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Muhammad M Hammami, 1, 2 Muhammad B Hammami, 3 Reem Aboushaar 4 1Clinical Studies and Empirical Ethics Department, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; 2Alfaisal University College of Medicine, Riyadh, Saudi Arabia; 3Division of Gastroenterology, Department of Medicine, John Hopkins University, Baltimore, MD, USA; 4MS IV, Florida Atlantic University, Boca Raton, FL, USACorrespondence: Muhammad M HammamiClinical Studies and Empirical Ethics Department, King Faisal Specialist Hospital and Research Centre, P O Box # 3354 (MBC 03), Riyadh 11211, Saudi ArabiaTel +966-11-442-4527Fax +966-11-442-7894Email Muhammad@kfshrc.edu.saBackground: Organ donation is commonly evaluated by biomedical ethicists based largely on principlism with autonomy at the top of the “moral mountain.” Lay people may differ in the way they invoke and balance the various ethical interests. We explored lay people’s ethical attitudes to organ donation.Methods: Respondents (n=196) ranked 42 opinion-statements on organ donation according to a 9-category symmetrical distribution. Statements’ scores were analyzed by averaging-analysis and Q-methodology.Results: Respondents’ mean (SD) age was 34.5 (10.6) years, 53% were women, 69% Muslims (30% Christians), 29% Saudis (26% Filipinos), and 38% healthcare-related. The most-agreeable statements were “Acceptable if benefit to recipient large,” “Explicit donor consent and family approval for live donation,” “Acceptable if directed to family member,” and “Explicit donor consent and family approval for postmortem donation.” The most-disagreeable statements were “Donor consent and family approval not required for postmortem donation,” “Acceptable with purely materialistic motivation,” and “Only donor no-known objection for postmortem donation.” Women, Christians, and healthcare respondents gave higher rank to “Explicit donor consent and family approval for live donation,” “Only donor family consent required for postmortem donation,” and “Acceptable if organ distribution equitable,” respectively, and Muslims gave more weight to donor/family harm (p ≤ 0.001). Q-methodology identified various ethical resolution models that were associated with religious affiliation and included relatively “motives-concerned,” “family-benefit-concerned,” “familism-oriented,” and “religious or non-religious altruism-concerned” models. Of 23 neutral statements on averaging-analysis, 48% and 65% received extreme ranks in ≥ 1 women and men Q-methodology models, respectively.Conclusion: 1) On average, recipient benefit, requirement of both explicit donor consent and family approval, donor-recipient relationship, and motives were predominant considerations; 2) ranking of some statements was associated with respondents’ demographics; 3) Q-methodology identified various ethical resolution models that were partially masked by averaging-analysis; and 4) strong virtue and familism approaches in our respondents provide some empirical evidence against principlism adequacy.Keywords: organ donation, familism, virtue, ethics of care, principlism, Q-methodology

Muhammad M Hammami,1,2 Safa Hammami,3 Reem Aboushaar,4 Ahmed S Aljomah1 1Clinical Studies and Empirical Ethics Department, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; 2Alfaisal University College of Medicine, Riyadh, Saudi Arabia; 3St. Mary Medical Center, San Francisco, CA, USA; 4MS IV, Florida Atlantic University, Boca Raton, FL, USACorrespondence: Muhammad M HammamiClinical Studies and Empirical Ethics Department, King Faisal Specialist Hospital and Research Centre, P O Box # 3354 (MBC 03), Riyadh 11211, Saudi ArabiaTel +966-1-442-4527Fax +966-1-442-7894Email Muhammad@kfshrc.edu.saBackground: Placebo-treatment acceptability is debated among ethicists, mostly due to conflict between respect-to-autonomy and beneficence principles. It is not clear how lay people balance these and other ethical principles.Methods: One hundred and eighty-seven respondents rank-ordered 42 opinion statements covering various ethical aspects of placebo-treatment, according to a 9-category symmetrical distribution. We analyzed statements’ scores using averaging-analysis and by-person factor analysis (Q-methodology).Results: Respondents’ mean (SD) age was 34.6 (10.6) years, 54% were women, 40% healthcare-related, 68% Muslims (31% Christians), and 39% received general education in Saudi Arabia (24% in the Philippines). On averaging-analysis, the most-agreeable statements were “Acceptable if benefit to patient large” and “Acceptable with physician intent to benefit patient”. The most-disagreeable statements were “Acceptable with physician self-benefit intent” and “Acceptable with large harm to other patients”. Muslims gave a higher rank to “Giving no description is acceptable”, “Acceptable with small benefit to patient”, and “Acceptable with physician intent to benefit patient” and a lower rank to “Acceptable to describe as inactive drug”, “Acceptable with physician intent to please patient caring relative”, and “Acceptable with moderate harm to other patients” (p

Muhammad M Hammami,1,2 Safa Hammami,1 Hala A Amer,1 Nesrine A Khodr1 1Clinical Studies and Empirical Ethics Department, King Faisal Specialist Hospital and Research Centre, 2College of Medicine, Alfaisal University, Riyadh, Saudi Arabia Background: Understanding culture-and sex-related end-of-life preferences is essential to provide quality end-of-life care. We have previously explored end-of-life choices in Saudi males and found important culture-related differences and that Q-methodology is useful in identifying intraculture, opinion-based groups. Here, we explore Saudi females’ end-of-life choices.Methods: A volunteer sample of 68 females rank-ordered 47 opinion statements on end-of-life issues into a nine-category symmetrical distribution. The ranking scores of the statements were analyzed by averaging analysis and Q-methodology.Results: The mean age of the females in the sample was 30.3 years (range, 19–55 years). Among them, 51% reported average religiosity, 78% reported very good health, 79% reported very good life quality, and 100% reported high-school education or more. The extreme five overall priorities were to be able to say the statement of faith, be at peace with God, die without having the body exposed, maintain dignity, and resolve all conflicts. The extreme five overall dis-priorities were to die in the hospital, die well dressed, be informed about impending death by family/friends rather than doctor, die at peak of life, and not know if one has a fatal illness. Q-methodology identified five opinion-based groups with qualitatively different characteristics: “physical and emotional privacy concerned, family caring” (younger, lower religiosity), “whole person” (higher religiosity), “pain and informational privacy concerned” (lower life quality), “decisional privacy concerned” (older, higher life quality), and “life quantity concerned, family dependent” (high life quality, low life satisfaction). Out of the extreme 14 priorities/dis-priorities for each group, 21%–50% were not represented among the extreme 20 priorities/dis-priorities for the entire sample.Conclusion: Consistent with the previously reported findings in Saudi males, transcendence and dying in the hospital were the extreme end-of-life priority and dis-priority, respectively, in Saudi females. Body modesty was a major overall concern; however, concerns about pain, various types of privacy, and life quantity were variably emphasized by the five opinion-based groups but masked by averaging analysis. Keywords: end-of-life priorities, end-of-life dis-priorities, Q-methodology, score-averaging, Muslims, Saudi females

Objective: The purpose of this randomized, crossover study was to compare the bioavailability of a generic and innovator formulation of gatifloxacin 400 mg tablets under fasting conditions.Methods: Seventeen blood samples per period were collected from 24 healthy, Arab male volunteers over 36 hours, plasma gatifloxacin concentrations were determined by HPLC assay, and pharmacokinetic parameters were deter-mined by the non-compartmental method.Results: Mean +/- SD C[max], T[max], AUC[for symbol see text] AUC[for symbol see t4st], and t[1/2]] were 4.88 +/- 1.02 and 4.88 +/- 0.99 microg/mL, 1.19 +/- 0.62 and 1.14 +/- 0.79h, 37.81 +/- 5.54 and 39.12 +/- 5.19 microg.h/mL, 39.68 +/- 5.86 and 38.00 +/- 5.43 microg.h/mL, and 8.07 +/- 0.62 and 8.08 +/- 0.75 h for the generic and innovator formulation, respectively. ANOVA revealed significant formulation effect for AUC[for symbol see text] and AUC[for symbol see text]. However, the parametric 90% confidence intervals on the mean of the difference between log-transformed values were within the bioequivalence accepted range of 80 to 125%, namely: 102.06% to 107.34%,101.69% to 107.10%, and 94.00% to 106.10%, for AUC [for symbol see text], AUC [for symbol see text], and C[max], respectively.Conclusion: The results indicate that the two formulations are both statistically different and equivalent, in the rate and extent of absorption. This may be due to a large sample size in relation to sample variance. [ABSTRACT FROM AUTHOR]

A simple and effective ultra-high-performance liquid chromatography assay linked to tandem mass spectrometry (UHPLC-MS/MS) for measuring cortisol and cortisone levels in human sweat has been developed and validated. A noninvasive world standard sweat collecting equipment was utilized to collect samples. The samples were analyzed using an Atlantis dC18 (2.1 × 100 mm, 3  μ m) column with a 2 mM ammonium acetate and acetonitrile (1 : 1, v : v) mobile phase. In an isocratic condition, the mobile phase was delivered at a flow rate of 0.3 ml/minute. A positive electrospray ionization interface with multiple-reaction monitoring mode was used to provide simultaneous quantification of cortisol, cortisone, and internal standard at transitions of 363.11 to 121.00, 361.18 to 163.11, and 367.19 to 121.24, respectively. The method was validated for cortisol and cortisone determination over a concentration range of 0.5-50 ng/mL The detection limits for cortisol and cortisone in human sweat were 0.3 and 0.2 ng/ml, respectively. The interday coefficients of variation of cortisol and cortisone were ≤8.5% and ≤10.01%, whereas bias was in the range from -7.9% to 2.1% and from -4.3% to 3.0%, respectively. The assay was successfully applied to evaluate the cortisol-to-cortisone ratio in sweat samples collected from healthy adult volunteers., Competing Interests: The authors declare that they have no conflicts of interest, (Copyright © 2022 Syed N. Alvi et al.)

Objective: To evaluate in-vitro quality of paracetamol 500 mg tablet brands marketed in Saudi Arabia., Results: Two reference (R1 and R2) and seven generic (G1-G7) brands were commercially available. Four brands were single-drug, containing paracetamol only (R1, G1-G3) and five contained additional active ingredients (R2, G4-G7). All brands were immediate-release. Weight variation (n = 20, range as percent difference from mean), active substance content (n = 20, mean (SD) as percent difference from label), breaking force (n = 10, mean (SD)), and friability (n = 20, as percent weight loss) ranged from 97 to 102%, 96.1% (2.9%) to 99.8% (1.1%), 9.9 (0.4) to 21.0 (0.9) kg, and 0.017% to 0.809%, respectively. Disintegration (water medium) time (n = 6, minute: second) ranged from 02:35-03:09 to 12:49-13:10. Dissolution (phosphate buffer, pH 5.8) profile showed a mean release at 30 min of 87% to 97% of label content, with seven brands passing stage-1 (≥ 85% for each of 6 test units) and two passing stage-2 (mean of 12 test units ≥ 85%) criteria. Despite statistically significant differences between R1 and R2 and some of their corresponding generic brands in active substance content, breaking force, and amount dissolved at 30 min, all nine brands met the pre-specified quality standards.

