02 - Consultant's Corner panel · Biomed Research International, Volume 2013, Article ID 150653 ... Pastuszak AW, Gomez LP, Scovell JM, Khera M, Lamb DJ, Lipshultz ... Baas W, Köhler

Consultant’s Corner

Andy Glasnapp, PharmDBruce Biundo, RPhMike Leake, RPh

International SeminarHouston, TX

November 10‐12, 2016

© 2016. All Rights Reserved. 1

Biofilms: The Basics

Andy Glasnapp, PharmD


Observations Chronic Infections


Case Report Chronic Infection

• 51 year old female• Jan 15th

– Upper respiratory distress and sinus pain– Rx Prednisone 20mg bid x4d and taper

• Feb 17th

– Severe sore throat and ear pain– Told, “you’re OK”



• Feb 21st

– Fever, chills, sore throat, unable to speak, cough, otitis media– Rx Amoxicillin 875mg x 10d– Benzonatate 100mg ‐ 200mg tid prn cough

• March 4th

– Emergency room

– Fever 101.5°, chills, malaise, severe abdominal pain right upper / lower quadrant, vasovagal attack



• March 4th

– WBC 26,000 normal under 4500?– Numerous abdominal and cranial CAT scans, MRIs, and ultrasound tests. All clear.

– Rx ‐ Levaquin® 500gm IV bid. Flagyl® 500mg tid. Morphine 10mg IV push prn.



• Numerous consultations from ER, GI, surgeon, hospitalist, radiologist

• March 6th ‐ 48 hrs in hospital– Discharged Rx ‐ Levaquin® 500mg qd x7d– Flagyl® 500mg tid x7d– Diagnosis: high WBC

• Cost $39,836.75




Deepwater Horizon‐ April 20, 2010


Mountain Streams


Reason Biofilms Exist

• Biofilms are formed in great places for bacteria and fungi to live. They may get a certain limited nutrient or environmental condition that helps them flourish.

• Biofilms are formed to survive a particular harsh condition or environment (survival mechanism)

• Can be helpful or harmful


Cellulose Biofilter to Clean Air


Plaque


Survival Questions

• What do humans do when threatened to survive?

• Bacteria have been on the planet longer than humans. What mechanisms do they have to survive a threat?

• If we understand these mechanisms maybe, could treat infections more effectively?

• Is their a difference in acute and chronic infections?


Biofilm Formation BasicsPlanktonic vs. Biofilm


Planktonic Bacteria

Mobile free floating Flagella


Bacteria Under Threat

Pili (hook to surface)Pili (hook to each other)

Quorum Sensing (act as one unit)


Biofilm Lifecycle


Biofilm Composition

• Water up to 97%• Microbial cells 2‐5% many species• Polysaccharides 1‐2% (Ca &Mg divalent cations)• Proteins < 1‐2% many including enzymes• DNA and RNA < 1‐2%


Theories to Treat Biofilms

• Light radiation• Inhibition of quorum sensing• Inhibition of biofilm formation (Disodium EDTA “bacteria”,

ibuprofen “fungus” prostaglandins, Efflux pumps)• Biofilm dispersion (get the colony to tear down it’s own biofilm

and return to planktonic state) “Chemotaxis”• Xylitol as a source of food• Xylitol in LoxaSperse™


Chronic Ear Infection

• IJPC May / June 2000• Written by some kid named Tricia Tribble?• Xylitol 40% syrup 5 x/day helped prevent chronic middle ear infection

• The mechanism was unclear at the time. Thought to prevent bacteria from adhering to mucus membrane.


