A Feasibility Study on Re-establishing the Bioavailability/Bioequivalence Unit of the Department of Pharmacology and Toxicology, College of Medicine-University of the Philippines Manila.

Objectives: The Bioavailability/Bioequivalence Unit (BA/BE Unit) of the Department of Pharmacology and Toxicology, College of Medicine, University of the Philippines Manila which has not been operational since 2012, is due for renewal of its accreditation. To date, there are only three Philippine Food and Drug Administration-accredited laboratories that perform bioequivalence studies in the Philippines. One of the prerequisites of registering specific generic medicines is the conduct of Bioequivalence (BE) studies which are performed to ensure that the generic drug is at par with the innovator drug. Thus, this study aimed to determine the feasibility of re-establishing the BA/BE Unit as a bioequivalence testing center. Methods: The feasibility study done is a qualitative descriptive analysis based on expansive literature review and performance of SWOT analysis within the BA/BE unit. Literatures were selected based on its assessed relevance to the study. The databases checked were PubMed and Google Scholar. The terms used were from the Medical Subject Heading (MeSH) including feasibility studies, therapeutic equivalency, and generic drugs. Literature review was performed on the factors affecting the four types of feasibility studies (market, technical, financial, and organizational). A SWOT analysis of the BA/BE Unit was done through the review of records and documents of previous BE studies and focus group discussion among the BA/BE Unit team members. Results: The BA/BE Unit conducted 24 bioequivalence studies from 2006-2009 and still receives inquiries from drug companies. It implements its QMS throughout the pre-analytical, analytical, and post-analytical stages of the workflow. Its organizational structure consists of qualified professionals with updated GCP and GLP certificates. Because of the adequately equipped facility, lower honoraria for government-employed personnel, and lower expenses for laboratories and in-patient admissions, the cost of conducting a bioequivalence study in the BA/BE Unit will be lower than in other BE centers. Conclusion: Based on the SWOT analysis and market, technical, financial, and organizational considerations, re-establishing the BA/BE Unit as a bioequivalence testing center is feasible.

Metformin extended-release versus metformin immediate-release for adults with type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials.

AIM: To compare the efficacy and tolerability of metformin extended-release (MXR) and the conventional metformin immediate-release (MIR) formulations in adults with type 2 diabetes mellitus (T2DM) METHODS: PubMed, the Cochrane Library, ClinicalTrials.gov and other sources were searched until 19 March 2021 for randomized controlled trials (RCTs) that compared equal daily doses of MXR and MIR in adults with T2DM. Random-effects model meta-analysis was performed to obtain pooled mean difference (MD) of change from baseline for continuous outcomes and risk ratio (RR) for dichotomous outcomes. Primary outcomes considered were HbA1c and key gastrointestinal (GI) symptoms (abdominal discomfort or pain, diarrhea, dyspepsia, and nausea & vomiting). RESULTS: Nine RCTs that randomized a total of 2609 adults revealed that MIR was statistically associated with better HbA1c lowering (MD 0.09% [95% confidence interval or CI, 0.01%, 0.17%]), MXR only reduced dyspepsia (RR 0.58 [95% CI, 0.34, 0.98]), and both formulations were associated with similar cumulative incidence of other key GI symptoms. CONCLUSIONS: MXR was associated with statistically worse but likely clinically similar HbA1c lowering and minimal improvement of GI intolerance compared to MIR. Protocol Registration: PROSPERO (CRD42019148008).

A systematic review and meta-analysis on the efficacy and safety of metformin as adjunctive therapy among women with metastatic breast cancer.