Background: Familial hypocalciuric hypercalcemia (FHH) is a heterogeneous autosomal-dominant disorder of calcium hemostasis that may be difficult to distinguish clinically from mild primary hyperparathyroidism. Loss-of-function mutations mainly involving Arg15 residue of the adaptor-related protein complex 2, sigma subunit 1 (AP2S1) cause a rarer, more recently recognized form of FHH, FFH type-3. Recently, 18 F-fluorocholine positron emission tomography/computed tomography (FCH-PET/CT) showed superior sensitivity to conventional imaging in localizing parathyroid adenomas. We report a new FFH type-3 patient who underwent unnecessary parathyroidectomy in association with misleading FCH-PET/CT imaging., Case Presentation: A 29-year old woman was initially evaluated for parathyroid hormone (PTH)-dependent hypercalcemia in 2013. Medical history was positive only for chronic constipation and malaise with no personal or family history of hypercalcemia, kidney stones, or neck surgery. Over seven years, serum calcium level was 2.51-2.89 mmol/L with concomitant PTH level of 58.7-94.8 mmol/L. Serum phosphate levels were in the low/low normal range. Serum creatinine and magnesium levels were normal. 25-hydroxy vitamin D level was 13 nmol/L. 24-hour urine calcium level was 1.92 mmol/day but increased to 6.99 mmol/day after treatment with cholecalciferol 1000 IU daily. Bone mineral density and renal ultrasound were normal. Parathyroid ultrasound showed two hypoechoic nodules inferior to the left and right thyroid lobes; however, 99m technitium-sestamibi scans (2013, 2016, 2018) were negative. FCH-PET/CT (2019) showed focal uptake co-localizing with the nodule inferior to the left thyroid lobe. The patient underwent left inferior parathyroidectomy and pathology was consistent with parathyroid hyperplasia. However, postoperatively, serum calcium and PTH levels remained elevated and FCH-PET/CT and ultrasound showed persistence of the uptake/nodule. Whole exome sequencing showed Arg15Cys mutation in the AP2S1 gene characteristic of FHH type-3., Conclusions: In this new case of FHH type-3, FCH-PET/CT failed to localize to the hyperplastic parathyroid glands and localized instead to apparently a lymph node. This, together with increased urinary calcium after vitamin D supplementation, led to unnecessary parathyroidectomy. Given the increasingly lower cost of genetic testing and the cost of follow up and unnecessary surgery, it may prudent to include genetic testing for FHH early on in patients with mild PTH-dependent hypercalcemia.

Objective: We previously reported the pharmaceutical quality of eight brands of 50 mg enteric-coated diclofenac sodium tablet available on the Saudi market. Here, we assess the quality of reference (R1) and four generic (G1-G4) brands of 50 mg immediate-release diclofenac potassium tablet and of reference (R2) and generic (G5) brands of 100 mg sustained-release diclofenac sodium tablet., Results: Weight variation (range as % difference from mean), active substance content (mean (SD) as % difference from label), breaking force [mean (SD)], and friability (as % weight loss) were 95-104% and 99-102%, 100.9% (3.4%) and 105.6 (4.2%), 12.2 (1.3) and 12.9 (1.8) kg, and 0.0014% and 0.0012%, for R1 and R2, respectively. For G1-G5, they were ≤ ± 2%, 98.8% (2.7%) to 109.2% (3.8%), 6.4 (0.6) to 13.3 (1.0) kg, and 0.0007% to 0.0261%, respectively. R1 and G1-G4 disintegrated within 04:50-17:20 min: seconds and released a mean of 89-100% of label active substance content by 60 min in buffer (pH 6.8). R2 and G5 did not disintegrate or dissolve in 0.1 N HCl for 2 h, disintegrated in buffer (pH 6.8) in 01:58-02:15 h: minutes, and fulfilled dissolution criteria (pH 7.5) for both United States Pharmacopoeia test-1 and test-2. Thus all seven brands met pre-specified quality criteria.

Background: Factors other than patient's preference may influence surrogate medical decision making in a culture- and viewpoint-dependent way. We explored the importance hierarchy of potential surrogate medical decision making determinants to Middle-Eastern (ME) and East-Asian (EA) men according to their norm-perception (N-viewpoint), preference as patients (P-viewpoint), and preference as surrogate decision-makers (S-viewpoint)., Methods: Each respondent (120 ME, 120 EA) sorted 28 items reflecting potential determinants into a fixed distribution of importance hierarchy according to the three viewpoints. Latent decision making models were explored by by-person factor analysis (Q-methodology)., Results: Six models were identified for each ME and EA viewpoint (total 36). Patient's health-related, patient's preference-related, and society's interests-related determinants were strongly embraced in 34, 3, and zero models and strongly discounted in 2, 5, and 21 models, respectively. Patient's religious/spiritual belief was strongly embraced in 6 EA models compared to 2 ME models and strongly discounted in 2 EA models compared to 5 ME models. Further, family-centric and surrogate's interest-related determinants were strongly embraced in 8 EA models compared to 1 ME model. They were also strongly embraced in 5 P-viewpoint compared to 2 S-viewpoint models and strongly discounted in 4 P-viewpoint compared to 11 S-viewpoint models. Despite the overall predominance of patient's health-related determinants and culture- and viewpoint-dependent differences, Q-methodology analysis identified relatively patient's preference-influenced, religious/spiritual beliefs-influenced, emotion-influenced, and familism-influenced models and showed notable overlap in models., Conclusions: Patient's health was more important than other potential medical surrogate decision making determinants, including patient's preference, for both ME and EA men and in all viewpoints. The relative importance of some determinants was culture- and viewpoint- dependent and allowed description of different albeit overlapping models.

Objective: To evaluate in vitro quality of enteric-coated 50 mg diclofenac sodium tablet formulations on Saudi market., Results: A reference and seven generic (G1-7) formulations were commercially available in December 2019/January 2020 and were assessed within 25-75% of manufacture-expiration period. Weight variation (range as% difference from mean, n = 20), active substance content (ASC, mean (SD) as% difference from label, n = 20), hardness (mean (SD), n = 10), and friability (% weight loss, n = 20) were 97-103%, 102.0% (3.4%), 15.4 (1.1) kg, and 0.24%, respectively, for the reference. For G2-7, they were ≤ ±5%, 98.6% (4.0%) to 109.9% (1.8%), 11.9 (0.9) to 18.3 (0.8) kg, and ≤ 0.00 to 0.75%, respectively. G1 ASC, hardness, and friability were 111.3% (1.7%), 20.1 (1.7) kg, and 1.10%, respectively. Disintegration time (n = 6) and dissolution profile (n = 8) were also determined. No formulation disintegrated or released ˃ 0.1% of label ASC in 0.1 N HCl for 2 h. The reference disintegrated in 15:00 min:seconds and released a mean (range) of 100% (99-103%) of label ASC by 45 min in phosphate buffer (pH = 6.8). G1-7 disintegrated in 8:53 to 20:37 min:seconds and released 81% (69-90%) (G1) to 109%. Except for borderline performance of G1, all formulations passed in vitro quality tests according to United States Pharmacopoeia.

Background: It is not clear how lay people prioritize the various, sometimes conflicting, interests when they make surrogate medical decisions, especially in non-Western cultures. The extent such decisions are perspective-related is also not well documented., Methods: We explored the relative importance of 28 surrogate decision-making factors to 120 Middle-Eastern (ME) and 120 East-Asian (EA) women from three perspectives, norm-perception (N), preference as patient (P), and preference as surrogate decision-maker (S). Each respondent force-ranked (one to nine) 28 opinion-items according to each perspective. Items' ranks were analyzed by averaging-analysis and Q-methodology., Results: Respondents' mean (SD) age was 33.2 (7.9) years; all ME were Muslims, 83% of EA were Christians. "Trying everything possible to save patient," "Improving patient health," "Patient pain and suffering," and/or "What is in the best interests of patient" were the three most-important items, whereas "Effect of caring for patient on all patients in society," "Effect of caring for patient on patients with same disease," and/or "Cost to society from caring for patient" were among the three least-important items, in each ME and EA perspectives. P-perspective assigned higher mean ranks to family and surrogate's needs and burdens-related items, and lower mean rank to "Fear of loss" than S-perspective (p<0.001). ME assigned higher mean ranks to "Medical facts" and "Surrogate own wishes for patient" and lower mean rank to "Family needs" in all perspectives (p<0.001). Q-methodology identified models that were relatively patient's preference-, patient's religious/spiritual beliefs-, or emotion-dependent (all perspectives); medical facts-dependent (N- and S-perspectives), financial needs-dependent (P- and S-perspectives), and family needs-dependent (P-perspective)., Conclusions: 1) Patient's health was more important than patient's preference to ME and EA women; society interest was least important. 2) Family and surrogate's needs/ burdens were more important, whereas fear of loss was less important to respondents as patients than as surrogate decision-makers. 3) Family needs were more important to EA than ME respondents, the opposite was true for medical facts and surrogate's wishes for patient. 4) Q-methodology models that relatively emphasized various surrogate decision-making factors overlapped the ME and EA women' three perspectives.

The aim of the study was to develop and validate a practical assay of clinically relevant testosterone levels in human plasma and saliva. We performed ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis on Atlantis dC18 steel column using a mobile phase of 2-mM ammonium acetate and acetonitrile (20:80, v: v) that was delivered at 0.3 ml/min. After adding d3-testosterone as an internal standard (IS), we extracted plasma and salivary samples with methyl tert-butyl ether. Mass spectrometry was performed in electrospray positive-ion mode. Targeted ion transitions were examined at m/z 289.18 → 97.04 and 292.24 → 97.04 for testosterone and IS, respectively. We validated the method according to the US Food and Drug Administration guidelines. Elution times for testosterone and IS were both around 1.35 min. Testosterone level was linearly associated ( r 2 = 0.9975 and 0.9958) with peak area ratio of testosterone to IS between 0.5-50 ng/ml and 10-400 pg/ml in plasma and saliva, respectively. The coefficient of variation and bias were ≤12.6% and ≤±12.1% in plasma and ≤10.2% and ≤±5.3% in saliva. The extraction recovery of testosterone was ≥92% from plasma and ≥94% from saliva. Testosterone was stable (≥91%) for 24 h at room temperature and for 8 weeks at -20°C in both plasma and salivary samples. We report a simple, validated, UPLC-MS/MS assay that can be used to determine clinically relevant levels of testosterone in human plasma and saliva., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Journal of Advanced Pharmaceutical Technology & Research.)

