Community pharmacists' perceptions on multidisciplinary heart failure care: an exploratory qualitative study.

BACKGROUND: Heart failure (HF) is an important health problem and guidelines recommend multidisciplinary management. The pharmacist is an important member of the multidisciplinary heart failure team, both in the hospital and community setting. This study aims to explore the perceptions of community pharmacists on their role in HF care. METHODS: We conducted a qualitative study based on face-to-face semi-structured interviews with 13 Belgian community pharmacists between September 2020 and December 2020. We used the Qualitative Analysis Guide of Leuven (QUAGOL) method as guidance for data analysis until data saturation was reached. We structured interview content into a thematic matrix. RESULTS: We identified two major themes: heart failure management and multidisciplinary management. Pharmacists feel responsible for the pharmacological and non-pharmacological management of heart failure, citing easy access and pharmacological expertise as important assets. Diagnostic uncertainty, lack of knowledge and time, disease complexity and difficulties in communication with patients and informal care providers are barriers to optimal management. General practitioners are the most important partners in multidisciplinary community heart failure management, although pharmacists perceive a lack of appreciation and cooperation and deplore communication difficulties. They feel intrinsically motivated to provide extended pharmaceutical care in HF but cite the lack of financial viability and information sharing structures as important barriers. CONCLUSION: The importance of pharmacist involvement in multidisciplinary heart failure teams is undisputed by Belgian pharmacists, who cite easy access and pharmacological expertise as important assets. They point out several barriers impeding evidence-based pharmacist care for outpatients with heart failure: diagnostic uncertainty and disease complexity, lack of multidisciplinary information technology and insufficient resources. We recommend that future policy should focus on improved medical data exchanges between primary and secondary care electronic health records as well as the reinforcement of interprofessional relationships between locally affiliated pharmacists and general practitioners.

Implementing standards of care for heart failure patients in general practice - the IMPACT-B study protocol.

BACKGROUND: Heart failure (HF) is an important health problem. Most chronic HF management occurs in primary care. Although guidelines exist, there is an important implementation gap in current HF care in Belgium. METHODS: We will conduct a non-randomised, non-controlled prospective observational trial to implement guideline-recommended disease management interventions in primary care in Leuven, a region of ±100.000 inhabitants. These interventions include education of general practitioners, reimbursement of the analysis of circulating natriuretic peptides and audits in the electronic health record (EHR), training and implementation of HF educators in primary care, and a protocol to structure transition to primary care after discharge. The main objective is to study and implement interventions in an iterative implementation process. CONCLUSIONS: We will evaluate the implementation of several guideline-recommended disease management interventions to optimise the diagnosis and treatment of heart failure in a real-world primary care setting. TRIAL REGISTRATION: NCT04334447 (clinicaltrials.gov).

Radiolabeled iodohypericin as tumor necrosis avid tracer: diagnostic and therapeutic potential.

It is estimated that 30-80% of solid tumor mass represents necrotic tissue that consists out of a significant number of dead and dying cells. The fact that these necrotic zones are restricted to dysplastic and malignant tissue and are rarely present in normal tissue makes necrosis an interesting target both for cancer diagnosis and therapy. In this study, the avidity of hypericin, [(123) I]iodohypericin and [(131) I]iodohypericin to tumor necrosis was explored for both diagnosis and therapy of experimental malignancies. The intratumoral distribution in RIF-1 tumors was investigated by means of fluorescence microscopy (hypericin) and autoradiography ([(123) I]iodohypericin). Results show high uptake of the tracers in necrosis at 24 hr, lasting for up to 72 hr p.i. Ratios of activity of [(123) I]iodohypericin in necrotic tissue over viable tumor reached up to 19.63 ± 4.66, correlating with 9.20% ID/g in necrosis. Nude mice bearing RIF-1 tumors that received three injections of 300 µCi over a 3-week treatment period showed stabilization in tumor growth for 5 days, as measured by caliper and micro-positron emission tomography using [(18) F]fluorodeoxyglucose. Based on these results, we suggest the potentials of radiolabeled hypericin (1) in diagnostic aspects including prognosis or staging assessment of bulky necrotic cancers, monitoring of treatments and therapeutic follow-up; and (2) in cancer treatment based on tumor necrosis. In conclusion, we showed that hypericin radiolabeled with iodine is a necrosis avid tracer that can be used both as a tumor diagnostic and therapeutic.