Xylitol and Biofilm Dispersion

• Stacy Sommerfield‐Ross• Nutrient dispersion enhances conventional antibiotic activity against Pseudomonas aeruginosa biofilms

• International Journal of Antimicrobial Agents• Copy of article on app


Treating Biofilms

• Nutrient dispersion “chemotaxis”

– Xylitol • Syrup ‐ PCCA Formula #4516 ‐ 40% Xylitol 5ml 5 x daily

• Oral rinse ‐ PCCA Formula #11383, 1197, 11768 ‐ dry mouth

• Nasal spray ‐ PCCA Formula #10761, 5595

• Lollipop ‐ PCCA Formula #5417

• Sinus irrigation ‐ LoxaSperse™ contains Xylitol

• General use guide ‐ 2% concentration at site of biofilm


Treating Biofilms

• Biofilm disruptive– Disodium EDTA ‐ binds Ca attached to Polysaccharide

• 0.1% max concentration in nasal / sinus use “Anosmia”• Up to 1% in other applications• Nasal ‐ PCCA Formula #11984, 11935• Sinus irrigation ‐ PCCA Formula #11983, 11935• MucoLox™ does contain a small amount of Disodium EDTA


Treating Fungal Biofilms

• Inhibit fungal biofilm formation– Ibuprofen via prostaglandin, efflux pump

• Cream ‐ PCCA Formula #4650, 9442, 5091, 9443• Gel ‐ PCCA Formula #11156• Nail solution ‐ PCCA Formula #4337• Favorite nail solution: 2% Azole antifungal, 2% Ibuprofen qs with pure DMSO USP

• Great alternative to Jublia®


Alternatives to Jublia®• Sited from “Clinical Pharmacology”

– Efinaconazole is a topical azole antifungal solution indicated for the treatment of onychomycosis of the toenails caused by Trichophyton rubrum and Trichophyton mentagrophytes. Approval was based on the results of two randomized, double‐blind, vehicle‐controlled clinical trials involving adults with onychomycosis of the toenail. In these trials, complete cure (defined as 0% clinical involvement of the target toenail plus negative KOH and negative culture) at 4 weeks post‐treatment was achieved in 17.8% and 15.2% of efinaconazole recipients compared to 3.3% and 5.5% of patients receiving the vehicle solution

• 4ml cost over $500• Next ‐ video from experts


Video from Some Experts




Thank you

• For your convenience the entire reference library is contained on the app


Bibliography* Pina‐Vaz C, Sansonetty F, Rodrigues AG, et al. Antifungal activity of ibuprofen alone and in

combination with fluconazole against Candida species. J. Med Microbiol. Vol. 49 (2000), 831‐840.

* Pina‐Vaz C, Rodrigues, AG, Costa‐de‐Oliveria S, et al. Potent synergic effect between ibuprofen and azoles on Candida relulting from blockade of efflux pumps as determined by FUN‐1 staining and flow cytometry. Journal of Antimicrobial Chemotherapy (2005) 56, 678‐685.

* Taraszkiewicz A, Fila G, Grinholc M, Nakonieczna J, Innovative Strategies to Overcome biofilm Resistance. Biomed Research International, Volume 2013, Article ID 150653 http://dx.dot.org/10.1155/2013/150653

* Sommerfild Ross S, Fiegel Jennifer. Nutrient dispersion enhances conventional antibiotic activity against Pseudomonas aeruginosa biofilms. International Journal of Antimicrobial Agents 40 (2012) 177‐181.

* Glasnapp A, Tribble PA. Xylitol in the Prevention of Otitis Media. International Journal of Pharmaceutical Compounding, vol. 4 No. 3 May/June 2000 171‐174.


Men’s Health Update

Bruce Biundo, RPh, FACA


• New Information on Diindolylmethane (DIM) for Prostate Health

• Recent Testosterone Research

• Vitamin D3 as it relates to Men’s Sexual Health

• Benefits of Sublingual (SL) Administration of Testosterone

• Examples of PCCA Formulas using SL Triturate Dosage Forms

Contents


Can DIM Slow Cancer Growth Rate in Prostate Cancer?