Background: Circumferential negative pressure wound therapy is commonly used to manage wounds and enhance the healing process. A theoretical concern was recently raised that circumferential negative pressure wound therapy may have a negative effect on perfusion distally., Methods: In a randomized study, we applied circumferential negative pressure (125 mm Hg) to the midarm of 13 healthy volunteers through InfoV.A.C. Therapy Unit device. The pressure was applied intermittently (5 minutes on and 2 minutes off) for 9 hours. The same device without negative pressure was applied to the contralateral midarm as control. Bilateral index finger O2 saturation (SpO2) was measured every 30 minutes using digital pulse oximetry., Results: Mean (SD) age of the volunteers was 32.2 (9.5) years, and 61.5% were male. Mean (SD) area under the curve from time 0 to 9 hours of SpO2 was 890.56 (6.69) and 889.71 (6.23) %xh in the intervention and control arms, respectively (P = 0.35). O2 saturation was ≥94% at all observation times in both arms, and no adverse events were identified., Conclusions: Circumferential negative intermittent pressure of 125 mm Hg applied to the midarm of healthy volunteers for 9 hours does not adversely affect digital SpO2.

Background: Measuring both serum amylase and lipase in the setting of acute pancreatitis is not recommended and monitoring changes in amylase and lipase levels after diagnostic results is of little added value. The extent of the two types of superfluous amylase/lipase testing at our institution is unknown., Objective: Explore the extent of superfluous amylase/lipase testing., Design: Medical record review., Settings: Tertiary care, teaching hospital., Patients and Methods: We retrospectively reviewed all amylase and lipase tests performed over a recent 12-month period. Amylase tests were considered superfluous if they were ordered with lipase tests at the same time or if they were repeated after diagnostic amylase results. They were considered questionably superfluous if they were repeated alone after non-diagnostic amylase results. Lipase tests were considered superfluous if they were repeated after diagnostic lipase results and questionably superfluous if they were repeated after non-diagnostic lipase results., Main Outcome Measures: Number and percentage of lipase and amylase tests that were superfluous or questionably superfluous., Sample Size: 23 950., Results: Superfluous testing was identified in 30.6% of 23 950 amylase/lipase tests and questionably superfluous testing in 12.4%. Of the 7330 superfluous tests, 94.8% were due to simultaneous amylase/lipase testing and 5.2% to repeated lipase testing after diagnostic results. The rate of superfluous and questionably superfluous testing was significantly higher in the inpatient setting compared to emergency department or outpatient settings ( P<.0001). Of the 6483 amylase tests obtained simultaneously with non-diagnostic lipase tests, only 36 (0.6%) showed a diagnostic result. Furthermore, only 0.7% and 3.6% of amylase tests that were repeated after normal and borderline results, respectively, were diagnostic and 1.1% and 9.3% of lipase tests that were repeated after normal and borderline results, respectively, were diagnostic., Conclusions: About one third of amylase/lipase testing appears to be superfluous, mainly due to simultaneous amylase/lipase testing. Since only 0.6% of simultaneous amylase/lipase tests showed diagnostic amylase with non-diagnostic lipase levels, quality improvement initiatives should be directed at reducing this low-value practice. Repeating amylase/lipase tests following normal results is of little value., Limitations: Clinical notes and imaging studies were not reviewed., Conflict of Interest: None.

Background: Substituted judgment assumes adequate knowledge of patient's mind-set. However, surrogates' prediction of individual healthcare decisions is often inadequate and may be based on shared background rather than patient-specific knowledge. It is not known whether surrogate's prediction of patient's integrative life-story narrative is better., Methods: Respondents in 90 family pairs (30 husband-wife, 30 parent-child, 30 sibling-sibling) rank-ordered 47 end-of-life statements as life-story narrative measure (Q-sort) and completed instruments on decision-control preference and healthcare-outcomes acceptability as control measures, from respondent's view (respondent-personal) and predicted pair's view (respondent-surrogate). They also scored their confidence in surrogate's decision-making (0 to 4 = maximum) and familiarity with pair's healthcare-preferences (1 to 4 = maximum). Life-story narratives' prediction was examined by calculating correlation of statements' ranking scores between respondent-personal and respondent-surrogate Q-sorts (projection) and between respondent-surrogate and pair-personal Q-sorts before (simulation) and after controlling for correlation with respondent-personal scores (adjusted-simulation), and by comparing percentages of respondent-surrogate Q-sorts co-loading with pair-personal vs. respondent-personal Q-sorts. Accuracy in predicting decision-control preference and healthcare-outcomes acceptability was determined by percent concordance. Results were compared among subgroups defined by intra-pair relationship, surrogate's decision-making confidence, and healthcare-preferences familiarity., Results: Mean (SD) age was 35.4 (10.3) years, 69% were females, and 73 and 80% reported ≥ very good health and life-quality, respectively. Mean surrogate's decision-making confidence score was 3.35 (0.58) and 75% were ≥ familiar with pair's healthcare-preferences. Mean (95% confidence interval) projection, simulation, and adjusted-simulation correlations were 0.68 (0.67-0.69), 0.42 (0.40-0.44), and 0.26 (0.24-0.28), respectively. Out of 180 respondent-surrogate Q-sorts, 24, 9, and 32% co-loaded with respondent-personal, pair-personal, or both Q-sorts, respectively. Accuracy in predicting decision-control preference and healthcare-outcomes acceptability was 47 and 52%, respectively. Surrogate's decision-making confidence score correlated with adjusted-simulation's correlation score (rho = 0.18, p = 0.01). There were significant differences among the husband-wife, parent-child, and sibling-sibling subgroups in percentage of respondent-surrogate Q-sorts co-loading with pair-personal Q-sorts (38, 32, 55%, respectively, p = 0.03) and percent agreement on healthcare-outcomes acceptability (55, 35, and 67%, respectively, p = 0.002)., Conclusions: Despite high self-reported surrogate's decision-making confidence and healthcare-preferences familiarity, family surrogates are variably inadequate in simulating life-story narratives. Simulation accuracy may not follow the next-of-kin concept and is 38% based on shared background.

A simple ultraperformance liquid chromatography-tandem mass spectrometry assay for measurement of cortisol level in human saliva was developed and validated. Saliva samples containing cortisol were spiked with tolperisone as internal standard (IS) and extracted with a mixture of methyl tert-butyl ether and hexane (8:2, v:v). After solvent evaporation, residue was reconstituted in 100 μ l mobile phase. Analysis was performed on Atlantis dC18 column (2.1 × 100 mm, 3 μ m particle size) with a mobile phase composed of acetonitrile and 2 mM ammonium acetate (50:50, v:v) and delivered at a flow rate of 0.3 ml/minute. Mass spectrometry acquisition was performed with multiple reaction monitoring in positive-ion mode for cortisol and IS (m/z: 363.1 → 121.0 and 246.0 → 97.9, respectively). Retention times of cortisol and IS were about 1.35 and 2.45 minutes, respectively. The relationship between cortisol level and peak area ratio of cortisol to IS was linear in the range of 0.5-100 ng/ml. Intra- and interday coefficient of variation and bias were ≤ 9.0% and ≤12.0%, respectively. Mean extraction recoveries of cortisol and IS from saliva samples were 92% and 94%, respectively. Using the method, cortisol was found to be ≥ 86% stable in processed (24 hours at room temperature or 48 hours at -20°C) and ≥ 91% stable in unprocessed (24 hours at room temperature or 20 weeks at -20°C) saliva samples. Further, the method was successfully applied to determine daily cortisol profile in saliva samples of a healthy volunteer.

Background: Vitamin-D2 (D2) treatment has been associated with a decrease in 25-hydroxy (25(OH)) vitamin-D3 (D3) level, suggesting that D3 treatment would be preferred to raise total 25(OH) vitamin-D (D) level. We postulated that D2 treatment-associated decrease in 25(OH)D3 level is related to the increase in 25(OH)D level rather than being D2-specific, and thus there would be a similar D3 treatment-associated decrease in 25(OH)D2 level., Methods: Fifty volunteers were block-randomized to 50,000 IU D2 or placebo orally once (study-1) and fifty volunteers received 50,000 IU D2 orally once and 4 days later block-randomized to 50,000 IU D3 or placebo orally once (study-2). Interventions were concealed from volunteers and research coordinators and blindly-administered. Serum 25(OH)D2 and 25(OH)D3 levels were blindly-determined at baseline and days 14, 28, 42, and 56, post-randomization by high performance liquid chromatography assay. Results of 97 participants were analyzed. Primary outcome measure was day-28 D2-associated change in 25(OH)D3 level in study-1 and D3-associated change in 25(OH)D2 level in study-2, adjusted for baseline levels., Results: Mean (95% confidence interval) difference between the active and placebo arms in the decrease in day-28 25(OH)D3 (study-1) and 25(OH)D2 (study-2) levels was 13.2 (9.7 to 16.6) and 9.8 (5.2 to 14.4) nmol/L, respectively. Corresponding differences at day-56 were 10.8 (6.8 to 14.8) and 1.7 (- 7.6 to 11.1) nmol/L, respectively. The difference between the placebo and active arms in area-under-the-curve at day-28 (AUC 28 ) and day-56 (AUC 56 ) were 262.3 (197.8 to 326.7) and 605.1 (446.3 to 784.0) for 25(OH)D3 (study-1) and 282.2 (111.2 to 453.3) and 431.2 (179.3 to 683.2) nmol.d/L for 25(OH)D2 (study-2), respectively. There were significant correlations between day-28 changes in 25(OH)D2 and 25(OH)D3 levels in study-1 (rho = - 0.79, p < 0.001) and study-2 (rho = - 0.36, p = 0.01), and between day-28 changes in 25(OH)D2 level and baseline 25(OH)D level in study-2 (rho = - 0.42, p = 0.003)., Conclusions: Compared to placebo, D3 treatment is associated with a decrease in 25(OH)D2 level similar in magnitude to D2-treatment associated decrease in 25(OH)D3 level; however, the D3-placebo difference in 25(OH)D2 level is shorter-lasting. Changes in 25(OH)D2 and 25(OH)D3 levels are correlated with each other and with baseline 25 (OH) D levels, suggesting a common regulatory mechanism., Trial Registration: ClinicalTrial.gov identifier: NCT03035084 (registered January 27, 2017).

Background: Limited sampling strategy (LSS) is a validated method to estimate pharmacokinetic (PK) parameters from a reduced number of samples. Omeprazole is used to phenotype in vivo cytochrome P450 (CYP) 2C19 activity. This study examined an LSS using 2 estimation methods to determine apparent oral clearance (CL/F) and thus CYP2C19 activity., Methods: Data from 7 previously published studies included healthy subjects receiving a single, oral dose of omeprazole with intensive PK sampling. CL/F was estimated using noncompartmental analysis (NCA) and population PK modeling. LSS was simulated by selecting the 1, 2, 4, and/or 6-hour postdose time points. Linear regression was performed to assess whether CL/F estimated from limited sampling could accurately predict CL/F from the full PK profile., Results: Median CL/F was 23.7 L/h by NCA and 19.3 L/h by population PK modeling. In comparing the LSS NCA estimated versus observed CL/F, all evaluated linear regression models had unacceptable coefficients of determination (r, range: 0.14-0.81). With the population PK approach, 737 plasma concentrations (n = 71) and CYP2C19 genotype data were described with a 1-compartment structural model with mixed zero and first-order absorption and lag time. In comparing the population PK LSS estimated versus observed CL/F, all evaluated linear regression models had unacceptable r (range: 0.02-0.74). Post hoc comparison of CYP2C19 poor metabolizers versus CYP2C19 extensive metabolizers resulted in significantly lower CL/F in poor metabolizers versus extensive metabolizers., Conclusions: Omeprazole LSS performed poorly in estimating CL/F using 2 separate estimation approaches and does not seem to be a suitable method for determining CYP2C19 activity.

