Newsletter – May 2015   Spiriva  Respimat:  A  Breath  of  Fresh  Air?   Written  By:  Brigham  Wilcox  –  ISU  Pharm  D  Candidate  2015  

Recently,  Boehringer  Ingelheim  Pharmaceuticals  gained   approval  from  the  FDA  for  a  new  form  of  tiotropium,  the  long-­‐ acting  anticholinergic  used  to  treat  COPD.  Some  people  may  be   thinking:  isn’t  tiotropium  already  available  as  Spiriva?  The   short  answer  to  this  question  is  yes,  but  Spiriva  HandiHaler  will   go  off  patent  in  early  2018.    This  poses  the  question,  is  the  new   dosage  form  a  way  to  keep  patients  on  a  lucrative  medication,   or  is  the  new  Spiriva  Respimat  honestly  superior  to  the   HandiHaler?    

Idaho Drug Information Center Idaho State University 921 S. 8th Ave, Stop 8092 Pocatello, ID 83209-8092 208-282-4689 [email protected] Director: Rebecca Hoover, PharmD, MBA, [email protected] Founding Editor: Ryan Jensen, PharmD Candidate 2016 Location: Third floor Eli

Spiriva  HandiHaler  requires  the  loading  of  a  powder  filled   capsule  into  the  inhaler  device.  This  highly  involved  process   includes  punching  the  capsule  out  of  its  foil  wrapper,  loading  it   into  the  inhaler  device,  closing  the  inhaler  (which  punctures  the   capsule  allowing  the  power  to  be  inhaled),  and  sharply  inhaling   at  least  two  breaths  to  ensure  the  powder  completely  exits  the   hole  in  the  capsule  and  enters  the  user’s  lungs.  This  process  is   repeated  each  day  with  a  new  capsule  of  medication.  Doesn’t   sound  too  difficult,  right?  Well,  that  depends  on  a  number  of   factors.  First  of  all,  many  patients  with  COPD  are  elderly,  and  the   elderly  can  sometimes  have  limited  dexterity  when  loading  the   capsule  into  the  inhaler.  Second,  once  it  is  loaded,  not  all  COPD   patients  can  inhale  sharply  and  deeply  enough  to  ensure  the   powdered  medication  is  fully  inhaled.  Finally,  older  patients   sometimes  have  poor  eyesight  and  do  not  recognize  which   capsule  is  which;  for  example,  what  might  happen  if  they  mix  up   their  Spiriva  capsule  with  their  omeprazole  medication.  They   may  be  swallowing  their  Spiriva  which  would  do  nothing  for   their  COPD.    

 

Newsletter – May 2015    Spiriva  Respimat  resolves  all  three  of  these  concerns.  The  Respimat  cartridge  contains  a   one-­‐month  supply  of  medication  that  only  needs  to  be  loaded  into  the  inhaler  device  once.   Although  the  Respimat  inhaler  requires  enough  dexterity  to  twist  the  top  180  degrees  for   each  dose,  this  is  considerably  easier  than  punching  a  small  capsule  out  of  foil  and  carefully   loading  it  into  the  HandiHaler.  The  Respimat  inhaler  requires  only  the  push  of  a  button  to   release  the  medication,  which  is  released  over  two  seconds  in  mist  form  and  is  slowly   inhaled  by  the  patient.  Finally,  unlike  Spiriva  HandiHaler,  the  Spiriva  Respimat  stores  the   medication  within  the  inhaler  so  patients  are  not  required  to  handle  a  capsule  for  each   dose.    This  eliminates  any  chance  that  a  capsule  might  be  taken  orally.     One  last  note  that  may  tip  the  scale  in  favor  of  the  Spiriva  Respimat  -­‐  the  total  daily  dose  is   5  mcg  (2  inhalations),  rather  than  18  mcg  (2  inhalations  from  the  same  capsule)  used  in  the   HandiHaler,  and  is  still  equally  effective.  So  why  not  go  with  the  medication  that  has  less   risk  of  adverse  effects?     Still  not  convinced?  Think  there’s  a  catch?  What  if   Boehringer  Ingelheim  Pharmaceuticals  listed  the   Spiriva  Respimat  at  the  exact  same  price  as  the  Spiriva   Handihaler?  Even  with  the  development  cost  likely   being  higher  for  this  new  inhaler  technology,  the   manufacturer  is  keeping  the  price  the  same  as  its   predecessor.  It’s  surprising  for  sure,  but  it  is  also  true.    