Exerts chemo‐preventive effects

Strong competitive inhibitor of DHT binding to AR

Decreases Prostate‐Specific Antigen (PSA)

DIM’s Affect on Androgen Receptors (AR) in the Prostate2


Consumption of Cruciferous Vegetables…

…May Help Reduce Risk of Prostate Cancer

Sources of DIM3


DIM May Slow the Rate or Reduce Serum PSA Levels4


Testosterone in the News5


Comparison of the Effects of Testosterone Gels, Injects, and Pellets…Pastuszak et al. (2015)6

Erythrocytosis is the most frequent dose‐limiting adverse side effect of Testosterone Therapy

Erythrocytosis is the most frequent dose‐limiting adverse side effect of Testosterone Therapy

Erythrocytosis defined as Hct ≥50% (Hct=%RBC)Erythrocytosis defined as Hct ≥50% (Hct=%RBC)

Monitor Hematocrit while on Testosterone TherapyMonitor Hematocrit while on Testosterone Therapy


Testosterone Undecanoate (TU) Improves Sexual Function in Men With Type 2 Diabetes and Severe Hypogonadism…Hackett et al. (2016)7


The Testosterone Conundrum: The Putative Relationship Between Testosterone Levels and Prostate Cancer (Loughlin (2016))8

Serum Testosterone

Levels

Intra‐Prostatic Testosterone

Levels

v.


Contrary to Popular Belief…

LUTS = Lower Urinary Tract SymptomsBPH = Benign Prostate Hyperplasia


Benefits of TRT


• Vitamin D has many important functions in the body – Important factor in immune system helping fight off bacteria and

viruses – Protects bones against osteoporosis by helping bones absorb

calcium– Helps prevent chronic diseases like cardiovascular disease and

diabetes– Deficiency may be associated with benign prostatic hyperplasia

(BPH)

Vitamin D3 may help boost testosterone levels

Importance of Vitamin D in Men’s Health13


Vitamin D: Vitamin or Steroid Hormone Precursor14

* Cholecalciferol (vitamin D3) is the prototypical secosteroid; a prohormone or precursor of steroid hormones

* Cholecalciferol (vitamin D3) is the prototypical secosteroid; a prohormone or precursor of steroid hormones


Steroidogenic Mechanism in Testicular Cells15,16


Various Ways Vitamin D Affects Testosterone

1. Expression of VDRs & Vitamin D enzymes in Leydig cells171. Expression of VDRs & Vitamin D enzymes in Leydig cells17

2. Vitamin D regulates Aromatase expression182. Vitamin D regulates Aromatase expression18

3. Active Vitamin D can stimulate the synthesis of Testosterone193. Active Vitamin D can stimulate the synthesis of Testosterone19


Is there a CAUSAL relationship

between serum vitamin D and Testosterone?20


Vitamin D Does NOT Increase Serum Testosterone Levels21


Vitamin D Significantly INCREASED Total, Bioactive, and Free Testosterone22


RCT Implications


* Bischoff‐Ferrari et al. (2006) systematic review suggests that the most advantageous 25(OH)D levels begin at 30 ng/mL and the best are between 36 – 40 ng/mL24

* IOM ranges suggest that there is NOT enough evidence that having a level >50 ng/mL is of any additional health benefit

What are the Range Guidelines for Vitamin D Levels?Is it More Beneficial to Have Higher Vitamin D levels?23


Tablet Triturate (SL) v. Troche (Buccal)25


Sublingual Mucosa as A Route for Systemic Drug DeliveryNarang N. & Sharma J. (2011)26


Pharmacokinetics of Three Doses of Sublingual Testosterone in Healthy Premenopausal Women. Rooij et al. (2012)27


SL Testosterone Key Points


Anastrozole 0.1 mg SL Tablet Triturate

Clomiphene Citrate 12.5 mg SL Tablet Triturate

Chorionic Gonadotropin 125 U Base ATablet Triturate 100mg Mold

Testosterone 10 mg Tablet Triturate

10970

10739

10219

12377

PCCA Men’s Health Sample FormulasSL Tablet Triturate Suggested Formulas



References1. https://upload.wikimedia.org/wikipedia/commons/8/83/3%2C3%27‐Diindolylmethane.svg2. Rahman KM, et al. (2009) 3,3’‐Diindolylmethane enhances taxotere‐induced apoptosis in hormone‐refractory

