Luminal A Versus B After Choosing Wisely: Does Lymph Node Surgery Affect Oncologic Outcomes?

BACKGROUND: In 2016, the Choosing Wisely campaign recommended against routine sentinel lymph node biopsy (SLNB) in women ≥ 70 years old diagnosed with early-stage hormone receptor positive (HR+), HER2 negative (HER2-) breast cancer. No distinction is made between luminal A and luminal B phenotypes, despite luminal B being considered more aggressive. This study evaluates the effect of SLNB on oncologic outcomes in HER2- luminal B versus luminal A breast cancer. PATIENTS AND METHODS: We performed an IRB-approved, single institution, retrospective cohort study from 2010 to 2020 of women aged ≥ 70 years with clinically node negative, HR+ breast cancer undergoing definitive surgical treatment. Luminal status was defined by gene expression panel testing, Ki67%, and/or pathologic grading. Primary endpoints included locoregional recurrence (LRR), disease free survival (DFS), and overall survival (OS). RESULTS: SLNB did not correlate with significant differences in LRR in luminal A (p = 0.92) or luminal B (p = 0.96) disease. SLNB correlated with improved DFS (p < 0.01) and OS (p < 0.001) in luminal A disease, but not in luminal B disease (DFS p = 0.73; OS p = 0.36). On multivariate analysis, age (HR = 1.17; p < 0.01) and tumor size (HR = 1.03; p < 0.05) were associated with DFS, while SLNB was not (p = 0.71). Luminal status (HR = 0.52, p < 0.05), age (HR = 1.15, p < 0.01), and comorbidities (HR = 1.35, p < 0.05) were associated with OS, but not SLNB (p = 0.71). CONCLUSIONS: Our results suggest that SLNB may be safely omitted in patients aged ≥ 70 years with luminal B disease given similar LRR in luminal A disease. Our findings suggest that DFS and OS are driven by tumor biology, patient age, and comorbidities rather than receipt of SLNB.

Water level changes, subsidence, and sea level rise in the Ganges-Brahmaputra-Meghna delta.

Being one of the most vulnerable regions in the world, the Ganges-Brahmaputra-Meghna delta presents a major challenge for climate change adaptation of nearly 200 million inhabitants. It is often considered as a delta mostly exposed to sea-level rise and exacerbated by land subsidence, even if the local vertical land movement rates remain uncertain. Here, we reconstruct the water-level (WL) changes over 1968 to 2012, using an unprecedented set of 101 water-level gauges across the delta. Over the last 45 y, WL in the delta increased slightly faster (∼3 mm/y), than global mean sea level (∼2 mm/y). However, from 2005 onward, we observe an acceleration in the WL rise in the west of the delta. The interannual WL fluctuations are strongly modulated by El Niño Southern Oscillation (ENSO) and Indian Ocean Dipole (IOD) variability, with WL lower than average by 30 to 60 cm during co-occurrent El Niño and positive IOD events and higher-than-average WL, by 16 to 35 cm, during La Niña years. Using satellite altimetry and WL reconstructions, we estimate that the maximum expected rates of delta subsidence during 1993 to 2012 range from 1 to 7 mm/y. By 2100, even under a greenhouse gas emission mitigation scenario (Representative Concentration Pathway [RCP] 4.5), the subsidence could double the projected sea-level rise, making it reach 85 to 140 cm across the delta. This study provides a robust regional estimate of contemporary relative WL changes in the delta induced by continental freshwater dynamics, vertical land motion, and sea-level rise, giving a basis for developing climate mitigation strategies.

Effects of late, repetitive remote ischaemic conditioning on myocardial strain in patients with acute myocardial infarction.