  A  New  Outlook:  Upcoming  Studies  Will  Evaluate  Verapamil  for  the   Reversal  of  Type  1  and  Type  2  Diabetes   Written  By:  Andrew  T.  Hibbard  –  ISU  Pharm  D  Candidate  2015  

Over  the  past  twelve  years,  researchers  have  gathered  significant  evidence  that  supports   the  repurposing  of  verapamil  as  a  potential  agent  that  may  halt  or  reverse  the  progression   of  newly  diagnosed  diabetes.1  Verapamil  is  an  oral  first  generation  L-­‐type  calcium  channel   blocker  that  has  been  used  for  over  thirty  years  for  the  treatment  of  hypertension  and   angina  pectoris.2  L-­‐type  calcium  channels  are  highly  concentrated  and  expressed  in  the   cardiovascular  system.  Inhibition  of  L-­‐type  calcium  channels  reduces  the  influx  of  calcium   ions  into  myocardial  and  vascular  smooth  muscle  cells  during  depolarization.  The   inhibition  of  calcium  influx  during  the  depolarization  stage  leads  to  relaxation  and   vasodilation.1,2,3    

 

 

 

 

Newsletter - May 2015 It  has  been  recently  elucidated  that  non-­‐dihydropyridine  calcium  channel  blockers   effectively  reduce  the  expression  of  thioredoxin-­‐interacting  protein  (TXNIP)  in  cardiac   myocytes  and  in  pancreatic  B-­‐cells.3,4  TXNIP  was  first  discovered  and  cloned  in  1994.  This   enzyme  interferes  with  thioredoxin  oxidoreductase  -­‐  an  important  enzyme  that  protects   cells  against  oxidative  stress  and  apoptosis.  It  was  first  believed  that  this  interaction   occurred  within  the  cytoplasm  of  the  cell.  However,  new  research  has  revealed  that  TXNIP   has  the  ability  to  promote  cellular  apoptosis  through  a  variety  of  pathways.  In  pancreatic  B-­‐ cells,  TXNIP  promotes  mitochondrial  release  of  cytochrome  C  from  the  mitochondria  and   induces  the  cleavage  of  caspase-­‐3,  leading  to  apoptosis.    In  addition,  TXNIP  acts  within  the   nucleus  of  B-­‐cells  and  regulates  expression  of  various  mRNA  that  effectively  down  regulate   important  insulin  transcription  factors  resulting  in  B-­‐cell  dysfunction.  Collectively,  TXNIP   plays  a  major  role  in  promoting  the  loss  of  functional  B-­‐cell  mass  -­‐  the  trademark  of  both   Type  1  and  Type  2  diabetes.  In  diabetes,  TXNIP  is  found  in  high  concentration  as  the   enzyme  is  strongly  up  regulated  in  response  to  glucose  in  a  concentration  dependent   fashion.  This  has  made  this  enzyme  an  attractive  target  for  novel  diabetes  therapies.4   Research  has  revealed  that  TXNIP  is  highly  up   regulated  in  diabetic  mice,  and  is  an  enzyme  that   induces  apoptosis.  However,  effective  TXNIP   inhibitors  were  not  available  until  recently.  Current   studies  have  revealed  that  verapamil  is  effective  in   reducing  B-­‐cell  TXNIP  expression  by  inhibiting   carbohydrate-­‐responsive  element-­‐binding  protein   (ChREBP)  from  occupying  and  activating  the  TXNIP   gene  promoter  region.  Further,  reduced  intercellular   calcium  levels  appear  to  be  a  class  effect  as  dilitiazem   and  calcium  chelating  compound  EGTA  exhibited  a  2   fold  reduction  in  TXNIP  mRNA  expression   concentrations  (p<0.001)  in  INS-­‐1  cell  lines.   Verapamil  reduced  TXNIP  mRNA  expression  in  a  dose   dependent  manner  in  human  islet  cells  (p=0.037)  and   in  vivo  mice  islet  cells  (p  =0.001).  Administration  of   verapamil  prevented  B-­‐cell  apoptosis  and  streptozotocin  (STZ)  induced  diabetes  in  mice  in   a  dose  dependent  fashion,  and  reduced  TXNIP  levels  by  80%  after  initiation.  In  the   verapamil  STZ  treated  group,  blood  glucose  levels  were  maintained  at  <250  mg/dL   compared  to  >400  mg/dL  in  the  STZ  control  group.  Immunohistochemistry  of  pancreas   cross-­‐sections  showed  severely  damaged  B-­‐cells  in  the  STZ  mice.  In  the  verapamil  and  STZ   treated  mice  group,  it  was  noted  that  B-­‐cell  apoptosis  was  significantly  reduced  in  response   to  verapamil  treatment.  These  findings  suggest  that  verapamil  promotes  B-­‐cell  survival,   and  thereby  prevents  diabetes  by  lowering  “pro-­‐apoptotic”  TXNIP  concentrations  (p<0.05).    

