Lonafarnib :It's use in treatment of cancer

A synthetic tricyclic derivative of carboxamide with antineoplastic activity.


MECHANISM OF ACTION:

Lonafarnib is a non-peptidomimetic inhibitor of farnesyl transferase, an enzyme responsible for
the post-translational lipid modification of a wide variety of cellular proteins that are involved in
the pathogenic pathways of various diseases including cancer and progeria.

Lonarfanib binds to and inhibits farnesyl transferase, an enzyme involved in the post-translational modification and activation of Ras proteins. Ras proteins participate in numerous signalling pathways (proliferation, cytoskeletal organization), and play an important role in oncogenesis. Mutated ras proteins have been found in a wide range of human cancers and progeria. Isoprenylation involves the enzyme farnesyltransferase (FTase) transferring a farnesyl group from farnesyl pyrophosphate (FPP) to the pre-Ras protein.(The membrane targeting COOH-terminal CAAX box (C = cysteine, A = aliphatic, X = any amino acid) is first prenylated followed by AAX proteolysis, carboxymethylation, and palmytoylation. These steps of posttranslational modification are of importance for the membrane tethering of Ras proteins. Icmt,isoprenylcysteine carboxyl methyltransferase; lys, lysine; P-P, PPI; PTI, prenyl transferase inhibitor; Rce1,Ras-converting enzyme 1.)



PHARMAKOKINETICS OF LONAFARNIB:

Nineteen patients had samples collected for pharmacokinetic evaluations. Lonafarnib was slowly absorbed after oral administration with food. Median Tmax ranged from 3 to 8 h. oral administration of lonafarnib with food. Mean plasma lonafarnib concentrations at 12 h after the dose were ∼34–99% of the corresponding mean Cmax values. The mean total body clearance ranged from 165 to 364 ml/min. No effect of food on pnarmacokinetics.

SIDE EFFECTS:

Mild diarrhea, fatigue, nausea, vomiting, anorexia,depressed serum hemoglobin,fever,Dehydration, Constipation, Hypokalemia

Lonafarnib side effect was reported by a Health Professional from UNITED STATES on June
28, 2006. Male patient, 50 years of age, weighting 136.0 lb, was diagnosed with adenocarcinoma and was treated with Lonafarnib. After drug was administered, patient experienced the following side effects: cardiac arrest , diarrhoea,hypotension,hypovolaemia, nausea , pancytopenia,sepsis.

Lonafarnib dosage: 150 MG PO BID. During the same period patient was treated with
DOCETAXEL, DURAGESIC, DECADRON, SYNTHROID, ZOFRAN.

CANCER:

Although extensive clinical research indicates limited activity of lonafarnib in solid tumors, there
is recent interest in combinations of farnesyl transferase inhibitors with imatinib or bortezomib in hematological malignancies.The initial expectations of specificity of FTIs for cells with ras mutations matched the original in vitro observations. However, subsequent in vitro and in vivo studies demonstrated that FTI-mediated inhibition of tumor growth was not tightly linked to rasmutation status. It is now clear that ras mutation is not a requirement for FTI effects on tumor cells. It has not, however, been shown that Ras signaling inhibition does not play a role in these effects.FTIs showed significant promise in preclinical studies. On the other hand, these studies also showed that there was tumor regrowth after treatment cessation in mice and that FTIs alone were not curative. The relatively poor response rates reported in clinical trials with FTIs alone might be explained by these preclinical results. However, combination of FTIs with other
therapies may have a good potential, if these are applied according to biological principals of
activity.

In using FTIs in combined modality treatment, the timing of FTI administration relative to chemo-
or radiotherapy may be critical. As discussed above, not every chemotherapeutic drug will be
suitable for combination with FTIs. The combination of FTIs with radiation is, in our experience,
well tolerated and engenders no additional radiation toxicity to normal tissues. The Phase I trial
of L-778,123 with radiation yielded encouraging results for this combination, consistent with our
preclinical findings. This may result from a combination of FTI effects on tumor cell radiosensitivity, perhaps via inhibition of PI3K activation, and effects on the tumor microenvironment as well as the antiproliferative effects of FTIs.

Phase I and II clinical trials confirmed relevant antitumour activity and low toxicity; however, no
improvement in overall survival has been reported in Phase III trials.