Exploration of the mechanism underlying the tumor necrosis avidity of hypericin.

Hypericin, a potent necrosis avid agent, features a peculiar affinity for necrotic tissue. Necrosis avid contrast agents have been investigated as markers for non-invasive imaging of different disorders. In view of the promising clinical applications, a more complete knowledge of the mechanism of action is important for the future development of new chemical structures with improved characteristics. To study whether a compound-specific or non-specific mechanism based on plasma lipoprotein transport is involved in the accumulation of hypericin in intratumoral necrosis, we performed a visual and quantitative fluoromicroscopic analysis of the colocalization of hypericin and DiOC18-labeled lipoproteins in subcutaneous murine radiation-induced fibrosarcoma tumors. Microscopic fluorescent overlay images of necrotic tumors demonstrated that hypericin already showed clear necrosis avid characteristics 4 h after injection, whereas a similar outstanding accumulation in necrosis was not demonstrated for the labeled lipoproteins. Moreover, a quantitative analysis of fluoromicroscopic images of tumor necrosis at 24 h after injection showed differences in normalized fluorescence intensities between hypericin and labeled lipoproteins of 50-100%, reflecting a shifted pattern in localization. We conclude that our results are indicative of a release of hypericin from the lipoprotein complex at some point along its way through the peri-necrotic tumor area and the necrotic tissue debris, which is in line with the hypothesis of a compound-specific mechanism.

Hypericin as a marker for determination of tissue viability after radiofrequency ablation in a murine liver tumor model.

In this proof-of-principle study, the necrosis avid agent hypericin was investigated as a potential indicator for early therapeutic response following radiofrequency ablation (RFA) of murine liver tumors. Eight mice bearing intrahepatic RIF-1 tumors were intravenously injected with hypericin 1 h before or 24 h after RFA treatment. Mice were euthanized 24 h after hypericin injection and excised livers were investigated by means of fluoromacroscopic and fluoromicroscopic examinations in combination with conventional histomorphology. Significant differences in hypericin fluorescence were found in necrosis, viable tumor and normal liver tissue in a decreasing order: in necrosis, mean fluorescence densities were about 5 times higher than in viable tumor and approximately 12 times higher than in normal liver (p<0.05). Mean fluorescence densities were not significantly different when hypericin was injected 24 h after or 1 h before RFA treatment (p>0.05). As a conclusion, hypericin features the property to specifically enhance the imaging contrast between necrotic and viable tissues and to non-specifically distinguish viable tumor from normal liver. The results suggest that hypericin offers significant potential in the early assessment of response following necrosis-inducing antineoplastic treatments such as RFA.

Murine liver implantation of radiation-induced fibrosarcoma: characterization with MR imaging, microangiography and histopathology.

We sought to establish and characterize a mouse liver tumor model as a platform for preclinical assessment of new diagnostics and therapeutics. Radiation-induced fibrosarcoma (RIF-1) was intrahepatically implanted in 27 C3H/Km mice. Serial in vivo magnetic resonance imaging (MRI) with a clinical 1.5-T-magnet was performed using T1- (T1WI), T2- (T2WI), and diffusion-weighted sequences (DWI), dynamic contrast-enhanced MRI (DCE-MRI), and contrast-enhanced T1WI, and validated with postmortem microangiography and histopathology. Implantation procedure succeeded in 25 mice with 2 deaths from overdosed anesthesia or hypothermia. RIF-1 grew in 21 mice with volume doubling time of 2.55+/-0.88 days and final size of 216.2+/-150.4 mm(3) at day 14. Three mice were found without tumor growth and one only with abdominal seeding. The intrahepatic RIF-1 was hypervascularized with negligible necrosis as shown on MRI, microangiography and histology. On DCE-MRI, maximal initial slope of contrast-time curve and volume transfer constant per unit volume of tissue, K, differed between the tumor and liver with only the former significantly lower in the tumor than in the liver (P<0.05). Liver implantation of RIF-1 in mice proves a feasible and reproducible model and appears promising for use to screen new diagnostics and therapeutics under noninvasive monitoring even with a clinical MRI system.