Late, repetitive or chronic remote ischaemic conditioning (CRIC) is a potential cardioprotective strategy against adverse remodelling following ST-segment elevation myocardial infarction (STEMI). In the randomised Daily Remote Ischaemic Conditioning Following Acute Myocardial Infarction (DREAM) trial, CRIC following primary percutaneous coronary intervention (P-PCI) did not improve global left ventricular (LV) systolic function. A post-hoc analysis was performed to determine whether CRIC improved regional strain. All 73 patients completing the original trial were studied (38 receiving 4 weeks' daily CRIC, 35 controls receiving sham conditioning). Patients underwent cardiovascular magnetic resonance at baseline (5-7 days post-STEMI) and after 4 months, with assessment of LV systolic function, infarct size and strain (longitudinal/circumferential, in infarct-related and remote territories). At both timepoints, there were no significant between-group differences in global indices (LV ejection fraction, infarct size, longitudinal/circumferential strain). However, regional analysis revealed a significant improvement in longitudinal strain in the infarcted segments of the CRIC group (from - 16.2 ± 5.2 at baseline to - 18.7 ± 6.3 at follow up, p = 0.0006) but not in corresponding segments of the control group (from - 15.5 ± 4.0 to - 15.2 ± 4.7, p = 0.81; for change: - 2.5 ± 3.6 versus + 0.3 ± 5.6, respectively, p = 0.027). In remote territories, there was a lower increment in subendocardial circumferential strain in the CRIC group than in controls (- 1.2 ± 4.4 versus - 2.5 ± 4.0, p = 0.038). In summary, CRIC following P-PCI for STEMI is associated with improved longitudinal strain in infarct-related segments, and an attenuated increase in circumferential strain in remote segments. Further work is needed to establish whether these changes may translate into a reduced incidence of adverse remodelling and clinical events. Clinical Trial Registration: http://clinicaltrials.gov/show/NCT01664611 .

Definition, prevalence, and clinical significance of mitral annular disjunction in different patient cohorts: A systematic review.

BACKGROUND: Mitral annular disjunction (MAD) is a structural abnormality involving a distinct separation of the left atrium/mitral valve annulus and myocardium continuum. The literature around MAD has increased over recent years, thus we sought to review the current data on the definition, prevalence, and clinical outcomes of MAD. METHODS: A search of MEDLINE and EMBASE was conducted to identify studies which evaluated MAD in any patient cohort. The study results were synthesized narratively. RESULTS: A total of 12 studies were included with 3925 patients (average age 62 years, 63% male). The pooled prevalence of MAD in patients with mitral valve prolapse and/or Barlow's disease was 30.1%. In a general population, MAD prevalence was 8.7%. The definition of MAD was not consistent across all studies. In terms of clinical outcomes, only one study reported MAD to be associated with ventricular arrhythmias. CONCLUSIONS: MAD is an increasingly recognized finding amongst patients undergoing cardiac imaging. This review highlights the need for agreed definitions for clinically significant MAD and how identified MAD should be managed. At present, there is insufficient evidence that MAD is associated adverse clinical outcomes.

Accuracy and Prognostic Value of Physiologist-Led Stress Echocardiography for Coronary Disease.

BACKGROUND: We demonstrated that physiologist-led stress echocardiography (PLSE) is feasible for coronary artery disease (CAD) assessment. We sought to extend our work by assessing its accuracy and prognostic value. METHODS: Retrospective study of 898 subjects undergoing PLSE (n=393) or cardiologist-led stress echocardiography (CLSE) (n=505) for CAD assessment using exercise or dobutamine. For accuracy assessment, the primary outcome was the ability of stress echocardiography to identify significant CAD on invasive coronary angiography (ICA). Incidence of 24-month non-fatal MI, total and cardiac mortality, revascularisation and combined major adverse cardiac events (MACE) were assessed. RESULTS: Demographics, comorbidities, CAD predictors, CAD pre-test probability and cardiac medications were matched between the PLSE and CLSE groups. PLSE had high sensitivity, specificity, positive and negative predictive value and accuracy (85%, 74%, 69%, 88%, 78% respectively). PLSE accuracy measures were similar and non-inferior to CLSE. There was a similar incidence of individual and combined outcomes in PLSE and CLSE subjects. Negative stress echocardiography conferred a comparably low incidence of non-fatal MI (PLSE 1.4% vs. CLSE 0.9%, p=0.464), cardiac mortality (0.6% vs. 0.0%, p=0.277) and MACE (6.8% vs. 3.1%, p=0.404). CONCLUSION: This is the first study of the accuracy compared with gold standard of ICA, and prognostic value of PLSE CAD assessment. PLSE demonstrates high and non-inferior accuracy compared with CLSE for CAD assessment. Negative PLSE and CLSE confer a similarly very low incidence of cardiac outcomes, confirming for the first time the important prognostic value of PLSE.

Plasma Tenascin-C: a prognostic biomarker in heart failure with preserved ejection fraction.