Background: The extents of generic-reference and generic-generic average bioequivalence and intra-subject variation of on-market drug products have not been prospectively studied on a large scale., Methods: We assessed bioequivalence of 42 generic products of 14 immediate-release oral drugs with the highest number of generic products on the Saudi market. We conducted 14 four-sequence, randomized, crossover studies on the reference and three randomly-selected generic products of amlodipine, amoxicillin, atenolol, cephalexin, ciprofloxacin, clarithromycin, diclofenac, ibuprofen, fluconazole, metformin, metronidazole, paracetamol, omeprazole, and ranitidine. Geometric mean ratios of maximum concentration (C max ) and area-under-the-concentration-time-curve, to last measured concentration (AUC T ), extrapolated to infinity (AUC I ), or truncated to C max time of reference product (AUC Reftmax ) were calculated using non-compartmental method and their 90% confidence intervals (CI) were compared to the 80.00%-125.00% bioequivalence range. Percentages of individual ratios falling outside the ±25% range were also determined., Results: Mean (SD) age and body-mass-index of 700 healthy volunteers (28-80/study) were 32.2 (6.2) years and 24.4 (3.2) kg/m 2 , respectively. In 42 generic-reference comparisons, 100% of AUC T and AUC I CIs showed bioequivalence, 9.5% of C max CIs barely failed to show bioequivalence, and 66.7% of AUC Reftmax CIs failed to show bioequivalence/showed bioinequivalence. Adjusting for 6 comparisons, 2.4% of AUC T and AUC I CIs and 21.4% of C max CIs failed to show bioequivalence. In 42 generic-generic comparisons, 2.4% of AUC T , AUC I , and C max CIs failed to show bioequivalence, and 66.7% of AUC Reftmax CIs failed to show bioequivalence/showed bioinequivalence. Adjusting for 6 comparisons, 2.4% of AUC T and AUC I CIs and 14.3% of C max CIs failed to show bioequivalence. Average geometric mean ratio deviation from 100% was ≤3.2 and ≤5.4 percentage points for AUC I and C max , respectively, in both generic-reference and generic-generic comparisons. Individual generic/reference and generic/generic ratios, respectively, were within the ±25% range in >75% of individuals in 79% and 71% of the 14 drugs for AUC T and 36% and 29% for C max ., Conclusions: On-market generic drug products continue to be reference-bioequivalent and are bioequivalent to each other based on AUC T , AUC I , and C max but not AUC Reftmax . Average deviation of geometric mean ratios and intra-subject variations are similar between reference-generic and generic-generic comparisons., Trial Registration: ClinicalTrials.gov identifier: NCT01344070 (registered April 3, 2011).

Background Average bioequivalence has been criticized for not adequately addressing individual variations. Importance of subjects' blinding in bioequivalence studies has not been well studied. We explored the extent of intra-subject pharmacokinetic variability and effect of drug-ingestion unawareness in subjects taking single caffeine product. Methods A single-dose randomized cross-over design was used to compare pharmacokinetics of 200 mg caffeine, described as caffeine (overt) or as placebo (covert). Maximum concentration (C max ), C max first time (T max ), area-under-the-concentration-time-curve, to last measured concentration (AUC T ), extrapolated to infinity (AUC I ), or to T max of overt caffeine (AUC Overttmax ), and C max /AUC I were calculated blindly using standard non-compartmental method. Percentages of individual covert/overt ratios that are outside the ±25% range were determined. Covert-vs-overt effect on caffeine pharmacokinetics was evaluated by 90% confidence interval (CI) and 80.00-125.00% bioequivalence range. Results 32 healthy subjects (6% females, mean (SD) age 33.3 (7.2) year) participated in the study (28 analysed). Out of the 28 individual covert/overt ratios, 23% were outside the ±25% range for AUC T , 30% for AUC I , 20% for AUC Overttmax , 30% for C max , and 43% for T max . There was no significant covert-vs-overt difference in any of the pharmacokinetic parameters studied. Further, the 90% CIs for AUC T , AUC I , C max , AUC Overttmax , and C max /AUC I were all within the 80.00-125.00% bioequivalence range with mean absolute deviation of covert/overt ratios of 3.31%, 6.29%, 1.43%, 1.87%, and 5.19%, respectively. Conclusions Large intra-subject variability in main caffeine pharmacokinetic parameters was noted when comparing an oral caffeine product to itself. Subjects' blinding may not be important in average bioequivalence studies., Competing Interests: Conflict of interest: The authors declare that there is no conflict of interests., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Medication effect is the sum of its drug, placebo, and drug*placebo interaction effects. It is conceivable that the interaction effect involves modulating drug bioavailability; it was previously observed that being aware of caffeine ingestion may prolong caffeine plasma half-life. This study was set to evaluate such concept using different drugs., Methods: Balanced single-dose, two-period, two-group, cross-over design was used to compare the pharmacokinetics of oral cephalexin, ibuprofen, and paracetamol, each described by its name (overt) or as placebo (covert). Volunteers and study coordinators were deceived as to study aim. Drug concentrations were determined blindly by in-house, high performance liquid chromatography assays. Terminal-elimination half-life (t ½ ) (primary outcome), maximum concentration (C max ), C max first time (T max ), terminal-elimination-rate constant (λ), area-under-the-concentration-time-curve, to last measured concentration (AUC T ), extrapolated to infinity (AUC I ), or to T max of overt drug (AUC Overttmax ), and C max /AUC I were calculated blindly using standard non-compartmental method. Covert-vs-overt effect on drug pharmacokinetics was evaluated by analysis-of-variance (ANOVA, primary analysis), 90% confidence interval (CI) using the 80.00-125.00% bioequivalence range, and percentage of individual pharmacokinetic covert/overt ratios that are outside the +25% range., Results: Fifty, 30, and 50 healthy volunteers (18%, 10%, and 6% females, mean (SD) age 30.8 (6.2), 31.4 (6.6), and 31.2 (5.4) years) participated in 3 studies on cephalexin, ibuprofen, and paracetamol, respectively. Withdrawal rate was 4%, 0%, and 4%, respectively. Eighteen blood samples were obtained over 6, 10, and 14 h in each study period of the three drugs, respectively. ANOVA showed no significant difference in any pharmacokinetic parameter for any of the drugs. The 90% CIs for AUC T , AUC I , C max , AUC Overttmax , and C max /AUC I were within the bioequivalence range, except for ibuprofen C max (76.66-98.99), ibuprofen C max /AUC I (77.19-98.39), and ibuprofen (45.32-91.62) and paracetamol (51.45-98.96) AUC Overttmax . Out of the 126 individual covert/overt ratios, 2.0-16.7% were outside the +25% range for AUC T , 2.0-4.2% for AUC I , 25.0-44.9% for C max , 67.3-76.7% for AUC Overttmax , and 45.8-71.4% for T max ., Conclusions: This study couldn't confirm that awareness of drug ingestion modulates its bioavailability. However, it demonstrates the trivial effect of blinding in bioequivalence studies and the extent of bio-variability that would be expected when comparing a drug product to itself., Trial Registration: ClinicalTrials.gov identifier: NCT01501747 (registered Dec 26, 2011).

Background: Vitamin D (D) supplements are indispensable for its world-wide deficiency. Controversy continues on ergocalciferol (D2) and cholecalciferol (D3) relative potency as well as on dosing-schedule and sex role in raising 25-hydroxy D (25(OH)D) level, the best indicator of D status., Methods: We randomized 279 adults to daily D2, D3, D2/D3, or placebo; 2-weekly D2 or D3; or 4-weekly D2 or D3 (250,000 IU over/140 days). Randomization sequence, stratified by body-mass-index (BMI) and sex, was concealed from study coordinators and participants who were then blinded to capsules' content. D2, D3, 25(OH)D2, and 25(OH)D3 Serum levels were determined blindly on days 0,1,2,3,4,7,14, and 2-weekly thereafter by high performance liquid chromatography assay. The results of 269 participants were available for analysis. Primary endpoint was area-under-the-curve (AUC) of 25(OH)D (25(OH)D2 + 25(OH)D3) adjusted for sex, BMI, and baseline 25(OH)D level., Results: Mean(SD) age was 33.0(8.5) year, 41% were males, and 85% completed follow-up. Baseline 25(OH)D level was 39.8(11.9) and increased by 3.3(11.6) and 28.6(16.3) nmol/L, in the placebo and active-treatment groups, respectively. AUC from day 0 to 140 (AUC 140 ) of 25(OH)D was 40% (D3 daily) to 55% (D3 2-weekly) higher with active-treatment than placebo (p < 0.001). 25(OH)D2 AUC 140 was higher in daily than 2-weekly (17%, p = 0.006) and 4-weekly (20%, p = 0.001) D2-treated groups. 25(OH)D3 AUC 140 was lower in daily than 2-weekly (11%, p = 0.002) and 4-weekly D3-treated groups (10%, p = 0.008). In D2-treated groups, there was 16.4 nmol/L decrease in 25(OH)D3 level that correlated (p < 0.001) with 25(OH)D2 level increase (r = 0.48) and baseline 25(OH)D level (r = 0.58), in one participant with measurable baseline 25(OH)D2 level, D3 caused a similar decrease in 25(OH)D2 level, while in the D2/D3-treated group, 25(OH)D3 level didn't increase. Incremental AUC from day 0 to 7 (AUC 7 ) of D3 and 25(OH)D3 in D3-treated groups were 118-243% higher and 31-39% lower, respectively, than incremental AUC 7 of D2 and 25(OH)D2 in D2-treated groups. Incremental AUC 7 of D3 and 25(OH)D3 in D3-treated groups and D2 and 25(OH)D2 in D2-treated groups were higher in females than males (55, 13, 64, and 28%, respectively). Baseline 25(OH)D level predicted response to D2 and D3 (p < 0.001), whereas, BMI was significant predictor only for early response to D2., Conclusions: Effects of D2 and D3 supplements on 25 (OH)D level may be dosing-schedule and sex-dependent. D2-associated reduction in 25(OH)D3 level may be related to total 25(OH)D level rather than being D2-specific. D2 may be 25-hydroxylated faster than D3., Trial Registration: ClinicalTrial.gov identifier: NCT01170494 (registered July 25, 2010).