BACKGROUND: Breast cancer is the most common cancer among women worldwide and is one of the leading causes of cancer-related mortalities. Metformin has been found to have direct and indirect antitumor mechanisms, and because of its availability and good safety profile, it has been investigated to be useful in various malignancies including breast cancer. OBJECTIVE: This study aims to determine the efficacy and safety of metformin administration as adjunctive therapy on mortality among females with breast cancer. METHODS: This is a systematic review and meta-analysis of randomized clinical trials (RCTs) on the use of metformin as adjunctive therapy when combined with standard chemotherapy on the outcomes of progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and clinical benefit rate (CBR). RESULTS: After a comprehensive literature search, only three phase 2 RCTs on the use of metformin as adjunctive therapy for locally advanced and metastatic breast cancer were included. Clinical trials on early breast cancer are still ongoing and none were included in the present review. This study, based on the systematic review, revealed that metformin added to standard chemotherapy does not improve the PFS and OS among women with metastatic breast cancer, and likewise, has no impact on the ORR with a relative risk of 1.42 95% CI 0.45-4.55 and CBR with an RR of 0.87, 95% CI 0.55-1.37. It appears to be safe and may even be protective for the development of neutropenia based on at least one study. CONCLUSION: This study clarifies that there is insufficient evidence on the benefits of metformin on survival among women with metastatic breast cancer.

Executive summary of the 2020 clinical practice guidelines for the management of hypertension in the Philippines.

Hypertension is the most common cause of death and disability worldwide with its prevalence rising in low to middle income countries. It remains to be an important cause of morbidity and mortality in the Philippines with poor BP control as one of the main causes. Different societies and groups worked and collaborated together to develop the 2020 Philippine Clinical Practice Guidelines of hypertension arising for the need to come up with a comprehensive local practice guideline for the diagnosis, treatment, and follow up of persons with hypertension. A technical working group was organized into six clusters that analyzed the 30 clinical questions commonly asked in practice, looking into the definition of hypertension, treatment thresholds, blood pressure targets, and appropriate medications to reach targets. This guideline also includes recommendations for the specific management of hypertension among individuals with uncomplicated hypertension, hypertension among those with diabetes, stroke, chronic kidney disease, as well as hypertension among pregnant women and pediatric populations. It also looked into the appropriate screening and monitoring of patients when managing hypertension, and identification of groups who are at high risk for cardiovascular (CV) events. The ADAPTE process was used in developing the statements and recommendations which were then presented to a panel of experts for discussion and approval to come up with the final statements. This guideline aims to aid Filipino healthcare professionals to provide evidence-based care for persons with hypertension and help those with hypertension adequately control their blood pressure and reduce their CV risk.

Association of sunlight exposure with 25-hydroxyvitamin D levels among working urban adult Filipinos.

OBJECTIVES: To determine the association of different levels of sunlight exposure, measured using the Filipino sunlight exposure questionnaire (SEQ) with 25-hydroxyvitamin D (25-OHD) levels among working urban adult Filipinos. METHODS: Seventy-five adult participants, living and working in Metro Manila, for at least 1 year, were grouped according to their perceived sunlight exposure pattern: low sunlight exposure (mostly indoor work); moderate sunlight exposure (both indoor and outdoor work); and high sunlight exposure (mostly outdoor work). After completion of the self-administered Filipino SEQ, they underwent serum 25-OHD level determination. Strength of correlation between the SEQ scores and 25-OHD levels was computed. RESULTS: Serum 25-OHD levels generally increased with increasing sunlight exposure levels. The overall Pearson's correlation between the SEQ scores and 25-OHD levels of the participants was 0.396 (P = 0.001). The correlation for the individual domains was 0.342 for intensity of sunlight exposure (P = 0.003), 0.321 for factors affecting sunlight exposure (P = 0.005), and 0.256 for sun protection practices (P = 0.027). CONCLUSIONS: The sunlight exposure of working urban adult Filipinos, as measured by the Filipino SEQ, has an overall significant, direct and moderate association with serum 25-OHD levels. This Filipino SEQ can serve as a valuable clinical tool for sunlight exposure assessment to identify individuals at risk for vitamin D deficiency.

The effect of Momordica charantia capsule preparation on glycemic control in type 2 diabetes mellitus needs further studies.