PROGERIA:

Progeria, also known as Hutchinson-Gilford Progeria Syndrome (HGPS), is a rare, fatal genetic disease characterized by an appearance of accelerated aging in children.Twenty-eight children from sixteen countries participated in the two-and-a-half year drug trial,representing 75 percent of known Progeria cases worldwide at the time the trial began. Of those, 26 are children with the classic form of Progeria.Researchers also examined arterial stiffness (a predictor of heart attack and stroke in the general population), bone density and rigidity (indicators of osteoporosis). Every child completing the study showed improvement in an ability to gain additional weight, increased flexibility of blood vessels or improved bone structure.

Results included improvement in one or more of the following areas:

 Weight: One in three children demonstrated a greater than 50 percent increase in annual rate of weight gain or switched from weight loss to weight gain, due to increased muscle and bone mass.

 Bone Structure: On average, skeletal rigidity (which was highly abnormal at trial initiation) improved to normal levels after FTI treatment.

 Cardiovascular: Arterial stiffness, strongly associated with atherosclerosis in the general aging population, decreased by 35 percent. Vessel wall density also improved with treatment.

Following the 2003 discovery of the gene that causes Progeria, researchers identified FTIs as a potential drug treatment for Progeria. Children with Progeria have a genetic mutation that leads to the production of the protein progerin, which is responsible for Progeria. Progerin blocks normal cell function and part of its toxic effect on the body is caused by a molecule called a "farnesyl group," which attaches to the progerin protein. FTIs act by blocking the attachment of the farnesyl group onto progerin.

REFERENCES:

1.Thomas B. Brunner, Stephen M. Hahn, Anjali K. Gupta, Ruth J. Muschel,W. Gillies McKenna,
and Eric J. Bernhard;Farnesyltransferase InhibitorsAn Overview of the Results of Preclinical and Clinical Investigations; Cancer Res September 15,2003 63; 5656
2. Fadlo R. Khuri 1 , Bonnie S. Glisson 2 , Edward S. Kim 2 , Paul Statkevich 3 ,Peter F.
Thall 2 , Michael L. Meyers 3 , Roy S. Herbst 2 , Reginald F. Munden 2 ,Craig Tendler 3 , Yali
Zhu 3 , Sandra Bangert 2 , Elizabeth Thompson 2 ,Charles Lu 2 , Xue-Mei Wang 2 , Dong M.
Shin 2 , Merrill S. Kies 2 ,Vali Papadimitrakopoulou 2 , Frank V. Fossella 2 , Paul Kirschmeier 3 ,W.Robert Bishop 3 , and Waun Ki Hong ;Phase I Study of the Farnesyltransferase Inhibitor
   Lonafarnib with Paclitaxel in Solid Tumors; Cancer Res May 1, 2004 10;2968
   3. Lonafarnib for cancer and progeria, Wong NS,Morse MA, 2012 Jul;21(7):1043-55.        doi:10.1517/13543784.2012.688950.Epub 2012 May 24.Morse MA.
4.http://cancerres.aacrjournals.org
5.http://www.pnas.org/content/suppl/2012/09/18/1202529109.DCSupplemental/pnas.2012022
9SI.pdf#nameddest=ST1
6.http://www.news-medical.net
7.www.progeriaresearch.org
8.www.ncbi.nlm.nih.gov/pubmed/22620979
9.clinicaltrials.gov/ct2/show/NCT00425607