Background: Conventional randomized placebo-controlled study design assumes the absence of drug*placebo interaction. We hypothesized the presence of such an interaction and that conventionally estimated drug effect might be biased. The objectives of the study were to determine the drug*placebo interaction effect (main) and compare conventionally estimated and interaction model-estimated drug effects (secondary)., Methods: We used a hybrid of balanced placebo and randomized placebo-controlled designs. Four hundred eighty healthy volunteers were randomized to three groups. The first received hydroxyzine (25 mg) described as hydroxyzine or placebo, the second received placebo described as hydroxyzine or placebo, and the third received hydroxyzine and placebo described as unknown; each in a randomized crossover design. Seven participants failed to crossover. Group assignment was concealed from participants and study coordinators. Coordinators were blinded to group and intervention assignment. Participants and coordinators were deceived as to study objectives. Main outcomes were mean area-under-the-curve of drowsiness (therapeutic outcome) and mouth-dryness (adverse outcome), self-reported on 100 mm visual analog scale over 7 h. Drug, placebo, placebo + interaction, and total effects were estimated using analysis of covariance by comparing received hydroxyzine/told placebo to received placebo/told placebo, received placebo/told hydroxyzine to received placebo/told placebo, received hydroxyzine/told hydroxyzine to received hydroxyzine/told placebo, and received hydroxyzine/told hydroxyzine to received placebo/told placebo, respectively. Drug effect was also conventionally estimated in the third group., Results: Mean (SD) age was 31.4 (6.6) years, 65% were males. There was significant difference between placebo + interaction effect and placebo effect for both drowsiness and mouth-dryness with a mean difference (95% confidence interval) of 35.1 (5.6 to 64.6) and 23.8 (2.4 to 45.2) mm*hr, respectively. Total effect was larger than the sum of drug and placebo effects for drowsiness (139.7 (109.8 to 169.6) vs. 99.1 (68.2 to 130.0) mm*hr) and mouth-dryness (63.6 (41.1 to 86.1) vs. 34.7 (11.1 to 58.4) mm*hr). Conventionally estimated drug effect was larger than interaction model-estimated drug effect for drowsiness (69.2 (45.5 to 92.8) vs. (58.3 (31.6 to 85.0) mm*hr) and mouth-dryness (19.9 (5.3 to 34.5) vs. 9.5 (-9.2 to 28.1) mm*hr)., Conclusions: There is significant and important drug*placebo interaction effect that may bias conventionally estimated drug effect., Trial Registration: ClinicalTrial.gov identifier: NCT01501591 (registered December 25, 2011).

Background: Vitamin D deficiency is common in many countries, including Saudi Arabia. Various population-level preventive measures have been implemented, including milk fortification with vitamin D., Objectives: The main objective of the study was to determine vitamin D levels in fortified low fat cow milk on the Saudi Arabian market and to compare it with the label claims., Design: Cross-sectional study., Setting: Academic research center., Materials and Methods: Five milk batches from five major producers were purchased in five replicates from five major retail stores in Riyadh, Saudi Arabia. We used a validated liquid chromatography assay to measure vitamin D levels. All samples were producer labeled to contain 400 IU/L (10 ng/mL) vitamin D and were analyzed within the first 40% of their validity period. Intra-batch, inter-batch, and inter-producer variations were determined as a coefficient of variation., Main Outcome Measures: Intra-batch, inter-batch and inter-producer variations in vitamin D level., Results: Overall, mean (SD) measured vitamin D level was 10.2 (1.6) with a range of 7.1-13.9 ng/mL. In 25 of 125 samples (20%), the vitamin D level was outside +/- 20% of the label claim (10.4% under-fortified, 9.6% over fortified). Intra-batch, inter-batch, and intra-producer variations were 1.6 -20.8%, 8.2-20.8%, and 16.1%, respectively., Conclusions: Vitamin D content in fortified low fat cow milk on the Riyadh market matches label claim in 85% of the samples of major retailers. Variations from label claim in 15% of the samples are small and may not be clinically important., Limitations: This study was limited to five major retailers in the Riyadh area and did not examine full-fat or non-fat milk samples.

Background: Quality end-of-life care depends on understanding patients' end-of-life choices. Individuals and cultures may hold end-of-life priorities at different hierarchy. Forced ranking rather than independent rating, and by-person factor analysis rather than averaging may reveal otherwise masked typologies., Methods: We explored Saudi males' forced-ranked, end-of-life priorities and dis-priorities. Respondents (n = 120) rank-ordered 47 opinion statements on end-of-life care following a 9-category symmetrical distribution. Statements' scores were analyzed by averaging analysis and factor analysis (Q-methodology)., Results: Respondents' mean age was 32.1 years (range, 18-65); 52% reported average religiosity, 88 and 83% ≥ very good health and life-quality, respectively, and 100% ≥ high school education. Averaging analysis revealed that the extreme five end-of-life priorities were to, be at peace with God, be able to say the statement of faith, maintain dignity, resolve conflicts, and have religious death rituals respected, respectively. The extreme five dis-priorities were to, die in the hospital, not receive intensive care if in coma, die at peak of life, be informed about impending death by family/friends rather than doctor, and keep medical status confidential from family/friends, respectively. Q-methodology classified 67% of respondents into five highly transcendent opinion types. Type-I (rituals-averse, family-caring, monitoring-coping, life-quality-concerned) and Type-V (rituals-apt, family-centered, neutral-coping, life-quantity-concerned) reported the lowest and highest religiosity, respectively. Type-II (rituals-apt, family-dependent, monitoring-coping, life-quantity-concerned) and Type-III (rituals-silent, self/family-neutral, avoidance-coping, life-quality & quantity-concerned) reported the best and worst life-quality, respectively. Type-I respondents were the oldest with the lowest general health, in contrast to Type-IV (rituals-apt, self-centered, monitoring-coping, life-quality/quantity-neutral). Of the extreme 14 priorities/dis-priorities for the five types, 29, 14, 14, 50, and 36%, respectively, were not among the extreme 20 priorities/dis-priorities identified by averaging analysis for the entire cohort., Conclusions: 1) Transcendence was the extreme end-of-life priority, and dying in the hospital was the extreme dis-priority. 2) Quality of life was conceptualized differently with less emphasize on its physiological aspects. 3) Disclosure of terminal illness to family/close friends was preferred as long it is through the patient. 4) Q-methodology identified five types of constellations of end-of-life priorities and dis-priorities that may be related to respondents' demographics and are partially masked by averaging analysis.

Background: Normalization of cortisol concentration by multikinase inhibitors have been reported in three patients with medullary thyroid cancer-related Cushing's syndrome. Aortic dissection has been reported in three patients with Cushing's syndrome. Diabetes insipidus without intrasellar metastasis, intestinal intussusception, and paraneoplastic dysautonomia have not been reported in medullary thyroid cancer., Case Presentation: An adult male with metastatic medullary thyroid cancer presented with hyperglycemia, hypernatremia, hypokalemia, hypertension, acne-like rash, and diabetes insipidus (urine volume >8 L/d, osmolality 190 mOsm/kg). Serum cortisol, adrenocorticoitropic hormone, dehydroepiandrostenedione sulfate, and urinary free cortisol were elevated 8, 20, 4.4, and 340 folds, respectively. Pituitary imaging was normal. Computed tomography scan revealed jejunal intussusception and incidental abdominal aortic dissection. Sorafenib treatment was associated with Cushing's syndrome remission, elevated progesterone (>10 fold), normalization of dehydroepiandrostenedione sulfate, but persistently elevated cortisol concentration. Newly-developed proximal lower limb weakness and decreased salivation were associated with elevated ganglionic neuronal acetylcholine receptor (alpha-3) and borderline P/Q type calcium channel antibodies., Conclusion: Extreme cortisol concentration may have contributed to aortic dissection and suppressed antidiuretic hormone secretion; which combined with hypokalemia due cortisol activation of mineralocorticoid receptors, manifested as diabetes insipidus. This is the first report of paraneoplastic dysautonomia and jejunal intussusception in medullary thyroid cancer, they may be related to medullary thyroid cancer's neuroendocrine origin and metastasis, respectively. Remission of Cushing's syndrome without measurable reduction in cortisol concentration suggests a novel cortisol-independent mechanism of action or assay cross-reactivity. Normalization of dehydroepiandrostenedione sulfate and elevation of progesterone suggest inhibition of 17-hydroxylase and 21-hydroxylase activities by sorafenib.

Background: Although informed consent is an integral part of clinical practice, its current doctrine remains mostly a matter of law and mainstream ethics rather than empirical research. There are scarce empirical data on patients' perceived purpose of informed consent, which may include administrative routine/courtesy gesture, simple honest permission, informed permission, patient-clinician shared decision-making, and enabling patient's self decision-making. Different purposes require different processes., Methods: We surveyed 488 adults who were planning to undergo or had recently undergone written informed consent-requiring procedures. Perceptions of informed consent purpose (from norm and current practice perspectives) were explored by asking respondents to rank (1 = most reflective) 10 randomly-presented statements: "meaningless routine", "courtesy gesture" "litigation protection", "take away compensation rights", "inform patient', "make sure patient understand", "document patient's decision", "discover patient's preferences", "have shared decision", and "help patient decide"., Results: Respondents' mean (SD) age was 38.3 (12.5); 50.4% were males, 56.8% had ≥ college education, and 37.3% had undergone a procedure. From the norm perspective, the least reflective statement was "meaningless routine" (ranked 1-3 by 2.6% of respondents) and the most reflective statements were "help patient decide", "make sure patient understand", and "inform patient" (ranked 1-3 by 65%, 60%, and 48% of respondents with median [25%,75%] ranking scores of 2 [1,5], 3 [2,4], and 4 [2,5], respectively). Compared to their counterparts, males and pre-procedure respondents ranked "help patient decide" better, whereas females and post-procedure respondents ranked "inform patient" better (p = 0.007 to p < 0.001). Age was associated with better ranking of "help patient decide" and "make sure patient understand" statements (p < 0.001 and p = 0.002, respectively), which were ranked 1-3 by only 46% and 42% of respondents from the current practice perspective (median ranking score 4 [2,6], p < 0.001 vs. norm perspective for both)., Conclusions: 1) the informed consent process is important to patients, however, patients vary in their views of its purpose with the dominant view being enabling patients' self decision-making, 2) males, pre-procedure, and older patients more favor a self decision-making purpose, whereas females and post-procedure patients more favor an information disclosure purpose, and 3) more self decision-making and more effective information disclosure than is currently practiced are desired. An informed consent process consistent with Mill's individual autonomy model may be suitable for most patients.