INTRODUCTION: Tenascin-C is a marker of interstitial fibrosis. We assessed whether plasma Tenascin-C differed between heart failure with preserved ejection fraction (HFpEF) and asymptomatic controls and related to clinical outcomes. MATERIALS AND METHODS: Prospective, observational study of 172 age- and sex-matched subjects (HFpEF n = 130; controls n = 42, age 73 ± 9, males 50%) who underwent phenotyping with 20 plasma biomarkers, echocardiography, cardiac MRI and 6-minute-walk-testing. The primary endpoint was the composite of all-cause death/HF hospitalisation. RESULTS: Tenascin-C was higher in HFpEF compared to controls (13.7 [10.8-17.3] vs (11.1 [8.9-12.9] ng/ml, p < 0.0001). Tenascin-C correlated positively with markers of clinical severity (NYHA, E/E', BNP) and plasma biomarkers reflecting interstitial fibrosis (ST-2, Galectin-3, GDF-15, TIMP-1, TIMP-4, MMP-2, MMP-3, MMP-7, MMP-8), cardiomyocyte stress (BNP, NTpro-ANP), inflammation (MPO, hs-CRP, TNFR-1, IL6) and renal dysfunction (urea, cystatin-C, NGAL); p < 0.05 for all. During follow-up (median 1428 days), there were 61 composite events (21 deaths, 40 HF hospitalizations). In multivariable Cox regression analysis, Tenascin-C (adjusted hazard ratio [HR] 1.755, 95% confidence interval [CI] 1.305-2.360; p < 0.0001) and indexed extracellular volume (HR 1.465, CI 1.019-2.106; p = 0.039) were independently associated with adverse outcomes. CONCLUSIONS: In HFpEF, plasma Tenascin-C is higher compared to age- and sex-matched controls and a strong predictor of adverse outcomes. Trial registration: ClinicalTrials.gov: NCT03050593.

Polymorphism in GSTM1 and GSTT1 genes influence DNA damage in personnel occupationally exposed to volatile anaesthetics (VA), from Peshawar, Pakistan.

OBJECTIVES: The objective of this study was to assess the influence of antioxidant gene GSTM1 and GSTT1 on DNA damage in personnel occupationally exposed to volatile anaesthetics (VA). METHODS: The study groups were composed of 50 exposed subjects (anaesthesia workers) and 49 controls. Blood samples were collected from both subjects. DNA damage was analysed through the comet assay technique. Biomarker genes GSTM1 and GSTT1 were inspected through PCR technique for polymorphism. RESULTS: The comet assay technique showed that the Total Comet Score (TCS) in exposed subjects was significantly higher (p=0.0001) than the control. Age and smoking had significant effects on TCS in the study groups (p<0.05). Duration of occupational exposure had significant positive correlation (r=0.755, p<0.001) with DNA damage. The null polymorphism in GSTM1 and GSTT1 gene showed a significant effect (p<0.001 and p<0.000) on the DNA damage. CONCLUSIONS: The polymorphism in GSTM1 and GSTT1 gene significantly damage DNA in personnel occupationally exposed to VA.

Impact of Ferroquine on the Solubilization of Artefenomel (OZ439) during in Vitro Lipolysis in Milk and Implications for Oral Combination Therapy for Malaria.

Milk is an attractive lipid-based formulation for the delivery of poorly water-soluble drugs to pediatric populations. We recently observed that solubilization of artefenomel (OZ439) during in vitro intestinal lipolysis was driven by digestion of triglycerides in full-cream bovine milk, reflecting the ability of milk to act as an enabling formulation in the clinic. However, when OZ439 was co-administered with a second antimalarial drug, ferroquine (FQ) the exposure of OZ439 was reduced. The current study therefore aimed to understand the impact of the presence of FQ on the solubilization of OZ439 in milk during in vitro intestinal digestion. Synchrotron small-angle X-ray scattering was used for in situ monitoring of drug solubilization (inferred via decreases in the intensity of drug diffraction peaks) and polymorphic transformations that occurred during the course of digestion. Quantification of the amount of each drug solubilized over time and analysis of their distributions across the separated phases of digested milk were determined using high-performance liquid chromatography. The results show that FQ reduced the solubilization of OZ439 during milk digestion, which may be due to competitive binding of FQ to the digested milk products. Interactions between the protonated FQ-H+ and ionized liberated free fatty acids resulted in the formation of amorphous salts, which removes the low-energy crystalline state as a barrier to dissolution of FQ, while inhibiting the solubilization of OZ439. We conclude that although milk could enhance the solubilization of poorly water-soluble OZ439 during in vitro digestion principally due to the formation of fatty acids, the solubilization efficiency was reduced by the presence of FQ by competition for the available fatty acids. Assessment of the solubilization of both drugs during digestion of fixed-dose combination lipid formulations (such as milk) is important and may rationalize changes in bioavailability when compared to that of the individual drugs in the same formulation.

