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Topical administration of psychotropic medications in pluronic lecithin organogel to treat patients with dementia: a retrospective observational study

Topical administration of psychotropic medications in pluronic lecithin organogel to treat patients with dementia: A retrospective observational studyCornelius W. Thomas, MD and Suzanne Holroyd, MD. Chair, Department of Psychiatry DOI: http://dx.doi.org/10.18590/mjm.2015.vol1.iss1.4Follow this and additional works at: Part of the , and the Recommended CitationThomas,, Cornelius W. MD and Holroyd,, Suzanne MD. Chair, Department of Psychiatry (2015) "Topical administration ofpsychotropic medications in pluronic lecithin organogel to treat patients with dementia: A retrospective observational study," MarshallJournal of Medicine: Vol. 1: Iss. 1, Article 4.
DOI: Available at: This Original Article is brought to you for free and open access by Marshall Digital Scholar. It has been accepted for inclusion in Marshall Journal ofMedicine by an authorized administrator of Marshall Digital Scholar. For more information, please contact .
Thomas, and Holroyd,: Topical administration of psychotropic medications with PLO cream Topical administration of psychotropic medications in pluronic
lecithin organogel (PLO) to treat patients with dementia: a
retrospective observational study

Cornelius Thomas, MD1, and Suzanne Holroyd MD2 Authors affiliations:
1. Department of Psychiatry – Veterans Affairs Medical Center, 1540 Spring Valley Drive, Huntington, WV 25704 2. Department of Psychiatry and Behavioral Medicine, Marshall University Joan C. Edwards School of Medicine All Authors have no conflict of interest to disclose. Corresponding Author:
Cornelius Thomas, MD Huntington VAMC - Dept. of Psychiatry Assistant Professor, Marshall University Joan C. Edwards School of Medicine Published by Marshall University's Joan C. Edwards School of Medicine, 2015 Marshall Journal of Medicine, Vol. 1 [2015], Iss. 1, Art. 4 Abstract:

Objective: Treatment of mood and behavioral symptoms in geriatric patients with advanced
dementia may be impeded by poor compliance with oral medications. Pluronic lecithin
organogel (PLO) is a compounding substrate that can be used for the topical administration of
psychotropic medications.
Methods: Charts of patients treated with psychotropic medications compounded with PLO
cream were reviewed for treatment outcomes. All patients were treated by a nursing home
outreach service.
Results: Records from twenty-four patients, mean age 86.8 + 5.9, were reviewed. Common
psychiatric symptoms included agitation, aggressive behavior, and depression. Medications
most commonly administered as a PLO cream included quetiapine and venlafaxine. All patients
had mild to marked improvement in psychiatric symptoms.
Conclusions: Pluronic lecithin organogel (PLO) may be an effective option for the topical
administration of psychiatric medications in geriatric patients with dementia who are not
compliant with oral medications.
Keywords: pluronic lecithin organogel, PLO, pharmacotherapy, geriatric, dementia
Thomas, and Holroyd,: Topical administration of psychotropic medications with PLO cream Introduction:
More than eighty percent of geriatric patients with dementia develop mood and behavioral
symptoms during the course of their illness.1,2 Psychotropic medications can effectively treat
these symptoms. However, patients with dementia may not comply with oral medications due to
behavioral issues, paranoia or swallowing difficulty. Alternative routes for administering
medications are needed to increase compliance and improve outcomes.
During the past 20 years, several drugs have been formulated for topical administration including
scopolamine, nitroglycerin, nicotine, rivastigmine and fentanyl. These drugs are combined with
permeation enhancers to increase passive transdermal diffusion through the skin into the
circulation. Currently, selegiline and methylphenidate are the only psychotropic medications
available in a transdermal formulation.
Pluronic lecithin organogel (PLO) is a synthetic compound developed in the 1990s as a
transdermal drug delivery substrate.3,4,5 When combined with a therapeutic agent, PLO forms
drug micelles in a thermodynamically stable cream. The FDA permits the mixing and physical
modification (compounding) of medications by a pharmacist upon receipt of a prescription from
a licensed practitioner to meet the unique needs of an individually identified patient.
Compounding psychotropic medications with PLO can offer new treatment options for geriatric
patients with dementia.
PLO has three major components; lecithin, isopropyl palmitate, and poloxamer (Pluronic). All
three components act as skin permeation enhancers. Lecithin is a naturally occurring fatty
substance which is a surfactant and acts as an emulsifier. Isopropyl palmitate is a palm oil based
moisturizer and thickening agent. Both lecithin and isopropyl palmitate are commonly used in
various topical products and can effectively dissolve lipophilic drugs. Poloxamer is a copolymer
of polyoxypropylene and polyoxyethylene, and is FDA approved for human use. The structure
of poloxamer promotes the formation of drug micelles when mixed with lecithin and isopropyl
palmitate. A thermodynamically stable cream is formed when the three components are mixed
together.
At this time, there are very few studies evaluating the clinical effectiveness of medications
applied topically using PLO. Two recent prospective trials reported improvement in nausea and
vomiting induced by chemotherapy when patients were treated with lorazepam,
diphenhydramine and haloperidol compounded with PLO.6,7 These trials concluded that
administering medications topically via PLO reduces gastrointestional side effects and improves
patient compliance, without significant skin irritation. However, in a study evaluating the
plasma concentrations of lorazepam (2mg), diphenhydramine (25mg) and haloperidol (2mg)
administered topically using PLO; lorazepam and haloperidol were not detectable, and only five
of the 10 subjects had detectable plasma levels of diphenhydramine.8
To our knowledge, there are no studies assessing the effectiveness of topically applied
psychotropic medications compounded with PLO cream for the treatment of psychiatric
symptoms. For a number of years, we have used PLO creams to administer psychiatric
medications in elderly patients who are unable or unwilling to take oral medications. For this
Published by Marshall University's Joan C. Edwards School of Medicine, 2015 Marshall Journal of Medicine, Vol. 1 [2015], Iss. 1, Art. 4 study, we reviewed the records of 24 geriatric patients who were treated with psychiatric
medications applied topically using PLO cream. All patients had advanced dementia with
psychiatric symptoms that significantly impacted the patient's quality of life or caretakers'
ability to provide basic care, and were unwilling or unable to take oral medications.