Background: The current doctrine of informed consent for clinical care has been developed in cultures characterized by low-context communication and monitoring-style coping. There are scarce empirical data on patients' norm perception of information disclosure in other cultures., Methods: We surveyed 470 adults who were planning to undergo or had recently undergone a written informed consent-requiring procedure in a tertiary healthcare hospital in Saudi Arabia. Perceptions of norm and current practice were explored using a 5-point Likert scale (1 = strongly agree with disclosure) and 30 information items in 7 domains: practitioners' details, benefits, risks, complications' management, available alternatives, procedure's description, and post-procedure's issues., Results: Respondents' mean (SD) age was 38.4 (12.5); 50.2% were males, 57.2% had ≥ college education, and 37.9% had undergone a procedure. According to norm perception, strongly agree/agree responses ranged from 98.0% (major benefits) to 50.5% (assistant/trainee's name). Overall, items related to benefits and post-procedure's issues were ranked better (more agreeable) than items related to risks and available alternatives. Ranking scores were better in post-procedure respondents for 4 (13.3%) items (p < 0.001 to 0.001) and in males for 8 (26.7%) items (p = 0.008 to <0.001). Older age was associated with better ranking scores for 3 (10.0%) items and worse for one (p < 0.001 to 0.006). According to current practice perception, strongly agree/agree responses ranged from 93.3% (disclosure of procedure's name) to 13.9% (lead practitioner's training place), ranking scores were worse for all items compared to norm perception (p < 0.001), and post-procedure status, younger age, and lower educational level were associated with better ranking scores for 15 (50.0%), 12 (40.0%), and 4 (13.3%) items, respectively (p < 0.001 to 0.009)., Conclusions: 1) even in an overall high-context communication culture, extensive and more information than is currently disclosed is perceived as norm, 2) the focus of the desired information is closer to benefits and post-procedure's issues than risks and available alternatives, 3) male, post-procedure, and older patients are in favor of more information disclosure, 4) male, older, and more educated patients may be particularly dissatisfied with current information disclosure. The focus and extent of information disclosure for clinical informed consent may need to be adjusted if a "reasonable" patient's standard is to be met.

Background: Hypothyroidism, commonly induced in preparation for radioiodine treatment of differentiated thyroid cancer, is a text-book cause for hyponatremia. Nausea, stress, and increased fluid intake associated with the treatment are expected to exacerbate hyponatremia., Methods: We prospectively studied 212 (80% females) consecutive thyroid cancer patients for the incidence of hypothyroidism-induced hyponatremia and associated risk factors., Results: Mean(SD) age was 39.7(14.1) year, creatinine 82.0(20.8) μmol/l, TSH 141.6(92.0) mU/l, pre- and post-isolation sodium 139.5(2.3) and 137.8(3.0) mEq/l, respectively, and estimated fluid intake during isolation 9.7(6.2) L. Mild hyponatremia (≥130 mEq/l) was present in 18 patients (8.5%) and moderate hyponatremia (≥120 mEq/l) in 4(1.9%), 3 of the latter had elevated creatinine concentration and 2 were on diuretics. There was no significant correlation between post-isolation sodium concentration and TSH concentration (r = 0.03, p = 0.69) or estimated fluid intake (r = 0.10, p =0.17). There was significant correlation between post-isolation sodium concentration and age (r = -0.24, p < 0.0001) and creatinine concentration (r = -0.22, p = 0.001). Pre-post-isolation drop in sodium concentration was more in females (mean difference 1.21, p = 0.02). Compared to eunatremic patients, hyponatremic patients were more likely to have pre-isolation hyponatremia (9% vs. 0.5%, p = 0.03), elevated creatinine concentration (36% vs. 13%, p = 0.008), and to be on diuretics (23% vs. 1%, p = 0.0001)., Conclusions: In the setting of acute severe hypothyroidism: 1) clinically-important hyponatremia is uncommon; sodium concentration may not need to be monitored unless patients have impaired renal function or are on diuretics, 2) age and female gender are associated with lower sodium concentration. Uncomplicated acute severe hypothyroidism didn't cause clinically-important hyponatremia/SIADH in this cohort of patients.

Background: Posthumous organ procurement is hindered by the consenting process. Several consenting systems have been proposed. There is limited information on public relative attitudes towards various consenting systems, especially in Middle Eastern/Islamic countries., Methods: We surveyed 698 Saudi Adults attending outpatient clinics at a tertiary care hospital. Preference and perception of norm regarding consenting options for posthumous organ donation were explored. Participants ranked (1, most agreeable) the following, randomly-presented, options from 1 to 11: no-organ-donation, presumed consent, informed consent by donor-only, informed consent by donor-or-surrogate, and mandatory choice; the last three options ± medical or financial incentive., Results: Mean(SD) age was 32(9) year, 27% were males, 50% were patients' companions, 60% had ≥ college education, and 20% and 32%, respectively, knew an organ donor or recipient. Mandated choice was among the top three choices for preference of 54% of respondents, with an overall median[25%,75%] ranking score of 3[2,6], and was preferred over donor-or-surrogate informed consent (4[2,7], p < 0.001), donor-only informed consent (5[3,7], p < 0.001), and presumed consent (7[3,10], p < 0.001). The addition of a financial or medical incentive, respectively, reduced ranking of mandated choice to 7[4,9], p < 0.001, and 5[3,8], p < 0.001; for donor-or-surrogate informed consent to 7[5,9], p < 0.001, and 5[3,7], p = 0.004; and for donor-only informed consent to 8[6,10], p < 0.001, and 5[3,7], p = 0.56. Distribution of ranking score of perception of norm and preference were similar except for no-organ donation (11[7,11] vs. 11[6,11], respectively, p = 0.002). Compared to females, males more perceived donor-or-surrogate informed consent as the norm (3[1,6] vs. 5[3,7], p < 0.001), more preferred mandated choice with financial incentive option (6[3,8] vs. 8[4,9], p < 0.001), and less preferred mandated choice with medical incentive option (7[4,9] vs. 5[2,7], p < 0.001). There was no association between consenting options ranking scores and age, health status, education level, or knowing an organ donor or recipient., Conclusions: We conclude that: 1) most respondents were in favor of posthumous organ donation, 2) mandated choice system was the most preferred and presumed consent system was the least preferred, 3) there was no difference between preference and perception of norm in consenting systems ranking, and 4) financial (especially in females) and medical (especially in males) incentives reduced preference.

We evaluated the documentation of ethical conduct (obtaining institutional review board approval and consent and following ethical guidelines) of human subject research studies published in Saudi Arabian medical journals between 1979 and 2007. Studies were classified as retrospective, prospective noninterventional, interventional or survey/interview. Of 1838 studies published in 286 journal issues of 11 Saudi Arabian medical journals, only 0.9% documented the ethical guidelines followed, with a significantly higher rate for studies published after year 2000 (1.7%). Of 821 studies requiring institutional review board approval, 8.6% documented obtaining the approval and informed consent, with a significantly higher rate for interventional studies (19.4%), post-year 2000 studies (19.7%) and studies performed outside Saudi Arabia (15.9%). The low documentation rate suggests editor's lack of rigor and/or investigators' ignorance of guidelines. The higher documentation rate after year 2000 suggests an ongoing improvement.

Background: The consistency of codes governing disclosure of terminal illness to patients and families in Islamic countries has not been studied until now., Objectives: To review available codes on disclosure of terminal illness in Islamic countries. DATA SOURCE AND EXTRACTION: Data were extracted through searches on Google and PubMed. Codes related to disclosure of terminal illness to patients or families were abstracted, and then classified independently by the three authors., Data Synthesis: Codes for 14 Islamic countries were located. Five codes were silent regarding informing the patient, seven allowed concealment, one mandated disclosure and one prohibited disclosure. Five codes were silent regarding informing the family, four allowed disclosure and five mandated/recommended disclosure. The Islamic Organization for Medical Sciences code was silent on both issues., Conclusion: Codes regarding disclosure of terminal illness to patients and families differed markedly among Islamic countries. They were silent in one-third of the codes, and tended to favour a paternalistic/utilitarian, family-centred approach over an autonomous, patient-centred approach.

Several high-performance liquid chromatography (HPLC) methods have been described for the determination of caffeine in human plasma. However, none have been cross validated using synthetic plasma. The present study describes a simple and reliable HPLC method for the determination of the caffeine level in human plasma. Synthetic plasma was used to construct calibration curves and quality control samples to avoid interference by caffeine commonly present in donor's human plasma. After deproteination of plasma samples with perchloric acid, caffeine and antipyrine (internal standard, IS) were separated on a Waters Atlantis C18 column using a mobile phase of 15 mM potassium phosphate (pH 3.5) and acetonitrile (83:17, v/v), and monitored by photodiode array detector, with the wavelength set at 274 nm. The relationship between caffeine concentrations and peak area ratio (caffeine-IS) was linear over the range of 0.05-20 μg/mL. Inter-run coefficient of variation was ≤ 5.4% and ≤ 6.0% and bias was ≤ 3% and ≤ 7% using human and synthetic plasma, respectively. Mean extraction recovery from human plasma of caffeine and the IS was 91% and 86%, respectively. Caffeine in human plasma was stable for at least 24 h at room temperature or 12 weeks at -20 °C, and after three freeze-thaw cycles. The method was successfully applied to monitor caffeine levels in healthy volunteers with correction of caffeine levels using the mean ratio of the slopes of the calibration's curves constructed using human and synthetic plasma.

Background: The total effect of a medication is the sum of its drug effect, placebo effect (meaning response), and their possible interaction. Current interpretation of clinical trials' results assumes no interaction. Demonstrating such an interaction has been difficult due to lack of an appropriate study design., Methods: 180 adults were randomized to caffeine (300 mg) or placebo groups. Each group received the assigned intervention described by the investigators as caffeine or placebo, in a randomized crossover design. 4-hour-area-under-the-curve of energy, sleepiness, nausea (on 100 mm visual analog scales), and systolic blood pressure levels as well as caffeine pharmacokinetics (in 22 volunteers nested in the caffeine group) were determined. Caffeine drug, placebo, placebo-plus-interaction, and total effects were estimated by comparing outcomes after, receiving caffeine described as placebo to receiving placebo described as placebo, receiving placebo described as caffeine or placebo, receiving caffeine described as caffeine or placebo, and receiving caffeine described as caffeine to receiving placebo described as placebo, respectively., Results: The placebo effect on area-under-the-curve of energy (mean difference) and sleepiness (geometric mean ratio) was larger than placebo-plus-interaction effect (16.6 [95% CI, 4.1 to 29.0] vs. 8.4 [-4.2 to 21.0] mm*hr and 0.58 [0.39 to 0.86] vs. 0.69 [0.49 to 0.97], respectively), similar in size to drug effect (20.8 [3.8 to 37.8] mm*hr and 0.49 [0.30 to 0.91], respectively), and its combination with the later was larger than total caffeine effect (29.5 [11.9 to 47.1] mm*hr and 0.37 [0.22 to 0.64]). Placebo-plus-interaction effect increased caffeine terminal half-life by 0.40 [0.12 to 0.68] hr (P=0.007)., Conclusions: Drug and placebo effects of a medication may be less than additive, which influences the interpretation of clinical trials. The placebo effect may increase active drug terminal half-life, a novel mechanism of placebo action., Trial Registration: ClinicalTrials.gov identification number - NCT00426010.