prostate cancer cells through surviving down‐regulation. Cancer Res;69: 4468‐4475. Hien T. Le, Charlene M. Schaldach, Gary L. Firestone, and Leonard F. Bjeldanes. Plant‐derived 3,3_‐Diindolylmethane Is a Strong Androgen Antagonist in Human Prostate Cancer Cells. Journal of Biological Chemistry Vol. 278, No. 23, Issue of June 6, pp. 21136‐21145, 2003. Li Y. & Sarkar F. H. Role of BioResponse 3,3′‐Diindolylmethane in the Treatment of Human Prostate Cancer: Clinical Experience. Medical principles and practice : international journal of the Kuwait University, Health Science Centre, (2015).10.1159/000439307

3. http://clipartpng.com/?464,broccoli‐png‐clipart; http://i3.mirror.co.uk/incoming/article6990748.ece/ALTERNATES/s1200/Brussel‐sprouts.jpg; http://weknowyourdreams.com/image.php?pic=/images/cabbage/cabbage‐07.jpg; http://nutrawiki.org/wp‐content/uploads/2015/09/Cauliflower.jpg; http://www.edtreatmentindia.com/images/ed‐prostate‐cancer‐treatment‐in‐india.jpg; Hwang C, Sethi S, Heilbrun LK, et al. Anti‐androgenic activity of absorption‐enhanced 3, 3'‐diindolylmethane in prostatectomy patients. Am J Transl Res. 2016;8(1):166‐76.


References4. Heath EI, Heilbrun LK, Li J, Vaishampayan U, Harper F, Pemberton P and Sarkar FH. A phase I dose‐escalation

study of oral BR‐DIM (BioResponse 3,3’‐Diindolylmethane) in castrate‐resistant, non‐metastatic prostate cancer. American Journal of Translational Research 2010; 2: 402‐411.; Hwang C, Sethi S, Heilbrun LK, et al. Anti‐androgenic activity of absorption‐enhanced 3, 3'‐diindolylmethane in prostatectomy patients. Am J Transl Res. 2016;8(1):166‐76.

5. http://redkiteprayer.com/wp‐content/uploads/2012/01/TestosteroneJPG.jpg; https://www.anaren.com/sites/default/files/uploads/Image/Anaren‐in‐the‐news.jpg

6. Pastuszak AW, Gomez LP, Scovell JM, Khera M, Lamb DJ, Lipshultz LI. Comparison of the Effects of Testosterone Gels, Injections, and Pellets on Serum Hormones, Erythrocytosis, Lipids, and Prostate‐Specific Antigen. Sex Med. 2015;3(3):165‐73. http://the‐healthcare.org/wp‐content/uploads/2013/07/HematocritLevels.jpg

7. Hackett G, Cole N, Saghir A, Jones P, Strange RC, Ramachandran S. Testosterone Undecanoate improves Sexual Function in Men with Type 2 diabetes and Severe Hypogonadism: Results from a 30 week randomized placebo controlled study. BJU Int. 2016;


References8. Loughlin KR. The testosterone conundrum: The putative relationship between testosterone levels and prostate

cancer. Urol Oncol. 2016; https://www.geo.tv/assets/uploads/updates/2015‐02‐19/health‐Nano‐drones‐cholesterol‐bloodstream‐study_2‐19‐2015_175575_l.jpg; http://www.livescience.com/images/i/000/065/810/original/prostate.jpg?interpolation=lanczos‐none&fit=around%7C300:200&crop=300:200;*,*

9. Khaw KT, Dowsett M, Folkerd E, et al. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC‐Norfolk) Prospective Population Study. Circulation. 2007;116(23):2694‐701.

10. Kaplan AL, Hu JC, Morgentaler A, Mulhall JP, Schulman CC, Montorsi F. Testosterone Therapy in Men With Prostate Cancer. Eur Urol. 2016;69(5):894‐903.

11. Baas W, Köhler TS. Testosterone Replacement Therapy and BPH/LUTS. What is the Evidence?. Curr Urol Rep. 2016;17(6):46.