Omega-3 dietary supplements pass the blood-brain barrier

Omega-3 dietary supplements pass the blood-brain barrier

New research from Karolinska Institutet shows that omega-3 fatty acids in dietary supplements can cross the blood brain barrier in people with Alzheimer’s disease, affecting known markers for both the disease itself and inflammation. The findings are presented in the Journal of Internal Medicine, and strengthen the evidence that omega-3 may benefit certain forms of this seriously debilitating disease.
"Earlier population studies indicate that omega-3 can protect against Alzheimer’s disease, which makes it interesting to study the effects of dietary supplements containing this group of fatty acids in patients who have already developed the disease," says the study’s lead author Dr Yvonne Freund-Levi.
Omega-3 and other essential polyunsaturated fatty acids accumulate in the central nervous system (CNS) during gestation. It has been assumed that these acids are continually replaced throughout life, but little is known about how this occurs and whether changes in diet can affect the transport of important fatty acids across the blood-brain barrier. The blood-brain barrier serves to protect the brain from harmful chemicals existing naturally in the blood, but also blocks the delivery of drug substances to the brain.
Several diseases can affect the fatty acid profile of the CNS; in patients with Alzheimer’s disease, for example, previous research has observed lower than normal brain concentrations of docosahexaenoic acid (DHA), an omega-3 fatty acid.
In the present study, part of the larger OmegAD project, scientists examined whether omega-3 dietary supplements change the fatty acid profile of the CNS in patients with mild Alzheimer’s disease. Thirty-three patients participated in the study, 18 of whom received a daily omega-3 supplement and 15 a placebo for six months. The results show that the first group had higher levels of both DHA and eicosapentaenoic acid (EPA, another omega-3 fatty acid) in their cerebrospinal fluid (which surrounds the CNS) and blood. No such change was seen in the placebo group.
Moreover, they also found that levels of DHA correlated directly with the degree of change in Alzheimer’s disease and inflammatory markers in the cerebrospinal fluid. Researchers in the field have long been interested in this link between Alzheimer’s disease and inflammation, but attempts to treat the disease using traditional anti-inflammatory drugs have failed to produce any improvements in memory function.
"In animals, DHA dietary supplements can lead to an increase in DHA concentrations in the CNS," says Professor Jan Palmblad, who initiated the study. "Here we show that the same applies to humans, which suggests that omega-3 fatty acids in dietary supplements cross the blood-brain barrier. However, much work remains to be done before we know how these fatty acids can be used in the treatment of Alzheimer’s disease to halt memory loss."

Pregabalin vs amitriptyline: safety and efficacy in neuropathic pain treatment

Pegabalin:

1.Efficacy and safety of pregabalin for treating neuropathic pain associated with diabetic peripheral neuropathy: a 14 week, randomized, double-blind, placebo-controlled trial:

Significant reductions in pain were observed in patients treated with pregabalin at 300 and 600 mg/day vs. placebo (P < 0.05). Improvements in weekly pain scores were observed as early as week 1 and were sustained throughout the study period (300 and 600 mg/day difference from placebo at study end-point, -0.63 and -0.74, respectively). Pregabalin produced significant improvements in weekly sleep interference scores, the short-form McGill Pain Questionnaire, the Medical Outcomes Study-Sleep Scale, the 36-item Short-Form Health Survey scale, and the Patient and Clinical Global Impression of Change. Patient impressions of numbness, pain and paraesthesia were also significantly improved. Regarding treatment responders, 29.1 and 35.6% of patients treated with 300 and 600 mg/day, respectively, reported ≥ 50% improvement in mean pain scores (vs. 21.5% for placebo). Pregabalin was well tolerated; somnolence (26%), dizziness (24%), peripheral oedema (13%) and weight gain (11%) were the most common adverse events and generally were reported as mild to moderate.

The two higher doses of pregabalin had similar responder rates of roughly 47%, whereas the placebo rate was 18%. These doses were also tied to significant improvements in sleep and quality of life. Improvements in pain and sleep were noted within 1 week of treatment and persisted throughout the study. A total dose of 300 mg/day has also been found effective in improving pain scores, sleep interference, and other secondary outcomes.

Conclusion:Pregabalin was effective in reducing pain and improving sleep disturbances due to pain, and was well tolerated in Japanese patients with painful DPN.

2. Amitriptyline vs. pregabalin in painful diabetic neuropathy: a randomized double blind clinical trial:

Good, moderate and mild pain relief were noted in 21 (48%), 6 (13%) and 7 (15%) patients on pregabalin and 15 (34%), 5 (11%) and 12 (27%) patients on amitriptyline, respectively, by patient's global assessment of efficacy and safety. Patient and physician's global assessment, McGill pain questionnaire, Likert pain scale and Patient Global Impression of Change showed no significant difference between the treatments, although improvement with both treatments was seen from the first week. Of the 52 adverse events reported, 34 (65.4%) were with amitriptyline, drowsiness being the commonest [in 19 (43%) patients]. Pregabalin caused adverse events in 18 (25%), of which drowsiness was the most common in nine (20%) patients. The preferred pregabalin dose was 150 mg twice daily.