Background: Disclosure of near miss medical error (ME) and who should disclose ME to patients continue to be controversial. Further, available recommendations on disclosure of ME have emerged largely in Western culture; their suitability to Islamic/Arabic culture is not known., Methods: We surveyed 902 individuals attending the outpatient's clinics of a tertiary care hospital in Saudi Arabia. Personal preference and perceptions of norm and current practice regarding which ME to be disclosed (5 options: don't disclose; disclose if associated with major, moderate, or minor harm; disclose near miss) and by whom (6 options: any employee, any physician, at-fault-physician, manager of at-fault-physician, medical director, or chief executive director) were explored., Results: Mean (SD) age of respondents was 33.9 (10) year, 47% were males, 90% Saudis, 37% patients, 49% employed, and 61% with college or higher education. The percentage (95% confidence interval) of respondents who preferred to be informed of harmful ME, of near miss ME, or by at-fault physician were 60.0% (56.8 to 63.2), 35.5% (32.4 to 38.6), and 59.7% (56.5 to 63.0), respectively. Respectively, 68.2% (65.2 to 71.2) and 17.3% (14.7 to 19.8) believed that as currently practiced, harmful ME and near miss ME are disclosed, and 34.0% (30.7 to 37.4) that ME are disclosed by at-fault-physician. Distributions of perception of norm and preference were similar but significantly different from the distribution of perception of current practice (P < 0.001). In a forward stepwise regression analysis, older age, female gender, and being healthy predicted preference of disclosure of near miss ME, while younger age and male gender predicted preference of no-disclosure of ME. Female gender also predicted preferring disclosure by the at-fault-physician., Conclusions: We conclude that: 1) there is a considerable diversity in preferences and perceptions of norm and current practice among respondents regarding which ME to be disclosed and by whom, 2) Distributions of preference and perception of norm were similar but significantly different from the distribution of perception of current practice, 3) most respondents preferred to be informed of ME and by at-fault physician, and 4) one third of respondents preferred to be informed of near-miss ME, with a higher percentage among females, older, and healthy individuals.

Background: Consenting for retrospective medical records-based research (MR) and leftover tissue-based research (TR) continues to be controversial. Our objective was to survey Saudis attending outpatient clinics at a tertiary care hospital on their personal preference and perceptions of norm and current practice in relation to consenting for MR and TR., Methods: We surveyed 528 Saudis attending clinics at a tertiary care hospital in Saudi Arabia to explore their preferences and perceptions of norm and current practice. The respondents selected one of 7 options from each of 6 questionnaires., Results: Respondents' mean (SD) age was 33 (11) years, 42% were males, 56% were patients, 84% had ≥ secondary school education, and 10% had previously volunteered for research. Respectively, 40% and 49% perceived that the norm is to conduct MR and TR without consent and 38% and 37% with general or proposal-specific consent; the rest objected to such research. There was significant difference in the distribution of choices according to health status (patients vs. companions) for MR (adjusted Kruskal-Wallis test P = 0.03) but not to age group, gender, education level, or previous participation in research (unadjusted P = 0.02 - 0.59). The distributions of perceptions of current practice and norm were similar (unadjusted Marginal Homogeneity test P = 0.44 for MR and P = 0.89 for TR), whereas the distributions of preferences and perceptions of norm were different (adjusted P = 0.09 for MR and P = 0.02 for TR). The distributions of perceptions of norm, preferences, and perceptions of current practice for MR were significantly different from those of TR (adjusted P < 0.009 for all)., Conclusions: We conclude that: 1) there is a considerable diversity among Saudi views regarding consenting for retrospective research which may be related to health status, 2) the distribution of perceptions of norm was similar to the distribution of perceptions of current practice but different from that of preferences, and 3) MR and TR are perceived differently in regard to consenting.

Background: Medical chaperones (MC) are underutilised. The influence of Islamic culture on the use of MC is not known., Aim: To examine physicians' use and perception of MC in Islamic culture., Setting: A major tertiary care hospital in Saudi Arabia., Methods: 315 self-administered questionnaires were distributed to attendees of grand rounds of 13 departments., Results: 186 (59%) questionnaires were completed. 64.5% of the respondents were 30-49 years old, 75.8% were men and 31.2% were in training; 79% had a clinic load of under 50 patients per week and 47.8% had postgraduate training (PGT) in an Islamic country. MC were reported to be infrequently (< or =25% of the time) used by 44.1% (69.2% female vs 39% male physicians, p = 0.001; 58.6% in training vs 36.8% attending, p = 0.007; 52.1% PGT in Islamic vs 35.6% in western countries, p = 0.027), offered by 52.7% (78.9% female vs 46.8% male physicians, p<0.001) and requested by 79% of patients. MC were reported to be commonly (>75% of the time) used, offered by physicians and requested by patients by 38.2%, 29% and 7.5% of respondents, respectively. The most frequently cited reasons for not using MC were privacy/confidentiality (36.6%) and understaffing (30.5%). Equal numbers of respondents perceived MC use as a protection for physicians or patients (67.7% and 65.6%, respectively)., Conclusions: MC are underutilised even in Islamic culture, especially among female physicians. Training in western countries is favourably associated with MC use. Underutilisation appears to be related to privacy/confidentiality, understaffing and failure of patients to request a MC.

A randomized, single-dose, crossover study was conducted to assess the bioavailability of two omeprazole (CAS 73590-58-6) capsule formulations, Emilok (test) and a commercially available original preparation (reference), under fasting conditions. A 20 mg dose of each formulation was administered to 36 healthy male volunteers with one-week washout period, 17 blood samples were collected over 12 h, plasma omeprazole concentrations were determined by a locally validated high performance liquid chromatography (HPLC) assay, and omeprazole pharmacokinetic parameters were analyzed by the standard non-compartmental method. Mean +/- SD of Cmax, Tmax, AUC(0 --> t), AUC(0 --> infinity), and t1/2 were 0.41 +/- 0.21 and 0.48 +/- 0.27 microg/ml, 1.98 +/- 1.02 and 1.63 +/- 0.78 h, 0.95 +/- 0.78 and 1.00 +/- 0.90 microg x h/ml, 0.99 +/- 0.81 and 1.04 +/- 0.95 microg x h/ml, and 1.30 +/- 0.64 and 1.14 +/- 0.61 h for the test and reference formulations, respectively. The parametric 90% confidence intervals on mean difference between log-transformed values of the two formulations were within the acceptable bioequivalence range of 80% to 125% for AUC(0 --> t) and AUC(0 --> infinity) (88.63% to 104.98%, and 91.71% to 106.86%, respectively) but not for Cmax (76.27% to 103.63%). ANOVA revealed significant subject's effect for AUC(0 --> t), AUC(0 --> infinity), Cmax, and t1/2 with a ratio of the inter-subject to intra-subject coefficient of variation of 3.66, 3.92, 1.25, and 1.46, respectively. The results confirm the presence of marked individual variations in the pharmacokinetics of omeprazole and indicate that the two formulations are equivalent in relation to the extent but not the rate of absorption.

A randomized, single-dose, crossover study was conducted to assess the bioavailability of two domperidone (CAS 57808-66-9) tablet formulations, Domperidone (test) and a commercially available original preparation (reference) under fasting conditions. A 10 mg dose of each formulation was administered to 36 healthy male volunteers with a one-week washout period, 17 blood samples were collected over 48 h, plasma concentrations of domperidone were analyzed by a locally validated LC-MS-MS assay, and the pharmacokinetic parameters were determined by the standard non-compartmental method. Mean +/- SD maximum concentration (C(max)), time to reach maximum concentration (T(max)), areas under the curve (AUC(0 --> t and AUC(0 --> infininty)), and elimination constant (K(el)) were 17.13 +/- 9.62 and 17.67 +/- 7.97 ng/ml, 0.87 +/- 0.58, and 0.89 +/- 0.33 h, 73.12 +/- 43.37 and 71.45 +/- 35.41 ng x h/ml, 90.32 +/- 48.55 and 87.08 +/- 40.29 ng x h/ml, and 0.069 +/- 0.046 and 0.068 +/- 0.048 h(-1) for the test and reference formulation, respectively. The parametric 90% confidence intervals on the mean difference between log-transformed values of the two formulations were within the acceptable bioequivalence range for AUC(0 --> t) (87.84% to 109.60%), AUC(0 --> infinity) (89.05% to 111.67%) and C(max) (83.28% to 107.50%). ANOVA revealed significant subject's effect for AU4C(0 --> t), AUC((0 -->infinity), C(max), and t1/2 with a ratio of the inter-subject to intra-subject coefficient of variation of 2.10, 1.55, 1.10, and 1.02, respectively. The results indicate that the two formulations are equivalent in relation to the extent and rate of absorption and confirm the previously reported marked intra-individual variations in the pharmacokinetics of domperidone.

A randomized single-dose cross-over study was conducted on 24 healthy male volunteers to compare the bioavailability of two metformin (CAS 657-24-9) tablet formulations, Emiphage (test) and a commercially available original preparation (reference). A dose of 850 mg was administered after an overnight fast with a washout period of seven days. Eighteen blood samples were collected over 32 h. Metformin concentrations in deproteinized serum were determined by a locally validated High Performance Liquid Chromatographic (HPLC) assay, and pharmacokinetic parameters were analyzed by the standard non-compartmental method. Mean +/- SD maximum concentration (C(max)), time to reach maximum concentration (T(max)), area under the curve (AUC(0 --> t) and AUC(0 --> infinity)), and elimination half-life (t(1/2)) were 1.73 +/- 0.54 and 1.86 +/- 0.67 microg/ml, 2.6 +/- 1.2 and 2.0 +/- 1.0 h, 10.72 +/- 3.93 and 10.82 +/- 3.72 microg x h/ml, 11.53 - 4.14 and 11.6 +/- 3.84 microg x h/ml, and 3.1 +/- 0.7 and 3.1 +/- 0.9 h for the test and reference formulation, respectively. The parametric 90% confidence intervals on the mean of the difference (test - reference) between log-transformed values of the two formulations were 82.92% to 98.78%, 85.95% to 101.47%, and 77.82% to 100.4% for AUC(0 --> t), AUC(0 --> infinity), and C(max), respectively. The results indicate that the two formulations can be considered equivalent in the extent of absorption under fasting conditions.