Hypericin as a marker for determination of tissue viability after intratumoral ethanol injection in a murine liver tumor model.

RATIONALE AND OBJECTIVES: In this preclinical proof-of-principle study, the necrosis avid agent hypericin was investigated as a potential early indicator for therapeutic response after ethanol-mediated chemical ablation in murine liver tumors. MATERIALS AND METHODS: Seven mice bearing intrahepatic radiation-induced fibrosarcoma-1 tumors were intravenously injected with hypericin 1 hour before (n = 3) or 24 hours after (n = 4) intratumoral ethanol injection. Mice were euthanized 24 hours after hypericin injection and, taking advantage of the fluorescent property of the compound, the excised livers were investigated qualitatively and quantitatively by means of fluoromacroscopic and fluoromicroscopic examinations, colocalized with conventional histomorphology. RESULTS: Significant differences in hypericin fluorescence were found in necrosis, viable tumor and normal liver tissue in decreasing order (P < .05) (ie, in necrosis, mean fluorescence densities were about 4.5 times higher than in viable tumor and approximately 14 times higher than in normal liver). When hypericin was injected 1 hour before, maximal blood concentrations were achieved at the time of ethanol treatment, so that on ablation an outstanding extravasation took place in the entire necrotic area in comparison with accumulation of hypericin only at the peripheral zone of necrosis when it was injected 24 hours after ablation. CONCLUSIONS: Hypericin specifically enhanced the imaging contrast between necrotic and viable tissues and nonspecifically distinguished viable tumor from normal liver. Injection of hypericin shortly before ablation is more favorable than after ablation, because it circumvents difficulties with no-entry zones for hypericin and requires shorter intervals between ethanol ablation and imaging.

Evaluation of tumor affinity of mono-[(123)I]iodohypericin and mono-[(123)I]iodoprotohypericin in a mouse model with a RIF-1 tumor.

In this study we have compared the tumour-seeking properties of mono-[(123)I]iodoprotohypericin and mono-[(123)I]iodohypericin in C3H mice with a subcutaneous radiation-induced fibrosarcoma-1 tumor. After intravenous injection, both tracers were rapidly cleared from all organs and were retained by the tumors. There was no significant difference in tumor uptake of the two tracers at all studied time points (p > 0.05). To study the plausible mechanism of hypericin and mono-iodohypericin uptake in tumor, their plasma binding profile was investigated. Both agents show high affinity for low-density lipoproteins and to a lesser extent high-density lipoproteins and other heavy proteins. Mono-[(123)I]iodohypericin appears to be more promising as a tumor diagnostic agent, given its faster clearance from all organs.

The impact of aggregation on the biodistribution of hypericin.

Hypericin is a potent agent in the photodynamic therapy of cancers and accumulates to a large extent in tumor tissue. To better understand the impact of hypericin aggregates present in the delivery vehicle on the biodistribution of the compound, we compared the in vivo tissue accumulation after administering hypericin suspended as coarse aggregates in phosphate-buffered saline, with the biodistribution found after injection of a solution of hypericin in a mixture of DMSO, polyethylene glycol and water. When administered as coarse aggregates, hypericin showed a pronounced uptake in liver, spleen and lung and a slow body clearance with a complete decline in tumor/normal tissue ratios (far less than 1). In contrast, delivery of hypericin as a solution resulted in dramatically improved tumor to normal tissue ratios and a relatively fast elimination from the body. To elucidate the exact localization of hypericin in both conditions, a fluorescence microscopy study was performed on sections of spleen, liver, lung and tumor tissue. At 24 h after injection, fluorescence in spleen, liver and lung was faint and homogeneous for dissolved hypericin, whereas bright fluorescent spots covering the entire tissue sections were found when coarse aggregates were injected. We found that aggregates get trapped within these tissues, followed by a gradual monomerization. A direct involvement of monocytes and macrophages, however, could not be demonstrated. In conclusion, it is of critical importance that the delivery vehicle prevents extensive aggregation of hypericin before injection and assures an efficient transfer to serum lipoproteins upon injection. These results may also be extended to radiolabeled derivatives and other lipophilic photosensitizers, such as porphyrins, phthalocyanines, naphthalocyanines and chlorines, with similar aggregation properties.