 

Newsletter – May 2015 Verapamil  appears  to  only  suppress  TXNIP  in  response  to  supra-­‐pathophysiologic   concentrations  as  seen  in  hyperglycemia.  Furthermore,  verapamil  appears  to  promote   insulin  secretion  and  increase  peripheral  insulin  sensitivity  (p<0.05).  It  also  promotes   glucose  uptake  in  muscle  and  adipose  tissue,  while  decreasing  hepatic  glucose  production   (p<0.05).  Finally,  studies  assessing  verapamil  in  obesity-­‐induced  diabetic  mice  revealed   that  verapamil  promoted  B-­‐cell  survival  (p<0.05),  improved  blood  glucose  (p<0.05),  and   increased  serum  insulin  concentrations  (p<0.05)  in  the  verapamil  treated  group.  5   Unlike  ACE-­‐inhibitors,  calcium  channel  blockers  are  generally  not  thought  of  as  first  line   therapy  in  diabetic  patients  for  the  treatment  of  hypertension.    In  the  International   Verapamil  SR/Trandolapril  (INVEST)  study,  newly  diagnosed  diabetes  was  noticeably  less   frequent  in  the  verapamil  SR  treated  patients  (p<0.01).  In  addition,  verapamil  reduced  the   risk  of  new  onset  diabetes  in  Hispanic  populations.6  A  first  of  its  kind  human  clinical  trial,   “The  repurposing  of  verapamil  as  a  beta-­‐cell  survival  therapy  in  Type  1  diabetes”  will  begin   in  2015.  The  study  will  randomize  52  newly  diagnosed  diabetic  patients,  who  will  be   administered  verapamil  or  a  placebo  for  12  months,  while  continuing  insulin-­‐pump   therapy.  Research  has  already  shown  that  verapamil  use  has  prevented  and  reversed   established  diabetes  in  mice  by  creating  an  environment  for  B-­‐cell  survival.  Diabetic   therapies  have  improved  drastically  over  the  years;  however,  these  series  of  human  trials   may  represent  a  potential  cure  or  at  the  very  least  a  slowing  down  in  the  progression  of   newly  diagnosed  diabetes.        