A comparative survey of microsatellites among wild and domestic cat provides valuable resources for marker development.

Information on the level and distribution of genetic variation is important for conservation plan of captive population of an endangered species such as tiger and cheetah. We assayed the frequency of microsatellites in the genomic and genic sequences of wild cats (Panthera tigris, Acinonyx jubatus) and compared it with the domestic cat (Felis catus). Frequency, relative abundance and density of microsatellites were highest in the domestic cat when compared with wild cats. The frequency of microsatellites was positively correlated with the G+C content of genomic and genic sequences. The maximum frequency of microsatellites among all three sequence sets was of di-nucleotide repeats (genomic-88.1%; genic-70.4%), whereas the hexa-nucleotide repeat represents < 0.5%. Motif conservation study among the genomic and genic sequences revealed conservation of 81.3% and 51.0% motif within the members of family Felidae. A total 40,233 primers from genic sequences were designed in order to enrich the members of family Felidae with genomic resources. The designed primers could be useful in determining the molecular genetics of population structure and individualization of a particular cat.

Mitral annular disjunction: A systematic review of the literature.

BACKGROUND: Mitral annular disjunction (MAD) is a structural abnormality where there is a separation between the mitral valve annulus and the left atrial wall which is not well understood. METHODS: We conducted a systematic review to evaluate the prevalence of MAD, factors associated with MAD and clinical outcomes among patients with MAD. RESULTS: A total of 19 studies were included in this review, and the number of noncase report studies had between 23 and 1439 patients. The pooled rate of MAD in studies of myxomatous mitral valve patients was 66/130 (50.8%, 3 studies), and among patients with mitral valve prolapse was 95/291 (32.6%, 3 studies). One study suggests that 78% of patients with MAD had mitral valve prolapse, and another suggested it was strongly associated with myxomatous mitral valve disease (HR 5.04 95% CI 1.66-15.31). In terms of clinical significance, it has been reported that MAD with disjunction > 8.5 mm was associated with nonsustained ventricular tachycardia (OR 10 95% CI 1.28-78.1). There is also evidence that gadolinium enhancement in papillary muscle (OR 4.09 95% CI 1.28-13.05) and longitudinal MAD distance in posterolateral wall (OR 1.16 95% CI 1.02-1.33) was predictive of ventricular arrhythmia and late gadolinium enhancement in anterolateral papillary muscle was strongly associated with serious arrhythmic event (OR 7.35 95% CI 1.15-47.02). CONCLUSIONS: Mitral annular disjunction appears to be common in myxomatous mitral valve disease and mitral valve prolapse which can be detected on cardiac imaging and may be important because of its association with ventricular arrhythmias and sudden cardiac death.

Interactions of Artefenomel (OZ439) with Milk during Digestion: Insights into Digestion-Driven Solubilization and Polymorphic Transformations.

Milk has been used as a vehicle for the delivery of antimalarial drugs during clinical trials to test for a food effect and artefenomel (OZ439) showed enhanced oral bioavailability with milk. However, the nature of the interaction between milk and OZ439 in the gastrointestinal tract remains poorly understood. To understand the role of milk digestion on the solubilization of OZ439 and polymorphism, we conducted real-time monitoring of crystalline drug in suspension during in vitro intestinal lipolysis of milk containing OZ439 using synchrotron X-ray scattering. OZ439 formed an unstable solid-state intermediate free base form (OZ439-FB form 1) at intestinal pH and was partially solubilized by milk fat globules prior to lipolysis. Dissolution of the free base form 1 and recrystallization of OZ439 in a more stable polymorphic form (OZ439-FB form 2) occurred during in vitro lipolysis in milk. Simply stirring the milk/drug suspension in the absence of lipase or addition of lipase to OZ439 in a lipid-free buffer did not induce this polymorphic transformation. The formation of OZ439-FB form 2 was therefore accelerated by the solubilization of OZ439-FB form 1 during the digestion of milk. Our findings confirmed that although crystalline precipitates of OZ439-FB form 2 could still be detected after in vitro digestion, milk-based lipid formulations provided a significant reduction in crystalline OZ439 compared to lipid-free formulations, which we attribute to the formation of colloidal structures by the digested milk lipids. Milk may therefore be particularly suited as a form of lipid-based formulation (LBF) for coadministration with OZ439, from which both an enhancement in OZ439 oral bioavailability and the delivery of essential nutrients should result.