Conclusion:As there are few differences between the two treatments in efficacy, pregabalin 150 mg twice daily might be the alternative choice as it is associated with fewer adverse effects

3.Comparative Study of Clinical Efficacy of Amitriptyline and Pregabalin in Postherpetic Neuralgia:

we found a clinically significantly better response with pregabalin compared to amitriptyline

 The study included 50 patients, 32 (64%) male and 18 (36%) female, randomized to receive either amitriptyline or pregabalin (n=25 each). Amitriptyline was administered in a dose of 25 mg once daily and pregabalin in a dose of 75 mg twice daily. Inclusion criteria were as follows: postherpetic neuralgia of more than 1 month duration; pain of at least moderate severity; and patient age 40 years or older and no pregnancy. Patients with a history of any serious diseases (renal, cardiac, hepatic or seizure) were excluded. Total treatment period spanned 8 weeks, with patient follow up visits at 2, 4 and 8 weeks to assess the degree of improvement in pain perception and any adverse reaction. Patients with four herpes zoster types were included in this study, of which thoracic type predominated (54%). Other types were cervical in 12 (24%), trigeminal in 8 (16%) and lumbosacral in 3 (6%) patients. Prodromal symptoms before herpes zoster were reported by 66% of study patients. Satisfactory improvements of pain perception at the end of 8 weeks (>75%) were noticed in pregabalin group, which was statistically significant (χ2=10.08; P<0.05).Dry mouth was the commonest complication in amitriptyline group and dizziness in pregabalin group.

If pregabalin dose is reduced, discontinued, or substituted with an alternative medication, this should be done gradually over a minimum interval of 1 week.

“In the United States, the Food and Drug Administration (FDA) has approved pregabalin for adjunctive therapy for adults with partial onset seizures, management of postherpetic neuralgia and neuropathic pain associated with spinal cord injury and diabetic peripheral neuropathy, and the treatment of fibromyalgia.[7] Pregabalin has also been approved in the European Union”.

Adverse drug reactions associated with the use of pregabalin include:

·         Very common (>10% of patients): dizziness, drowsiness.

·         Common (1–10% of patients): blurred vision, diplopia, increased appetite, euphoria, confusion, vivid dreams, changes in libido (increase or decrease), irritability, ataxia, attention changes, abnormal coordination, memory impairment, tremors, dysarthria, parasthesia, vertigo, dry mouth and constipation, vomiting and flatulence, erectile dysfunction, fatigue, peripheral edema, drunkenness, abnormal walking, weight gain, asthenia, nasopharyngitis, increased creatine kinase level.

·         Infrequent (0.1–1% of patients): depression, lethargy, agitation, anorgasmia, hallucinations, myoclonus, hypoaesthesia, hyperaesthesia, tachycardia, excessive salivation, sweating, flushing, rash, muscle cramp, myalgia, arthralgia, urinary incontinence, dysuria, thrombocytopenia, kidney calculus

·         Rare (<0.1% of patients): neutropenia, first degree heart block, hypotension, hypertension, pancreatitis, dysphagia, oliguria, rhabdomyolysis, suicidal thoughts or behavior

Amitriptyline:

Disadvantages:

·         risk of fatality in overdose

·         narrow therapeutic index

·         strong anticholingergic properties, and as a result severe anticholingergic side effects

·         sedation and mental or motor impairment

·         can lower the seizure threshold

·         cardiotoxicity

·         weight gain (greater increase in weight than with nortriptyline, desipramine, zimelidine, and imipramine) 39, 24

·         possible decreased amount of REM sleep

Amitriptyline was not approved by US FDA for this use.

References:

1.Bansal D, Bhansali A, Hota D, Chakrabarti A, Dutta P. Amitriptyline vs. pregabalin in painful diabetic neuropathy: a randomized double blind clinical trial. Diabet Med. 2009 Oct;26(10):1019-26. doi: 10.1111/j.1464-5491.2009.02806.x.Available from: http://www.ncbi.nlm.nih.gov/pubmed/19900234

2Arun Achar1, Partha Pratim Chakraborty2, Samiran Bisai3, Asish Biswas4,Tapobrata Guharay5. Comparative Study of Clinical Efficacy of Amitriptyline and Pregabalin in Postherpetic Neuralgia. Acta Dermatovenerol Croat. 2012;20(2):89-94.