Methods:
A retrospective chart review was carried out by the authors on all geriatric psychiatry patients
treated with topical psychotropic medications using PLO. A structured data collection form was
used to collect data including age, gender, living situation, medications, medical and psychiatric
diagnoses, psychiatric/behavioral symptoms and the Mini Mental State Exam score (MMSE).9
The authors accessed response to therapy by reviewing the medical record, which contained the
nursing staff and physician's clinical assessment of patients. Response was rated on a 4 point
scale; (1) no improvement, (2) mild improvement, (3) moderate improvement, or (4) marked
improvement. Statistical analysis was carried out using SPSS for descriptive variables.
Results:
Twenty-four geriatric psychiatry records were reviewed. Demographic and clinical variables are
shown in Table 1. All patients had severe dementia and resided in skilled nursing facilities.
Psychiatric diagnoses included major depression (n = 17, 70.8%) and mood disorder secondary
to general medical condition (n = 3, 12.5%). Medical conditions included hypertension (n = 17,
70.8%), stroke (n = 12, 50%), coronary artery disease (n = 8, 33.3%), hyperlipidemia (n = 6,
25%), diabetes (n = 2, 8.3%), hypothyroidism (n = 5, 20.8%), seizure disorder (n = 3, 12.5%)
and osteoarthritis (n = 5, 20.8%).
Thomas, and Holroyd,: Topical administration of psychotropic medications with PLO cream Table 1. Demographics, Clinical Characteristics and Outcomes
Demographics Age, years [mean (SD)] Type of dementia Alzheimer's and Vascular MMSE, previous 6 months, 9 pts [mean (SD)] MMSE, previous 2 years, 15 pts [mean (SD)] Psychiatric symptoms Depressed mood [number (%)] Aggression and agitation Decreased appetite Minimal improvement Moderate improvement Marked improvement
Reasons for starting PLO psychiatric medications included: physical aggressiveness and
agitation (n = 19, 79.2%), depressive symptoms (n = 15, 62.5%), decreased appetite (n = 10,
41.7%), insomnia (n = 5, 20.8%), and psychotic symptoms (n = 2, 8.3%). Six different
psychiatric medications were used in PLO formulation: quetiapine, venlafaxine, trazodone,
buspirone, escitalopram and lorazepam.
Quetiapine was used in eighteen patients at an individual dosage range from 12.5 mg to 100 mg
(mean = 57.6 ± 34.9), given one to four times a day, for a total daily dose of 25 mg to 300 mg
(mean = 136.1 ± 97.5). Mean duration of treatment was 5.3 ± 4.6 months.
Venlafaxine was used in fifteen patients at an individual dose range of 37.5 mg to 100 mg (mean
= 66.6 ± 17.6). Venlafaxine was administered twice a day in fourteen patients and three times a
day in one patient. Total daily dose of venlafaxine ranged between 75 mg to 200 mg (mean=
135.7 ± 37.9), and mean duration of treatment was 5.5 ± 4.4 months at time of review. Nine
patients were treated with both quetiapine PLO cream and venlafaxine PLO cream.
Five patients received trazodone PLO cream at a dose of 50 mg to 100 mg at bedtime for
insomnia (mean= 70 ± 27.4). The mean duration of treatment with trazodone was 3 + 1.4
months at time of chart review. Four patients who were treated with topical trazodone also
received topical quetiapine and two received topical venlafaxine. Two patients received topical
Published by Marshall University's Joan C. Edwards School of Medicine, 2015 Marshall Journal of Medicine, Vol. 1 [2015], Iss. 1, Art. 4 buspirone at a dose of 5-10 mg (mean = 7.5 ± 3.5). Buspirone was administered three times a
day with a total daily dose between 15-30 mg (mean= 22.5 ± 10.6). One hospice patient received
1mg lorazepam PLO cream four times a day. One patient received 20mg escitalopram PLO
cream daily for 11 months.
Before starting PLO medication, all patients had been non-compliant with or unable to take oral
medications. PLO compounded medications were applied to the inner aspect of the forearm in
all patients except one who had PLO cream applied to his back due to physical aggressiveness.
No side effects were reported in any of the patients.
All patients benefited from PLO medications as shown in Table 1. Improvement in symptoms
were as follows: 12 patients (50%) were more compliant with oral medications, 13 of 19 (68.4%)
patients with severe agitation improved, 11 of 15 (73.3%) patients with depressive mood
improved, 6 of 10 (60%) patients had improved appetite, and 2 of 5 (40%) had improvement in
sleep. Two patients who received PLO for psychotic symptoms were rated as moderately
improved.
The following two clinical vignettes illustrate the use of psychotropic PLO cream.