Cervical Cancer, Human Papillomavirus Infection, and Vaccine-Related Knowledge: Awareness in Chinese Women.

Cervical cancer (CC) has a high incidence and mortality and is accompanied by lack of organized CC screening programs, lack of health-care facilities, and a lack of human papillomavirus (HPV) vaccination among female population in the world, particularly China. We recruited 487 females who visited the outpatient department of the First People's Hospital of Yunnan Province from November 2015 to January 2016 to complete a standardized-designed questionnaire. We found that only 39.6% of the females knew about the role of HPVs in the development of cervical cancer. Moreover, none of the females knew that HPV could cause penile carcinomas, perianal carcinomas, and head and neck carcinomas. The majority of the participants acquired information about cervical cancer, HPV, and the HPV vaccine from medical workers. Only 15.6% of the recruited females had heard about the HPV vaccine. The overall HPV vaccine acceptance rate was higher (91.2%) if the vaccine was available free of cost. In this study, we found high acceptability of the HPV vaccine in Chinese women and high awareness about cervical cancer. However, very low levels of knowledge about HPVs and their role in cancer development among the recruited women is alarming. Therefore, it is very important to initiate educational programs to raise awareness and knowledge about cervical cancer, HPV, and the HPV vaccine in this region.

The Relationship between Levels of Physical Activity and Academic Achievement among Medical and Health Sciences Students at Cyberjaya University College of Medical Sciences.

BACKGROUND: This study aimed to explore the prevalence of physical activity among medical and health sciences students at Cyberjaya University College of Medical Sciences (CUCMS) and to determine the relationship of their physical activity level with their academic achievement and self-determination level. METHODS: An analytical cross-sectional study was conducted among 244 Medical and Health Sciences undergraduate students at CUCMS from January to April 2017 using self-administered short-form version of the International Physical Activity Questionnaire (IPAQ-SF) and the third version of the Behavioural Regulation in Exercise Questionnaire (BREQ-3). Multiple regression models were fitted using SPSS version 20 to examine the relationships between study variables. RESULTS: Half of the male students (51.7%) were in the health-enhancing physical activity (HEPA) group, as compared to only 24.7% of females. The odds of having a good grade point average was twice as high among HEPA active students (odds ratio [OR] = 1.89, 95% CI [1.09, 3.27], P = 0.023) than among non-HEPA active students. Further, the odds of being HEPA active was higher for males (OR = 3.16, 95% CI [1.61, 6.14], P < 0.01) than for females and higher for overweight students than for normal weight students (OR = 2.58, 95% CI [1.24, 5.57], P = 0.017). The odds of being HEPA active was 1.79 times higher for each unit increase in the integrated regulation score (OR = 1.79, 95% CI [1.14, 2.91], P = 0.020). CONCLUSION: The prevalence of physical inactivity was higher among females than males. This study also confirmed a significant association between physical activity level and academic achievement. HEPA active students performed better academically than those who were non-HEPA active.

Comparison of global myocardial strain assessed by cardiovascular magnetic resonance tagging and feature tracking to infarct size at predicting remodelling following STEMI.

BACKGROUND: To determine if global strain parameters measured by cardiovascular magnetic resonance (CMR) acutely following ST-segment Elevation Myocardial Infarction (STEMI) predict adverse left ventricular (LV) remodelling independent of infarct size (IS). METHODS: Sixty-five patients with acute STEMI (mean age 60 ± 11 years) underwent CMR at 1-3 days post-reperfusion (baseline) and at 4 months. Global peak systolic circumferential strain (GCS), measured by tagging and Feature Tracking (FT), and global peak systolic longitudinal strain (GLS), measured by FT, were calculated at baseline, along with IS. On follow up scans, volumetric analysis was performed to determine the development of adverse remodelling - a composite score based on development of either end-diastolic volume index [EDVI] ≥20% or end-systolic volume index [ESVI] ≥15% at follow-up compared to baseline. RESULTS: The magnitude of GCS was higher when measured using FT (-21.1 ± 6.3%) than with tagging (-12.1 ± 4.3; p < 0.001 for difference). There was good correlation of strain with baseline LVEF (r 0.64-to 0.71) and IS (ρ -0.62 to-0.72). Baseline strain parameters were unable to predict development of adverse LV remodelling. Only baseline IS predicted adverse remodelling - Odds Ratio 1.05 (95% CI 1.01-1.10, p = 0.03), area under the ROC curve 0.70 (95% CI 0.52-0.87, p = 0.04). CONCLUSION: Baseline global strain by CMR does not predict the development of adverse LV remodelling following STEMI.