3.Satoh J, Yagihashi S, Baba M, Suzuki M, Arakawa A, Yoshiyama T, Shoji S.Efficacy and safety of pregabalin for treating neuropathic pain associated with diabetic peripheral neuropathy: a 14 week, randomized, double-blind, placebo-controlled trial. Diabet Med. 2011 Jan;28(1):109-16. doi: 10.1111/j.1464-5491.2010.03152.x.Available from: http://www.ncbi.nlm.nih.gov/pubmed/21166852

4.Amitriptyline HCL (Elavil). Last updated: April 12, 2012.Available from: http://www.emedexpert.com/facts/amitriptyline-facts.shtml

Progeria: causes,pathophysiology and treatment upto date

PROGERIA

progeria family India

 

Hutchinson-Gilford Progeria Syndrome ("Progeria", or "HGPS") is a rare, fatal genetic condition characterized by an appearance of accelerated aging in children. Its name is derived from the Greek and means "prematurely old." While there are different forms of Progeria,the classic type is Hutchinson-Gilford Progeria Syndrome, which was named after the doctors who first described it in England; in 1886 by Dr.Jonathan Hutchinson and in 1897 by Dr. Hastings Gilford.

HGPS is caused by a mutation in the gene called LMNA (pronounced, lamin - a). The LMNA gene produces the Lamin A protein, which is the structural scaffolding that holds the nucleus of a cell together. Researchers now believe that the defective Lamin A protein makes the nucleus unstable. That cellular instability appears to lead to the process of premature aging in Progeria.

Although they are born looking healthy, children with Progeria begin to display many characteristics of accelerated aging at around 18-24 months of age. Progeria signs include growth failure, loss of body fat and hair, aged-looking skin, stiffness of joints, hip dislocation, generalized atherosclerosis, cardiovascular (heart) disease and stroke. The children have a remarkably similar appearance, despite differing ethnic backgrounds. Children with Progeria die of atherosclerosis (heart disease) at an average age of thirteen years.

Progeria affects approximately 1 in 4 - 8 million newborns.  There are an estimated 200-250 children living with Progeria worldwide at any one time.  It affects both sexes equally and all races.  Since The Progeria Research Foundation was created in 1999, we have discovered children with Progeria living in over 40 countries.

HGPS is not usually passed down in families.

Pathophisiology:

The gene defect causing HGPS and most progeroid laminopathies has been identified as a mutation in the gene LMNA, coding for the nuclear protein lamin A. Lamin A is normally expressed by most differentiated cells, and requires posttranslational farnesylation to incorporate into the nuclear membrane. The lamin A C-terminal peptide, including the farnesyl group, is subsequently cleaved, and mature lamin A becomes a prominent component of the nuclear scaffold just internal to the nuclear membrane, affecting nuclear structure and function.
In most cases, HGPS is a sporadic autosomal dominant disease caused by a single base alteration (henceforth designated as G608G) in the LMNA gene, which creates a cryptic splice site giving rise to an altered lamin A protein product in which 50 amino acids are deleted. The defective protein product in HGPS (henceforth progerin) lacks the cleavage site for removal of the C-terminal farnesylated peptide, and likely produces disease via dominant negative effects on the nuclear structure and function of various cell types that express lamin A. Most other progeroid laminopathies are caused by various mutations in the LMNA gene, which also subsequently creates abnormally functioning lamin A.





Prominent symptoms and signs of progeria are listed as follows:-
• Dwarfism / limited growth
• Alopecia or baldness
• Small face and a pinched nose
• Small jaw in comparison to head size
• Delayed tooth development 
• Aged-looking, wrinkled skin
• Loss of eyebrows / hair
• Stiff joints / limited range of motion
• Frequent hip dislocations                                                                                                                                                                             
• Premature arteriosclerosis
• Cardiovascular problems
• No sexual maturation

Their bodies are extremely fragile, like the very old,and this is because these children age at a rate that is seven times faster than that of normal children. Is it of any wonder then, that a child of ten years would give stiff competition to his seventy year old grandfather? Now the sad saga does not end with just the looks; these hapless children suffer from all the ailments of the aged and are likely to die either of heart disease, stroke or heart attack, even while in their early teens.

Case reported in India:
The family of Bisul Khan and Razia Khatooon living in Bihar India, had seven children – five of them with progeria. Three of the couple’s affected daughters are dead. Two of his progeric sons are alive, aged 23 and 22 (medical ages 70 and 66). The couple, also have two normal children.

Rural Bihar, with all its backwardness, is hardly a place for Khan’s special family. They were considered a bad omen and were ostracized. 

It is not common for a family to have more than one child with progeria. Bisul Khan’s is the only family in the world with 5 cases of this dreadful condition.

