potential to become dizzy or faint when standing up suddenly, giving the drug the potential to cause falls, which can be particularly dangerous to the elderly. Invokana’s action takes place in the kidneys – it blocks an enzyme, sodium-glucose co- transporter 2, from putting sugar removed by the kidneys back in the bloodstream. Therefore some members of the FDA’s advisory panel expressed concern that Invokana should not be taken by people with moderate to severe kidney disease. Invokana was found in trials to raise cholesterol, both LDL or bad cholesterol and HDL, or “good” cholesterol. An elevated risk of stroke and heart attack was found in the first 30 days after starting the medication, but after 30 days Invokana reduced these risks. Some diabetes drugs, in particular the former “blockbuster” Avandia, have run into trouble because of increased heart attack risk. Avandia is now restricted to patients who’ve tried and failed to respond to other medications, and is banned in Europe. The FDA required Johnson & Johnson to conduct five additional long-term studies of Invokana’s effects on cardiac health, liver problems, cancer, and pancreatic disease. Any diabetes drug that works well – and has limited side effects – has major market potential simply because there are so many people with diabetes.