Case Vignettes
Subject 1
Ms. A was a 78 year-old woman with vascular dementia, who was referred for evaluation of
depression, behavioral disturbance and poor appetite. Ms. A stated that her mood was "not too
good", and she was irritable, anxious and uncooperative with care by nursing home staff. Mini-
Mental State Examination was 7/30. She was treated with oral venlafaxine extended-release
75mg daily with improvement of appetite and mood, however she continued to be anxious and
was uncooperative. Buspirone 5mg bid was used with good results. Over the following year,
her cognitive impairment progressed and she became uncooperative with all oral medication.
Her depressive and behavioral symptoms returned. She was started on venlafaxine 50mg PLO
topical cream bid and buspirone 10mg PLO topical cream bid. Four weeks after starting PLO
cream, the nursing home staff reported significant improvement in her depressive and behavioral
symptoms.
Subject 2
Mr. B was an 84 year-old man diagnosed with mixed type (Alzheimer's and Vascular) dementia,
who was referred for evaluation of insomnia and severe aggression toward staff and other
residents. MMSE was 0/30. Eventually, the patient was treated with a medication regimen of
quetiapine 100mg bid, valaproic acid syrup 750mg bid and trazodone 50mg qhs, with marked
improvement in his behavior. However after 2 years, he became uncooperative with oral
medications and experienced recurrence of aggression. Strategies to improve compliance were
unsuccessful and oral medications were discontinued. PLO quetiapine cream 100mg bid and
trazodone 50mg PLO cream qpm were begun. He was compliant with PLO medications and
within two months his behavior markedly improved.
Thomas, and Holroyd,: Topical administration of psychotropic medications with PLO cream Discussion:
Patients with advanced dementia frequently do not comply with oral medications due to
behavioral issues, paranoid thoughts about treatment intentions, or difficulty with swallowing
pills. Transdermal administration of medications in this patient population offer many
advantages including improved tolerability, ease of administration, and steady continuous
delivery rate. Pluronic lecithin organogel (PLO) is a synthetic compound that has been
developed as a substrate for the topical administration of therapeutic agents.
A limited number of studies have evaluated the bioavailability of medications administered
topically when combined with PLO cream. Finding from these studies typically reveal low or
undetectable serum levels of medications, however, the doses of medications used in these
studies may be too low for adequate transdermal absorption.10,11 For example, Glisson et al.
administered promethazine 50mg compounded with PLO in 15 subjects; blood samples were
collected over a 6 hour period.12 Only 65% of the blood samples had measurable serum
concentrations of promethazine, and only 39.2% of these samples contained quantifiable
concentrations of the drug equal to or greater than 1 ng/mL. Interestingly, eleven of the fifteen
subjects in this study experienced drowsiness. In another study, methadone (dose range 10mg to
45mg) compounded with PLO was administered topically to ten subjects.13 Only one subject
who received the 45mg dose of methadone achieved measurable serum levels. These studies
suggest that when compounding a medication with PLO for topical application, a higher dose of
medication is needed in order to obtain serum levels similar to that observed with oral
administration. The reduced absorption of medications when administered transdermally is
reflected by the fact that currently available transdermal therapeutic patches are formulated with
significantly higher doses of the therapeutic agent when compared to oral formulations. For
example, methylphenidate patch contain between 27.5mg to 82.5mg per patch, selegiline patch
contain between 20mg to 40mg per patch, and rivastigmine patch contains 9mg to 27mg per
patch.
In our case series, a variety of psychotropic medications were administered topically using PLO
cream in patients unwilling or unable to take oral medications. Based on our retrospective chart
reviews, all patients demonstrated some clinical improvement in their psychiatric symptoms.
This case series was limited to geriatric patients with dementia; however other groups of patients
with psychiatric disorders may benefit from PLO compounded medications.