  Creatine   Written  By:  Nathan  Algate  –  ISU  Pharm  D  Candidate  2016  

Creatine  is  an  oral  supplement  that  is  used  most  commonly  for  athletic  performance  and   muscle  building.    The  Natural  Medicines  Comprehensive  Database  rates  creatine  as  being   likely  safe  when  “used  in  appropriate  doses  in  healthy  adults”  and  possibly  unsafe  when   used  in  higher  doses.1    This  is  due  to  the  risk  creatine  may  have  on  renal,  hepatic,  and   cardiac  function.    Creatine  is  rated  as  possibly  effective  for  athletic  performance  and  there   are  studies  that  support  this  claim.       Creatine  is  a  substance  that  is  produced  naturally  in  the  body.    It  is  mainly  found  in  skeletal   muscles  but  can  also  be  found  in  other  parts  of  the  body.    The  mechanism  of  actions   through  which  athletic  performance  is  increased  takes  place  in  the  skeletal  muscle.     Creatine  is  in  a  one-­‐to-­‐one  ratio  with  phosphocreatine-­‐-­‐  a  precursor  to  ATP.    Through   increasing  the  available  creatine  in  muscle  tissue,  the  levels  of  phosphocreatine  also   increase,  which  results  in  higher  production  of  ATP.    This  is  thought  to  increase  energy  for   shorts  bursts  of  exercise  and  also  improved  muscle  recovery  and  healing.1    

 

 

 

 

Newsletter - May 2015   Creatine  is  typically  started  with  a  loading  phase  followed  by  a  daily  maintenance  dose.    In   some  studies,  up  to  twenty  grams  of  creatine  has  been  used  for  five  days  for  the  loading   phase.  The  loading  phase  of  creatine  is  controversial  with  some  studies  that  show  five   grams  daily  is  just  as  beneficial  for  athletic  performance.1    Creatine  is  found  in  many  foods   at  low  concentrations,  most  of  which  are  animal  meats.    One  pound  of  steak  contains   approximately  two  grams  of  creatine.    For  this  reason,  creatine  is  usually  increased  through   supplementation  rather  that  dietary  sources.1    While  taking  creatine,  liver  and  kidney   function  should  be  monitored.    With  the  risk  that  creatine  supplementation  may  be   nephrotoxic,  other  nephrotoxic  drugs  should  be  avoided  as  much  as  possible,  including   NSAIDS.1   In  a  randomized,  double-­‐blind,  placebo-­‐ controlled  parallel-­‐group  study  by  Claudino   et  al,  creatine  was  tested  in  Brazilian  soccer   players  to  see  if  it  helped  improve  muscle   performance  in  the  lower-­‐limb  muscles   after  a  designed  training  session.2    In  this   study,  one  group  received  creatine   supplementation  and  the  other  group   received  a  placebo.    Both  groups  had  a   baseline  vertical  jump  height  measured  and   then  went  through  the  same  soccer  training   drills.    They  were  then  tested  again  post   training.    The  placebo  group  had  a  greater   reduction  in  jumping  performance  when   compared  to  the  creatine  group.  The  P-­‐ value  in  this  study  was  <0.05.  The  author   concluded  that  creatine  helped  prevent  a   decrease  in  lower-­‐limb  muscle  power  after   a  soccer  training  session.2     In  conclusion,  creatine  has  been  thought  to  have  multiple  medical  uses,  but  athletic   performance  is  the  most  studied.    It  has  been  shown  to  help  with  muscle  recovery  and   performance  when  supplemented  daily  without  regard  to  loading  dose.    Only  health  adults   who  are  free  from  kidney  and  liver  disease  should  consider  using  creatine.  If  a  patient  is   interested  in  creatine,  they  should  be  counseled  on  its  potential  nephrotoxicity  and  advised   to  avoid  NSAIDs  and  other  nephrotoxic  drugs.    Overall,  creatine  supplementation  is  likely   safe  and  can  have  some  potential  benefits  in  athletic  performance.      