Strategies to attenuate micro-vascular obstruction during P-PCI: the randomized reperfusion facilitated by local adjunctive therapy in ST-elevation myocardial infarction trial.

BACKGROUND: Microvascular obstruction (MVO) following primary percutaneous coronary intervention (PPCI) treatment of ST-segment elevation myocardial infarction (STEMI) contributes to infarct expansion, left ventricular (LV) remodelling, and worse clinical outcomes. The REFLO-STEMI trial tested whether intra-coronary (IC) high-dose adenosine or sodium nitroprusside (SNP) reduce infarct size and/or MVO determined by cardiac magnetic resonance (CMR). METHODS AND RESULTS: REFLO-STEMI, a prospective, open-label, multi-centre trial with blinded endpoints, randomized (1:1:1) 247 STEMI patients with single vessel disease presenting within 6 h of symptom onset to IC adenosine (2-3 mg total) or SNP (500 µg total) immediately following thrombectomy and again following stenting, or to standard PPCI. The primary endpoint was infarct size % LV mass (%LVM) on CMR undertaken 24-96 h after PPCI (n = 197). Clinical follow-up was to 6 months. There was no significant difference in infarct size (%LVM, median, interquartile range, IQR) between adenosine (10.1, 4.7-16.2), SNP (10.0, 4.2-15.8), and control (8.3, 1.9-14.0), P = 0.062 and P = 0.160, respectively, vs. CONTROL: MVO (% LVM, median, IQR) was similar across groups (1.0, 0.0-3.7, P = 0.205 and 0.6, 0.0-2.4, P = 0.244 for adenosine and SNP, respectively, vs. control 0.3, 0.0-2.8). On per-protocol analysis, infarct size (%LV mass, 12.0 vs. 8.3, P = 0.031), major adverse cardiac events (hazard ratio, HR, 5.39 [1.18-24.60], P = 0.04) at 30 days and 6 months (HR 6.53 [1.46-29.2], P = 0.01) were increased and ejection fraction reduced (42.5 ± 7.2% vs. 45.7 ± 8.0%, P = 0.027) in adenosine-treated patients compared with control. CONCLUSIONS: High-dose IC adenosine and SNP during PPCI did not reduce infarct size or MVO measured by CMR. Furthermore, adenosine may adversely affect mid-term clinical outcome. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01747174; https://clinicaltrials.gov/ct2/show/NCT01747174.

Management Of Penetrating Injury To Thoracic Inlet And Lower Neck With Retained Foreign Body Using Video Assisted Thoracoscopic Surgery.

Penetrating neck and chest injuries are a common form of occupational injuries. We hereby report a unique case in which a metallic rod had penetrated the left chest and neck of a plastic factory worker. The patient was vitally stable when he presented to Emergency Room. Chest X-ray was performed and the patient was rushed to the operating room. VATS (video assisted thoracoscopic surgery) and neck dissection was done for retrieval of the metallic rod. On table, endoscopy was also done to rule out injury to oesophagus. No injury to vital structures was found and the subsequent recovery was uneventful.

Lipid-Based Formulations Can Enable the Model Poorly Water-Soluble Weakly Basic Drug Cinnarizine To Precipitate in an Amorphous-Salt Form During In Vitro Digestion.