Our study has a number of limitations, including the retrospective observational design and small
sample size. Because of the observational design, we cannot rule out the possibility that the
observed improvements were due to placebo effect of PLO cream application. Also, we assessed
the effectiveness of several different psychotropic medications applied topically with PLO
cream, which limits the conclusions that can be draw concerning the effectiveness of any specific
agent. However, the goal of this study was to demonstrate that compounding medications with
PLO for topical application may offer an effective alternative for treatment of complex geriatric
patients. There may be concerns about the patient population in this study; however clinical
trials have not consistently revealed any significant differences in transdermal absorption of
medications when comparing young and old patients.14
Published by Marshall University's Joan C. Edwards School of Medicine, 2015 Marshall Journal of Medicine, Vol. 1 [2015], Iss. 1, Art. 4 In conclusion, compounding psychotropic medications with pluronic lecithin organogel (PLO) provides the opportunity for topical application of a wide range of medications. However, more research is needed to determine the absorption rates and bioavailability of different medications when administered with PLO cream. Although our series was limited to the use of six medications, we expect that other psychiatric medications could be effectively administered as a PLO creams, thereby expanding the treatment options for geriatric patients, as well as psychiatric patients in general. Thomas, and Holroyd,: Topical administration of psychotropic medications with PLO cream References:
1. Selbaek G, Kirkevold O, Encreamal K. The course of psychiatric and behavioral symptoms and the use of
psychotropic medication in patients with dementia in Norwegian nursing homes, a 12 month follow-up study. Am J Geriatr Psychiatry. 2008;16:528-36. 2. Shin IS, Carter M, Masterman D, Fairbanks L, Cummings JL. Neuropsychiatric symptoms and quality of life in Alzheimer disease. Am J Geriatr Psychiatry. 2005;13:469-74. 3. Vintiloiu A, Leroux JC. Organocreams and their use in drug delivery, a review. J Control Release. 2008;125:179-92. 4. Avramiotis S, Papadimitriou V, Hatzara E, Bakiari V, Lianos P, Xenakis A. Lecithin organocreams used as bioactive compounds carriers. A microdomain properties investigation. Langmuir. 2007;23:4438-4447. 5. Kumar R, Katar e OP. Lecithin organocreams as a potential phospholipids-structured system for topical drug delivery: a review. AAPS Pharm Sci Tech. 2005;6:E298-310. 6. Silberstein PT, Bhaskara A. Transdermal creams: a novel delivery system for rescue of delayed nausea and vomiting. J Clin Oncology. 2005;23:8201. 7. Bleicher J, Bhaskara A, Huyck T, Constantino S, Bardia A, Loprinzi CL, et al. Lorazepam, diphenhydramine, and haloperidol transdermal cream for rescue from chemotherapy-induced nausea/vomiting: results of two pilot trials. J Support Oncol. 2008;6:27-32. 8. Smith TJ, Ritter JK, Poklis JL, Fletcher D, Coyne PJ, Dodson P, et al. ABH gel is not absorbed from the skin of normal volunteers. J Pain Symptom Manage. 2012;43(5):961-966. 9. Folstein MF, Folstein SE, McHugh PR. "Mini-Mental State": a practical method for grading the cognitive state of patients for the clinician. J Psychiar Res. 1975;12:189-198. 10. Weiland AM, Protus BM, Kimbrel J, Grauer PA, Hirsh J. Chlorpromazine bioavailability from a topical gel formulation in volunteers. J Support Oncol. 2013;11(3):144-8. 11. Paice JA, Von Roenn JH, Hudgins JC, Luong L, Krejcie TC, Avram MJ. Morphine bioavailability from a topical gel formulation in volunteers. J Pain Symptom Manage. 2008;35:314-320. 12. Glisson JK, Wood RL, Kyle PB, Cleary JD. Bioavailability of promethazine in a topical pluronic lecithin organogel: a pilot study. Int J of Pharm Compounding. 2005;9:242-246. 13. Sylvester RK, Schauer C, Thomas J, Steen P, Weisenberger A. Evaluation of methadone absorption after topical administration to hospice patients. J Pain Symptom Manage. 2011;41(5):828-35. 14. Kaestli LZ, Wasilewski-Rasca AF, Bonnabry P, Vogt-Ferrier N. Use of transdermal drug formulations in the elderly. Drugs Aging. 2008;25(4):269-80. Published by Marshall University's Joan C. Edwards School of Medicine, 2015

Source: http://mds.marshall.edu/cgi/viewcontent.cgi?article=1003&context=mjm

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