BACKGROUND AND OBJECTIVES: Momordica charantia, locally known as Ampalaya, is being widely used and advertised for its hypoglycemic effects. However, to date, no large clinical trial has been published on the efficacy of any type of preparation. The main objective of this study is to determine if addition of M. charantia capsules to standard therapy can decrease glycosylated hemoglobin (hemoglobin A1c or HbA1c) levels in diabetic patients with poor sugar control. STUDY DESIGN AND SETTING: A randomized, double-blind, placebo-controlled trial was conducted between April and September 2004 at the outpatient clinics of the Philippine General Hospital. The trial included 40 patients, 18 years old and above, who were either newly diagnosed or poorly controlled type 2 diabetics with A1c levels between 7% and 9%. On top of the standard therapy, the patients were randomized to either M. charantia capsules or placebo. The treatment group received two capsules of M. charantia three times a day after meals, for 3 months. The control group received placebo at the same dose. The primary efficacy endpoint was change in the A1c level in the two groups. The secondary efficacy endpoints included its effect on fasting blood sugar, serum cholesterol, and weight. Safety endpoints included effects on serum creatinine, hepatic transaminases (Alanine aminotransferase/ALT and Aspartate aminotransferase/AST), sodium, potassium, and adverse events. RESULTS: Baseline characteristics between the treatment and control groups were similar. The difference in mean change in A1c between the two groups was 0.22% in favor of M. charantia (95% CI: -0.40 to 0.84) with P=0.4825. There was no significant effect on mean fasting blood sugar, total cholesterol, and weight or on serum creatinine, ALT, AST, sodium, and potassium. There were few adverse events and these were generally mild. CONCLUSION: This is the first randomized controlled trial to shed light on the issue concerning the hypoglycemic effects of M. charantia. The investigators targeted a 1% decline in A1c at the outset with an estimated power of 88%. With the observed decline of 0.24%, the achieved power was only 11%. For this reason, we are unable to make a definite conclusion about the effectiveness of M. charantia. However, the results of this study can be used estimate the sample size for bigger studies.

Factors Associated with Postoperative Diabetes Insipidus after Pituitary Surgery.

BACKGROUND: Determining risk factors for diabetes insipidus (DI) after pituitary surgery is important in improving patient care. Our objective is to determine the factors associated with DI after pituitary surgery. METHODS: We reviewed records of patients who underwent pituitary surgery from 2011 to 2015 at Philippine General Hospital. Patients with preoperative DI were excluded. Multiple logistic regression analysis was performed and a predictive model was generated. The discrimination abilities of the predictive model and individual variables were assessed using the receiving operator characteristic curve. RESULTS: A total of 230 patients were included. The rate of postoperative DI was 27.8%. Percent change in serum Na (odds ratio [OR], 1.39; 95% confidence interval [CI], 1.15 to 1.69); preoperative serum Na (OR, 1.19; 95% CI, 1.02 to 1.40); and performance of craniotomy (OR, 5.48; 95% CI, 1.60 to 18.80) remained significantly associated with an increased incidence of postoperative DI, while percent change in urine specific gravity (USG) (OR, 0.53; 95% CI, 0.33 to 0.87) and meningioma on histopathology (OR, 0.05; 95% CI, 0.04 to 0.70) were significantly associated with a decreased incidence. The predictive model generated has good diagnostic accuracy in predicting postoperative DI with an area under curve of 0.83. CONCLUSION: Greater percent change in serum Na, preoperative serum Na, and performance of craniotomy significantly increased the likelihood of postoperative DI while percent change in USG and meningioma on histopathology were significantly associated with a decreased incidence. The predictive model can be used to generate a scoring system in estimating the risk of postoperative DI.

Targeted next generation sequencing of the entire vitamin D receptor gene reveals polymorphisms correlated with vitamin D deficiency among older Filipino women with and without fragility fracture.

This study aimed to discover genetic variants in the entire 101 kB vitamin D receptor (VDR) gene for vitamin D deficiency in a group of postmenopausal Filipino women using targeted next generation sequencing (TNGS) approach in a case-control study design. A total of 50 women with and without osteoporotic fracture seen at the Philippine Orthopedic Center were included. Blood samples were collected for determination of serum vitamin D, calcium, phosphorus, glucose, blood urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase and as primary source for targeted VDR gene sequencing using the Ion Torrent Personal Genome Machine. The variant calling was based on the GATK best practice workflow and annotated using Annovar tool. A total of 1496 unique variants in the whole 101-kb VDR gene were identified. Novel sequence variations not registered in the dbSNP database were found among cases and controls at a rate of 23.1% and 16.6% of total discovered variants, respectively. One disease-associated enhancer showed statistically significant association to low serum 25-hydroxy vitamin D levels (Pearson chi-square P-value=0.009). The transcription factor binding site prediction program PROMO predicted the disruption of three transcription factor binding sites in this enhancer region. These findings show the power of TNGS in identifying sequence variations in a very large gene and the surprising results obtained in this study greatly expand the catalog of known VDR sequence variants that may represent an important clue in the emergence of vitamin D deficiency. Such information will also provide the additional guidance necessary toward a personalized nutritional advice to reach sufficient vitamin D status.