 

 

Newsletter – May 2015   References   Spiriva  Respimat:  A  Breath  of  Fresh  Air?   1. Tiotropium.  Drug  Facts  and  comparisons.  Facts  &  Comparisons  [databaseonline].  St.  Louis,   MO:  Wolters  Kluwer  Health,  Inc;  January  2015.  Accessed  February  19,  2015.   2. PL   Detail-­‐Document,   Inhalers   for   COPD.   Pharmacist’s   Letter/Prescriber’s   Letter.   January   2015.   van  Noord  JA,  Cornelissen  PJ,  Aumann  JL,  Platz  J,  Mueller  A,  Fogarty  C.  The  efficacy  of   tiotropium   administered   via   Respimat   Soft   Mist   Inhaler   or   HandiHaler   in   COPD   patients.   Respir  Med.  2009;103(1):22-­‐9.     3. http://www.uspto.gov/patent/laws-­‐and-­‐regulations/patent-­‐term-­‐extension/patent-­‐terms-­‐ extended-­‐under-­‐35-­‐usc-­‐156   4. http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs /pulmonary-­‐allergydrugsadvisorycommittee/ucm410982.pdf.   5. Image  (page  1  -­‐  top  left)  Courtesy  of  dailymail.co.uk   6. Image  (page  2  –  middle  right)  Courtesy  of  pixgood.com     A  New  Outlook:  Upcoming  Studies  Will  Evaluate  Verapamil  for  the  Reversal  of  Type  1  and   Type  2  Diabetes   1. Hyunjoo  Cha-­‐Molstad,  Guanlan  Xu,  Junqin  Chen,  et  al.  Calcium  Channel  Blockers  Act  through   Nuclear  Factor  Y  to   Control  Transcription  of  Key  Cardiac  Genes.  Mol  Pharmacol.  2012.  82:541-­‐549.     2. Lexicomp  Online®.  Verapamil  Lexi-­‐Drugs®,  Hudson,  Ohio:  Lexi-­‐Comp,  Inc.;  December  20,   2015   3. Chen  J,  Cha-­‐Molstad  H,  Szabo  A,  and  Shalev  A.  Diabetes  induces  and  calcium  channel   blockers  prevent  cardiac  expression  of  proapoptotic  thioredoxininteracting  protein.  Am  J   Physiol  Endocrinol  Metab,  2009,  296:1133–1139.   4. Shalev,A.  Minireview:  Thioredxon-­‐Interacting  Protein:  Regulation  and  Function  in  the   Pancreatic  B-­‐cell.  Mol  Endocrinol,  2014,  28(8):  1211-­‐1220.   5. Xu,  G,  Chen,  J,  Jing,  G  &  Shalev,  A.  Preventing  B-­‐cell  Loss  and  Diabetes  With  Calcium  Channel   Blockers.  Diabetes,  2012,  61:848-­‐856.   6. Cooper-­‐DeHoff,  RM,  Aranda,  JM,  Gaxiola,  E,  et  al.  INVEST  Investigators.  Blood  pressure   control  and  cardiovascular  outcomes  in  high-­‐risk  Hispanic  patients-­‐findings  from  the   International  Verapamil  SR/Trandolapril  Study  (INVEST).  Am  Heart  J,  2006,  151:1072-­‐ 1079.   7. Image  (Page  3:  middle  right)  coutesy  of  UAB.edu     Creatine     1.  Naturaldatabase.therapeuticresearch.com.  CREATINE  Monograph:  Natural  Medicines   Comprehensive  Database.  2014.  Available  at:   http://naturaldatabase.therapeuticresearch.com/nd/Search.aspx?cs=STUDENT&s=ND&pt= 100&id=873&ds=&name=CREATINE&searchid=49120837.  Accessed  September  10,  2014.   2. Claudino  JG,  Mezêncio  B,  Amaral  S,  et  al.  Creatine  monohydrate  supplementation  on  lower-­‐ limb  muscle  power  in  Brazilian  elite  soccer  players.  J  Int  Soc  Sports  Nutr.  2014  Jun;  11:32   3. Image  (page  5:  middle  right)  courtesy  of  iherb.com