The tendency for poorly water-soluble weakly basic drugs to precipitate in a noncrystalline form during the in vitro digestion of lipid-based formulations (LBFs) was linked to an ionic interaction between drug and fatty acid molecules produced upon lipid digestion. Cinnarizine was chosen as a model weakly basic drug and was dissolved in a medium-chain (MC) LBF, which was subject to in vitro lipolysis experiments at various pH levels above and below the reported pKa value of cinnarizine (7.47). The solid-state form of the precipitated drug was analyzed using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and crossed polarized light microscopy (CPLM). In addition, the phase distribution of cinnarizine upon lipolysis was analyzed using high-performance liquid chromatography (HPLC). Cinnarizine precipitated in a noncrystalline form during lipolysis experiments at pH 6.5, pH 5.5, and pH 4.0 but precipitated in a crystalline form at pH 8.0 according to XRD measurements on the pellets. Differences were also observed in the FTIR spectra of the pellet phases at pH 8.0 and pH 6.5, with the absorption bands in the C-N stretch region of the IR spectra supporting a shift from the starting free base crystalline material to the hydrochloride salt, thus supporting the case that ionic interactions between weak bases and fatty acid molecules during digestion are responsible for producing amorphous-salts upon precipitation. The conclusion has wide implications for understanding past in vitro and in vivo data for lipid-based formulations of basic drugs, as well as future formulation design and optimization.

The Precipitation Behavior of Poorly Water-Soluble Drugs with an Emphasis on the Digestion of Lipid Based Formulations.

An increasing number of newly discovered drugs are poorly water-soluble and the use of natural and synthetic lipids to improve the oral bioavailability of these drugs by utilizing the digestion pathway in-vivo has proved an effective formulation strategy. The mechanisms responsible for lipid digestion and drug solubilisation during gastrointestinal transit have been explored in detail, but the implications of drug precipitation beyond the potential adverse effect on bioavailability have received attention only in recent years. Specifically, these implications are that different solid forms of drug on precipitation may affect the total amount of drug absorbed in-vivo through their different physico-chemical properties, and the possibility that the dynamic environment of the small intestine may afford re-dissolution of precipitated drug if present in a high-energy form. This review describes the events that lead to drug precipitation during the dispersion and digestion of lipid based formulations, common methods used to inhibit precipitation, as well as conventional and newly emerging characterization techniques for studying the solid state form of the precipitated drug. Moreover, selected case studies are discussed where drug precipitation has ensued from the digestion of lipid based formulations, as well as the apparent link between drug ionisability and altered solid forms on precipitation, culminating in a discussion about the importance of the solid form on precipitation with relevance to the total drug absorbed.

Infarct size following complete revascularization in patients presenting with STEMI: a comparison of immediate and staged in-hospital non-infarct related artery PCI subgroups in the CvLPRIT study.

BACKGROUND: The CvLPRIT study showed a trend for improved clinical outcomes in the complete revascularisation (CR) group in those treated with an immediate, as opposed to staged in-hospital approach in patients with multivessel coronary disease undergoing primary percutaneous intervention (PPCI). We aimed to assess infarct size and left ventricular function in patients undergoing immediate compared with staged CR for multivessel disease at PPCI. METHODS: The Cardiovascular Magnetic Resonance (CMR) substudy of CvLPRIT was a multicentre, prospective, randomized, open label, blinded endpoint trial in PPCI patients with multivessel disease. These data refer to a post-hoc analysis in 93 patients randomized to the CR arm (63 immediate, 30 staged) who completed a pre-discharge CMR scan (median 2 and 4 days respectively) after PPCI. The decision to stage non-IRA revascularization was at the discretion of the treating interventional cardiologist. RESULTS: Patients treated with a staged approach had more visible thrombus (26/30 vs. 31/62, p = 0.001), higher SYNTAX score in the IRA (9.5, 8-16 vs. 8.0, 5.5-11, p = 0.04) and a greater incidence of no-reflow (23.3 % vs. 1.6 % p < 0.001) than those treated with immediate CR. After adjustment for confounders, staged patients had larger infarct size (19.7 % [11.7-37.6] vs. 11.6 % [6.8-18.2] of LV Mass, p = 0.012) and lower ejection fraction (42.2 ± 10 % vs. 47.4 ± 9 %, p = 0.019) compared with immediate CR. CONCLUSIONS: Of patients randomized to CR in the CMR substudy of CvLPRIT, those in whom the operator chose to stage revascularization had larger infarct size and lower ejection fraction, which persisted after adjusting for important covariates than those who underwent immediate CR. Prospective randomized trials are needed to assess whether immediate CR results in better clinical outcomes than staged CR. TRIAL REGISTRATION: ISRCTN70913605 , Registered 24th February 2011.