Dispensing of banned phenolphthalein and ketoconazole: simulated patients method

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INTRODUCTION
Harmful medicines are still available in developing countries.Some drugs banned in their country of origin are marketed in developing countries by a few pharmaceutical companies.Due to a lack of legislation and weak legal regulation of drugs in developing countries, these drugs are dispensed to patients without consideration of their potential hazards.Some international corporations that have established their roots in evolving countries have a goal of attaining the maximum level of income irrespective of humanitarian foresight.However, pharmaceutical and many other companies also use developing countries' markets for selling goods they cannot dispose of elsewhere, such as contaminated food and radioactive waste [1].
There are two drugs available in Aden community pharmacies (phenolphthalein (PP) and ketoconazole (KZ)) that are globally banned.PP was the essential constituent in several over-the-counter laxatives for most of the 20 th century.The U.S. Food and Drug Administration FDA categorized PP as "safe and effective" in 1975 [2].However, in 1997, the FDA anticipated that PP should be reclassified as "not commonly documented as safe and effective" [3] after a 2-year feeding study in rodents showed elevated frequencies of neoplasms of the ovary, adrenal gland, kidney, and hematopoietic system [4].Consequently, the United States voluntarily withdrew most PP, including that contained in laxatives, from the market.Studies indicated the genotoxicity of PP [4] and its ability to cause oxidative damage [5] and bind to estrogen receptors [6].The individual data on laxative usage and human cancers specified that its use is not associated with an increased risk of large-bowel cancer [7][8][9][10][11][12][13].
The United States Food and Drug Administration (FDA) issued a Drug Safety Communication restricted the use of Nizoral (KZ) oral tablets on July 26, 2013 [14].However, KZ was the only existing systemic remedy for a wide variety of fungal infections.The FDA's warning emphasized the potential of a possibly fatal drug-induced liver injury (DILI) related to KZ usage, in addition to other risks.The declaration stated that "Nizoral oral tablets should not be a first-line treatment for any fungal infection, [and] Nizoral should be used only when alternative antifungal therapies are not available or tolerated."At the same time, the European Medicines Agency's Committee on Medicinal Products for Human Use (EMA-CHMP) [15] has suggested that the selling authorization for oral KZ as an antifungal be postponed.
The CHMP stated that the hepatoxic risk associated with the usage of KZ overshadows its benefits.Physicians should select an alternative medicine to treat patients with fungal infections.The patients being treated with KZ should consult their physicians.Oral KZ for Cushing's syndrome and topical dosage forms containing KZ are not included in this warning.The FDA Communication [14] states the following: "Serious hepatic injury was identified as the major toxicity for Nizoral tablets and was noted to be unrelated to dose, duration, or indication for treatment.In showing the benefit-risk evaluation, normal side effect shows the DILI, including mortalities and hepatic transplantations, feedback from the FDA Adverse Event Reporting System (AERS) were judged independently by a hepatology expert in FDA.The total hazard for KZ-induced serious liver injury seemed higher than that accompanying other azole antifungal drugs as indicated from pharmacoepidemiologic studies." As part of a larger medication safety study among community pharmacists in Yemen, this study was performed to assess the availability of two banned medicines in Yemen i.e.PP and KZ.

METHODS
This preliminary cross-sectional explorative study applied simulated patients to gather data on dispensing behavior.Simulated patients were trained in the accessibility of banned drugs existing in the community pharmacies (CP).The availability of these two banned drugs was observed and recorded.The pharmacists were asked about the availability of a PP laxative for treating constipation called in Yemen a khat laxative (Sharbat Alkhat ) and KZ for fungal infections in 50 convenient samples of CPs that were selected based on ease of access by the simulated patients.
A small simulated patient case study was carried out to recognize and eradicate the barriers associated with simulated patients and to prepare a training module.The simulated patient visited two randomly chosen CPs in Aden.During the visit, the simulated patient requested medications to treat symptoms of constipation and fungal infection.All details and observations of the consultation were documented by the simulated patient.The findings suggested poor professional practices in both pharmacies and paved the way for the study to compare the dispensing practices of banned drugs and prohibited medicines in CPs in Aden.These two pharmacies were not included in the major study.
A literature review, case study, and training session informed a simulated patient interview method to observe, assess and compare dispensing practices.Twenty students from the Faculty of Pharmacy Aden University were trained to present as simulated patients to determine the availability of banned and prohibited medicines.
For standardization and validation of the study, the 20 simulated patients were randomly grouped in ten pairs, and each pair was randomly assigned to visit five pharmacies.Each pair of simulated patients in an interchangeable manner visited two pharmacies.Two encounters with two simulated patients resulting in a total of 100 encounters in pharmacies.
The stimulated patient interacted with the staff at the pharmacy and asked questions about the availability of the 2 prohibited medicines PP and KZ in the Yemeni market and recorded the answer of the CP S after each visit to a pharmacy.
Descriptive statistics were used for data analysis.

RESULTS
The main intention of the current study was to determine the availability of the banned drugs, which will potentially affect patients' safety in terms of using banned medicines.The dispensing behavior for the two banned drugs (PP and KZ) was observed and recorded in 50 CPs.PP was found in 3/50 (6%) pharmacies, while 31/50 (62%) pharmacies kept KZ in the premise.

DISCUSSION
To the authors best knowledge, the current study is considered the first of its kind in Yemen on the availability of the two banned drugs in the CPs.Likewise, no official document from the High Authority for Medicines was found that prohibited their use in the Yemeni CPs.The PP is dispensed informally in the CPs under the name of Sharbat Alkhat .Although the name is different, the active ingredient is the same.Additionally, KZ is sold in most pharmacies without any restrictions on its use.
The data from one study revealed that the infrequent use of PP did not increase the risk of some types of cancers that were identified in animal studies (ovarian cancer, kidney cancer, leukemia, and lymphoma).However, this study could not verify the risks of using PP on average once a week for no less than two years.The study's authors thought that level of use could increase the risk of developing some types of cancer [16].The percentage of CPs dispensing PP is considerable lower than the percentage dispensing KZ.
The data from the present study revealed that the percentage of pharmacies keeping and selling KZ is high (n=31, 62% of CPs sold it) in comparison to PP. KZ was approved in 1981 as an oral antifungal drug and since that time it has been recognized to cause liver damage or impairment.Studies determined that the hepatic injury was the result of direct hepatocellular toxicity rather than immunologically intermediated effects.The active metabolite of KZ, N-desacetyl-ketoconazole, may be responsible for the hepatic damage and toxicity as shown in experimental models.However, that toxicity is related to its dosage, concentration and period of application [17].Nevertheless, information that has been gathered to the present time and published in the biomedical studies shows that KZ is occasionally a quantitatively significant offending medicine that can trigger a process of drug-related liver damage and even liver failure.
The study would like to recommend the following: 1.The health ministry should issue an official document to limit the import of these medicines into the country and prevent their dispensation in the CPs. 2. The Ministry of Health needs to organize a periodic inspection committee to monitor the dispensing of these drugs.3. The community pharmacists should be made aware of the potential health hazards associated with the long-term use of banned medicines.4. The list of banned drugs should be periodically renewed and provided to the CPs. 5.The students in the Faculty of Medicine and Health Sciences should be educated about the risk of using the banned medicines.

CONCLUSION
The availability of these drugs in Yemeni pharmacies is alarming.The high authority for medicines must put restrictions on their use or provide suitable alternatives for them in the local markets to ensure patient safety.
that all of the data gathered would be handled with full confidentiality, and it would only be used for research purposes.

FUNDING
This research was not funded.