12. Nian Y, Ding M, Hu S, et al. Testosterone replacement therapy improves health‐related quality of life for patients with late‐onset hypogonadism: a meta‐analysis of randomized controlled trials. Andrologia. 2016;


References13. http://www.healthline.com/health/herbs‐vitamins‐supplements‐testosterone‐levels‐balance#Puncturevine4;

Zhang W. et al. Vitamin D Deficiency as a Potential Marker of Benign Prostatic Hyperplasia. Urology. 2016. 14. http://mpkb.org/home/pathogenesis/vitamind/forms; Norman AW. From vitamin D to hormone D:

fundamentals of the vitamin D endocrine system essential for good health. Am J Clin Nutr. 2008;88(2):491S‐499S.L. Zanatta, A. Zamoner, A.P. Zanatta, H. Bouraima‐Lelong, C. Delalande, C. Bois, et al., Nongenomic and genomic effects of 1alpha,25(OH)2 vitamin D3 in rat testis, Life Sci. 89 (October (15–16)) (2011) 515–523. Hanson JR (2010). "Steroids: partial synthesis in medicinal chemistry". Nat Prod Rep. 27 (6): 887–99. doi:10.1039/c001262a. PMID 20424788.

15. D. Hofer, J. Munzker, V. Schwetz, M. Ulbing, K. Hutz, P. Stiegler, et al., Testicular synthesis and vitamin D action, J. Clin. Endocrinol. Metab. 99 (October (10)) (2014) 3766–3773.

16. Blomberg Jensen, M., Nielsen, J.E., Jorgensen, A. et al. (2010) Vitamin D receptor and vitamin D metabolizing enzymes are expressed in the human male reproductive tract. Human Reproduction, 25, 1303–1311.

17. A.V. Krishnan, S. Swami, L. Peng, J. Wang, J. Moreno, D. Feldman, Tissue selective regulation of aromatase expression by calcitriol: implications for breast cancer therapy, Endocrinology 151 (January (1)) (2010) 32–42.

18. Parikh, G., Varadinova, M., Suwandhi, P., 2010. Vitamin D regulates steroidogenesis and insulin‐like growth factor binding protein‐1 (IGFBP‐1) production in human ovarian cells. Horm. Metab. Res. 42, 754–757.


References19. https://dqam6mam97sh3.cloudfront.net/blog/ausl/wp‐content/uploads/sites/2/2015/02/homer.png20. Jorde R, Grimnes G, Hutchinson MS, Kjærgaard M, Kamycheva E, Svartberg J. Supplementation with vitamin D

does not increase serum testosterone levels in healthy males. Horm Metab Res. 2013;45(9):675‐81.; Heijboer AC, Oosterwerff M, Schroten NF, et al. Vitamin D supplementation and testosterone concentrations in male human subjects. Clin Endocrinol (Oxf). 2015;83(1):105‐10.

21. Pilz S, Frisch S, Koertke H, et al. Effect of vitamin D supplementation on testosterone levels in men. Horm MetabRes. 2011;43(3):223‐5.

22. https://www.vitamindcouncil.org/about‐vitamin‐d/testing‐for‐vitamin‐d/; Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press, 2010. Holick MF, Binkley NC, Bischoff‐Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM; Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011 Jul;96(7):1911‐30.

23. Bischoff‐ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson‐hughes B. Estimation of optimal serum concentrations of 25‐hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr. 2006;84(1):18‐28.


References24. http://image.slidesharecdn.com/drugdosageforms‐vinaygupta‐150914183925‐lva1‐app6891/95/drug‐dosage‐

forms‐vinay‐gupta‐18‐638.jpg?cb=1442256086; http://www.ensoleilpharmacy.com/s/cc_images/cache_3026755504.png?t=1314602186; https://www.google.com/search?q=troche&biw=1020&bih=883&source=lnms&tbm=isch&sa=X&ved=0ahUKEwi64KzViL_PAhXHGz4KHUsGBMcQ_AUIBygC#tbm=isch&q=troche+medication&imgrc=SsoqoZbPdneB0M%3A

25. http://www.ijppsjournal.com/Vol3Suppl2/1092.pdf26. Van rooij K, Bloemers J, De leede L, et al. Pharmacokinetics of three doses of sublingual testosterone in healthy

premenopausal women. Psychoneuroendocrinology. 2012;37(6):773‐81.