A simple reversed-phase high performance liquid chromatography (HPLC) method for the determination of gatifloxacin stability in human plasma was developed and validated. Using ciprofloxacin as an internal standard (IS), separation was achieved on X Terra MS C18 (3 mm x 50 mm, 5 microm) column. The mobile phase, 0.025 M disodium hydrogen phosphate (pH 3.0) and acetonitrile (80:20 v/v), were delivered at a flow rate of 1.0 ml/min. The eluent was monitored using spectrophotometeric detection at 293 nm. Plasma samples were deproteinized using Amicon Centrifree system. No interference in blank plasma or of commonly used drugs was observed. The relationship between gatifloxacin concentration and peak height ratio of gatifloxacin to the IS was linear over the range of 0.10-6.0 microg/ml. The intra-day and inter-day coefficients of variation were < or = 2.77 and < or = 4.59%, respectively. The extraction recovery of gatifloxacin and the IS from plasma samples was > or = 85%. Gatifloxacin was found to be stable for at least 5 h at RT, 7 weeks at -20 degrees C, and after 3 freeze-thaw cycles in plasma; 16 h at RT and 48 h at -20 degrees C in deproteinized plasma; and 24 h at RT and 7 weeks at -20 degrees C in phosphate buffer.

An expedient high-performance liquid chromatography (HPLC) assay for nizatidine measurement in human plasma was developed and validated. After deproteinization of 200 microL of plasma by filtration, nizatidine and 4-amino-antipyrine (internal standard) were separated (capacity ratio 3.0 and 6.63, respectively) on Nova-Pak C18 cartridge at room temperature (RT), and detected spectrophotometrically at 320 nm. The mobile phase, 0.02 mol/L disodium hydrogen phosphate, acetonitrile, methanol, and triethylamine (80:10:10:0.05 vol/vol), was delivered at 1.5 mL/min. Calibration curves were linear (r2 > or = 0.999) in the range 0.02 to 5 microg/mL, detection and quantification limits were 0.01 and 0.02 microg/mL, respectively, intra-run and inter-run coefficients of variation were < or = 3.5% and < or = 4.2%, respectively, and recovery was >90%. Nizatidine was stable for at least 4 hours at RT, 12 weeks at -20 degrees C, and 3 freeze-thaw cycles in plasma; 16 hours at RT and 48 hours at -20 degrees C in deproteinized plasma; and 6 hours at RT and 3 weeks at -20 degrees C in water.

A randomized single-dose crossover study was conducted in 24 healthy male volunteers to compare the bioavailability of two amoxicillin (CAS 26787-78-0) formulations, Glomox tablet (test) and a commercially available original preparation, amoxicillin capsule (reference). One thousand milligram of each formulation were administered after an overnight fast with a washout period of three days. Sixteen blood samples were collected over 10 h, amoxicillin concentrations in deproteinized serum were determined by a high performance liquid chromatographic (HPLC) assay, and pharmacokinetic parameters were analyzed by the standard non-compartmental method. Mean +/- SD maximum concentration (Cmax), time to reach maximum concentration (Tmax), area under the curve (AUC0-->t and AUC0-->infinity), and elimination half-life (t1/2) were 13.30 +/- 4.52 and 12.99 +/- 3.56 microg/ml, 1.92 +/- 0.76 and 2.02 +/- 0.62 h, 42.50 +/- 13.62 and 42.24 +/- 12.35 microg x h/ml, 46.31 +/- 13.23 and 46.08 +/- 12.14 microg x h/ml, and 1.54 +/- 0.39 and 1.48 +/- 0.48 h for the test and reference formulation, respectively. The parametric 90 % confidence intervals of the mean of the difference (test-reference) between log-transformed values of the two formulations were 92.61% to 109.50%, 92.83% to 109.12%, and 93.11% to 109.41% for AUC0-->t, AUC0-->infinity, and Cmax, respectively. The results indicate that the two formulations can be considered equivalent with regard to the rate and extent of absorption under fasting conditions.

A randomized, two-period, two-sequence, crossover study was conducted on 28 healthy male volunteers to compare the bioavailability of two rosiglita-zone (CAS 122320-73-4) tablet formulations, a test and a commercially available original preparation (reference), under fasting conditions. The two preparations were given in a dose of 8 mg with a 7-day washout period between the two preparations. Eighteen blood samples were collected over 24 h, plasma rosiglitazone concentrations were determined by locally validated high performance liquid chromatography (HPLC) assay, and pharmacokinetic parameters were analyzed by the standard non-compartmental method. The mean+/-SD of AUC0-->t, AUC0-->infinity, Cmax, Tmax, and t1/2 were 4.80+/-1.89 and 4.76 +/-1.94 microg x h/ml, 5.17+/-2.11 and 5.08 +/- 2.27 microg x h/ml, 0.93+/-0.24 and 0.99+/-0.34 microg/ml, 1.0 +/-0.4 and 0.8+/-0.5 h, and 5.0+/-2.0 and 5.0+/-2.0 h for the test and reference formulation, respectively. ANOVA did not show significant formulation, period, or sequence effect for any of the pharmacokinetic parameters. The 90 % confidence intervals of the mean differences between log-transformed values of the two formulations were 93.09 % to 109.73 %, 94.04 % to 111.70 %, and 89.70 % to 103.24 % for AUC0-->t, AUC-->infinity, and Cmax, respectively. It is concluded that the two formulations are equivalent in relation to the rate and extent of absorption.

A randomized crossover study was conducted on 26 healthy Arab males to compare the bioavailability of two formulations of fluconazole 150 mg capsules, Fluconazole (test) and Diflucan (reference). The formulations were administered after an overnight fast with a washout period of 2 weeks. Twenty blood samples (per period) were collected over 168 h, plasma fluconazole concentrations were determined by locally validated high performance liquid chromatography (HPLC) assay and pharmacokinetic parameters were analysed by the standard non-compartmental method. The mean +/- SD maximum concentration (C(max)), time to reach maximum concentration (T(max)), area under the curve (AUC(0-->t) and AUC(0-->infinity)) and elimination half-life (t(1/2)) were 3.17+/-0.47 and 3.24+/-0.59 microg/ml, 2.62+/-2.01 and 2.65+/-1.63 h, 149.52+/-29.49 and 151.36+/-25.84 microg.h/ml, 163.57+/-29.9 and 164.89+/-26.46 microg.h/ml, and 36.81+/-5.72 and 36.56+/-5.36 h for the test and reference drug, respectively. These values are similar to previously reported values in other ethnic groups. The parametric 90% confidence intervals on the mean of the difference (test-reference) between the log-transformed values of the two formulations were 95.484% to 101.035%, 96.382% to 101.245% and 94.621% to 102.074% for AUC(0-->t), AUC(0-->infinity) and C(max), respectively. The results indicate that the two formulations are equivalent in the rate and extent of absorption. Further, a review of the literature indicates that there is no apparent ethnic variation in the absorption and elimination rates of fluconazole., (Copyright (c) 2005 John Wiley & Sons, Ltd.)

Purpose: The purpose of this randomized, crossover study was to compare the bioavailability of a generic and an innovator formulation of nizatidine 300 mg capsules under fasting conditions., Methods: Twenty blood samples per period were collected from 20 healthy, Arab male volunteers over 16 h, plasma nizatidine concentrations were determined by HPLC assay, and pharmacokinetic parameters were determined by the non-compartmental method., Results: Mean+/-SD C(max), T(max), AUC(0-->t), AUC(0-->infinity), and t1/2 were 2.96+/-0.54 and 3.28+/-0.68 microg/ml, 1.31+/-0.70 and 0.93+/-0.38 h, 9.04+/-1.66 and 9.03+/-1.94 microg x h/ml, 9.17+/-1.64 and 9.12+/-1.94 microg x h/ml, and 1.64+/-0.21 and 1.58+/-0.22 h for the generic and innovator formulation, respectively. The parametric 90% confidence intervals on the mean of the difference between log-transformed values were 98.06% to 103.21%, 98.74% to 103.71%, and 83.37% to 101.34%, for AUC(0-->t), AUC(0-->infinity), and C(max), respectively., Conclusion: The results indicate that these two formulations are equivalent in the rate and extent of absorption., (Copyright 2005 John Wiley & Sons, Ltd.)

The accumulation of advanced glycation end products (AGEs) in the tissue and serum of subjects with diabetes has been linked to the pathogenesis of vascular complications. Because diabetes may be also complicated by increased susceptibility to recurrent infection, we investigated the effects of AGEs on human neutrophils, because their burst of activity immediately upon engagement of pathogens or other inflammatory triggers is critical to host response. We demonstrate the presence of receptor for advanced glycation end products (RAGE) at the message and protein levels. We also demonstrate that AGE albumin (but not control albumin) binds with high affinity to human neutrophils (K(d) of 3.7 +/- 0.4 nM). The binding was blocked almost completely by excess soluble RAGE, anti-RAGE antibodies, or antibodies to CML-modified albumin. AGE albumin induced a dose-dependent increase in intracellular-free calcium as well as actin polymerization. Further, AGE albumin inhibited transendothelial migration and Staphylococcus aureus-induced but not fMLP-induced production of reactive oxygen metabolite. Moreover, although AGE albumin enhanced neutrophil phagocytosis of S. aureus, it inhibited bacterial killing. We conclude that functional RAGE is present on the plasma membrane of human neutrophils and is linked to Ca(2)(+) and actin polymerization, and engagement of RAGE impairs neutrophil functions.

Objective: To determine whether hyperthermia activates an anti-inflammatory response., Design: A prospective study., Setting: Heatstroke Center, Makkah, and King Faisal Specialist Hospital, Riyadh, Saudi Arabia., Patients: Twenty-five heatstroke patients pre-cooling (rectal temperature 42.4 +/- 0.8 degrees C) (group 1) and 13 normothermic heat-stressed subjects were studied (group 2). Twelve of the 25 heatstroke patients were also studied post-cooling (group 3). Mononuclear cells from six healthy blood donors resting at 24 degrees C were used for in vitro study., Interventions: Mononuclear cells were cultured at a concentration of 1 x 10(6)/ml without and with lipopolysaccharide (LPS) added at concentration of 10, 100, and 1000 ng/ml. The cells were incubated for 24 h at 37, 39, 41, and 43 degrees C. ELISA was used to measure IL-10 in the supernatant and plasma from heatstroke and heat-stressed subjects., Results: All patients in group 1, 40% of group 2, and 37% of group 3, showed elevation of IL-10 (1289 +/- 2519, 248 +/- 393, and 172 +/- 226 pg/ml, respectively) compared with normal control levels, (< 100 pg/ml) P < 0.05. IL-10 level on admission did not correlate with degree of hyperthermia. During 24 h incubation at 37 degrees C without LPS, no IL-10 was detected, whereas with 10 ng/ml LPS, monocytes released 658 +/- 291 pg IL-10/10(6) cells. At 39 degrees C and 41 degrees C IL-10 release was decreased to 225 +/- 114, and 245 +/- 90 pg/10(6) cells, respectively; and was completely inhibited at 43 degrees C (67 +/- 10 pg/10(6) cells), P < 0.0001., Conclusion: Heat-stress with and without hyperthermia is associated with anti-inflammatory response in vivo. However, it does not seem to be the direct effect of heat on monocytes, suggesting that other environmental or genetic factors may be involved.