A documentary titled “The 80 Year Old Children” was made in 2005, based on the real-life story of Bisul Khan’s special family
Treatment: (is at the stage of clinical trails)

The care of people with progeria is aimed at minimizing symptoms and maximizing the quality of life as much as possible.

Treatment plans are individualized and may include physical therapy occupational therapy to minimize joint stiffness and improve activity and mobility. Dietary treatments may include tube feeding for infants and supplements to help reduceweight loss.

Low-dose daily aspirin may be recommended to prevent stroke and heart attack.

Surgical procedures may be recommended in some children with progeria. These include pulling out the baby teeth so that prematurely erupting adult teeth have enough room to develop.

Artery bypass surgery or angioplasty may also be recommended to slow the development of cardiovascular disease.

Research:
Twenty-eight children from sixteen countries participated in the two-and-a-half year drug trial, representing 75 percent of known Progeria cases worldwide at the time the trial began. Of those, 26 are children with the classic form of Progeria.
Lonafarnib is a farnesyltransferase inhibitor that blocks the post-translational farnesylation of prelamin A and other proteins that are targets for farnesylation. Farnesylation is essential for the function of both mutant and non-mutant lamin A proteins, including progerin. Therefore, farnesyltransferase inhibitors are ideal candidates for treatment of HGPS, which is caused by a protein (progerin) that likely depends on carrying a farnesyl group to execute its aberrant functions.
Both cell culture and mouse model studies of HGPS demonstrate improved phenotype after exposure to FTI. In vitro, exposure of HGPS skin fibroblasts and progerin-transfected HeLa cells to FTIs, including lonafarnib, prevents preprogerin from intercalating into the nuclear membrane where it normally functions, and eliminates nuclear deformity. In vivo, three Progeria-like mouse models show no appreciable signs of toxicity after FTI administration. In all three of these models, disease is significantly reduced when compared to age-matched controls after oral administration of FTI.
Researchers also examined arterial stiffness (a predictor of heart attack and stroke in the general population), bone density and rigidity (indicators of osteoporosis). Every child completing the study showed improvement in an ability to gain additional weight, increased flexibility of blood vessels or improved bone structure.
Results included improvement in one or more of the following areas:

• Weight: One in three children demonstrated a greater than 50 percent increase in annual rate of weight gain or switched from weight loss to weight gain, due to increased muscle and bone mass.
• Bone Structure: On average, skeletal rigidity (which was highly abnormal at trial initiation) improved to normal levels after FTI treatment.
• Cardiovascular: Arterial stiffness, strongly associated with atherosclerosis in the general aging population, decreased by 35 percent. Vessel wall density also improved with treatment.

Following the 2003 discovery of the gene that causes Progeria, researchers identified FTIs as a potential drug treatment for Progeria. Children with Progeria have a genetic mutation that leads to the production of the protein progerin, which is responsible for Progeria. Progerin blocks normal cell function and part of its toxic effect on the body is caused by a molecule called a "farnesyl group," which attaches to the progerin protein. FTIs act by blocking the attachment of the farnesyl group onto progerin.

Good Pharmacy Practice

GPP is defined as "the practice of pharmacy that responds to the needs of the people who use the pharmacists’ services to provide optimal, evidence-based care. To support this practice it is essential that there be an established national framework of quality standards and guidelines."

The 2011 GPP document underlines the requirements of Good Pharmacy Practice and how to set standards required for GPP, (which also imply a quality management framework and a strategic plan for developing services).
GPP are organised around 4 major roles for pharmacists

1. Role 1: Prepare, obtain, store, secure, distribute, administer, dispense and dispose of medical products
2. Role 2: Provide effective medication therapy management
3. Role 3: Maintain and improve professional performance
4. Role 4: Contribute to improve effectiveness of the health-care system and public health

Each function is structured in several roles, and for each role, a list of minimum national standards to be established have been set.

WHO/FIP GPP should serve as a guidance document for the development of specific standards of GPP at national levels by national pharmacists associations and other related stakeholders.
When establishing minimum standards on GPP, it is important to define the roles played by pharmacists, as expected
by patients and society. Secondly, relevant functions for which pharmacists have direct responsibility and accountability need to be determined within each role. Thirdly, minimum national standards should then be established, based upon the need to demonstrate competency in a set of activities supporting each function and role.