Comparison of Fixed versus Calculated Activity of Radioiodine for the Treatment of Graves Disease in Adults.

BACKGROUND: Radioactive iodine as a treatment modality has been shown in several studies to be a safe and effective therapy for Graves disease. However, there is still no uniformity regarding optimal dosing method. The aim of this study is to compare the efficacy of calculated and fixed dosing of radioiodine for the treatment of Graves disease. METHODS: A hundred twenty-two patients diagnosed with Graves disease were randomized to receive either fixed or calculated dose of radioiodine. Those randomized to fixed activity received either low fixed activity at 9.9 mCi for thyroid gland size <40 g or high fixed activity at 14.9 mCi for thyroid gland size 40 to 80 g, and those grouped to calculated activity received 160 µCi/g of thyroid tissue adjusted for 24 hours radioiodine uptake. Thyroid function tests (free thyroxine [T4] and thyroid stimulating hormone [TSH]) were monitored at 10, 16, and 24 weeks after radioactive iodine therapy. The primary outcome, treatment failure was defined as persistently elevated free T4 and low TSH. RESULTS: Of the 122 patients randomized, 56 in the fixed dose group and 56 in the calculated dose group completed the follow-up. At the end of 6 months, the percentage of treatment failure was 37.50% in the calculated dose group versus 19.64% in the fixed dose group with a relative risk of 0.53 (95% confidence interval, 0.28 to 0.98) favoring the fixed dose group. CONCLUSION: Fixed dose radioiodine has a significantly lower incidence of persistent hyperthyroidism at 6 months post-radioactive therapy.

Primary hyperparathyroidism from a probable ectopic parathyroid adenoma with severe skeletal disease and vitamin D deficiency.

Primary hyperparathyroidism (PHPT) may lead to skeletal deformities, fractures and renal failure in symptomatic patients if untreated. We present a case of a 30-year-old woman presented with muscle weakness, weight loss, hypercalcaemia and a pathological fracture, eventually with rapidly progressive musculoskeletal disease. Subsequent biochemical, radiographic and scintigraphy findings were consistent with PHPT from an ectopic mediastinal adenoma, and concomitant vitamin D deficiency. The severe hypercalcaemia was adequately temporised with hydration, forced diuresis and intravenous bisphosphonates. Removal of the adenoma by video-assisted thoracoscopic surgery was contemplated; however, consent was withdrawn precluding histological confirmation. A review of literature shows the changing profiles of patients with PHPT, the uncommon occurrence of parathyroid adenomas in ectopic locations and possible association between severity of PHPT and vitamin D status.

Knowledge, attitudes and practices of persons with type 2 diabetes in a rural community: phase I of the community-based Diabetes Self-Management Education (DSME) Program in San Juan, Batangas, Philippines.

AIMS: 1. To determine the knowledge, attitudes, and practices of persons with type 2 diabetes in the rural community of San Juan, Batangas, Philippines. 2. To determine the association between patient factors such as age, sex, duration of diabetes, and type of diabetes on knowledge, attitudes, and practices regarding diabetes. METHODS: Cross-sectional analytic study done among persons with type 2 diabetes in the rural community. Participants were selected using stratified cluster sampling. Data were collected using two main methods: use of investigator-administered questionnaires and focus group discussions (FGDs). RESULTS: 156 diabetic residents were included. The overall mean percentage score on knowledge was 43%. Less than half of the respondents strongly believed in the need for patient autonomy (38%). 35 respondents were included in the FGDs. Only 4 out of 35 diabetic respondents owned a glucose meter while only 16 out of the 35 consult their doctors on a regular basis. CONCLUSIONS: The study comprises Phase I of the proposed 5-year community-based DSME Program in the Philippines. It highlights the importance of evaluating knowledge, attitudes and practices as crucial means to understand observed behaviors and guide behavioral change.