Consultant’s Corner

Mike Leake, RPh


Powder Insufflator (PCCA Part #35‐1579)

• Insufflator User Instructions – PCCA Document # 97090


Formulas

• PCCA Formula #1777 CSF Capsule• PCCA Formula #11440 CSF Capsule (Current)


30 mL Collapsible Bottle

PCCA Item #35‐1283


• PCCA Item #30‐4782 • MucoLox™ Technical Report: Assessment of

Mucoadhesive Properties of MucoLox™ Using a 3D Model of the Human Oral Mucosa

• PCCA Formula #11157 ‐ Acyclovir 5% / Lidocaine HCL 1% / Deoxy‐D‐Glucose (2) 2% Oral Rinse (MucoLox™)

• PCCA Formula #11127 ‐ Amitriptyline HCL 2% / Gabapentin 6% / Lidocaine HCL 0.5% Oral Rinse (MucoLox™) for Burning Mouth Syndrome

MucoLox™


• Riboflavin– PCCA Item #30‐1532

LoxOral ™


Requested Formulas

• Diclofenac 3% / Tizanidine 0.1% / Topiramate 2% / Lidocaine 2.5% / Prilocaine 2.5% / Montelukast 0.15%

• Lidocaine 3% / Prilocaine 3% / Lamotrigine 2.5% / Meloxicam 0.9%. Can we use lamotrigine and meloxicam tablets?

• Flurbiprofen 20% / Cyclobenzaprine 2% / Baclofen 2% / Gabapentin 6% / Lidocaine 2%


PCCA Pain Formulas

• PCCA Formula #9375 ‐ Amitriptyline HCl 2% / Ketoprofen 2% / Carbamazepine 2% W/W Topical Lipoderm®

• PCCA Formula #10013 ‐ Baclofen 2% / Ketoprofen 10% / Lidocaine 5% / Gabapentin 5% W/W Topical Lipoderm® ActiveMax™

• PCCA Formula #9377 ‐ Amitriptyline 2% / Baclofen 2% topical Lipoderm®

• PCCA Formula #9376 ‐ Amitriptyline HCl 2%/Baclofen 2%/Ketamine HCl 5%/ Ketoprofen 10% Topical Lipoderm®


Neuropathy, Chronic Algorithm ‐ PCCA Document #94064


• Management of Pain: Compounding Clinical Practice Guidelines– PCCA Document #98174


• Neuropathy, Chronic Algorithm – References– PCCA Document #99047


Recent PCD Calls• Making Minoxidil 10% Solution (PCCA Formula #10653), and after

about 4 to 5 days it starts to crystalize. Warming it causes the crystals to dissolve, but when it cools to room temperature it recrystallizes again. Any idea why?

• We are compounding "Sun Block SPF 30 + Zinc + Titanium". How much zinc and Titanium are needed?

• We would like to increase the concentration of PCCA Formula #4576 (Co‐Enzyme Q10 30mg/ml in Oil Oral Suspension) to 250mg/ml and want to know if we need to change the quantities of the other ingredients in the formula.


Recent PCD Calls (cont’d)

• Have a request from a podiatrist for a formula to treat Plantar Fasciitis

• We are currently compounding a Benzocaine 20% / Lidocaine 8% / Tetracaine 8% / Phenylephrine 0.01% in PLO for botox injections for a spa and they are beginning to do laser procedures. They want something that would be longer acting.


Thank you

Questions?


Documents

02 - Consultant's Corner panel · Biomed Research International, Volume 2013, Article ID 150653 ... Pastuszak AW, Gomez LP, Scovell JM, Khera M, Lamb DJ, Lipshultz ... Baas W, Köhler