Microencapsulation of curcumin by spray drying: Characterization and fortification of milk.

Curcumin, the major bioactive component of turmeric (Curcuma longa), was microencapsulated by spray drying in the matrix of HI-CAP 100 (resistant starch)/ maltodextrin and whey protein isolate to improve its oral bioavailability and solubility. Taguchi orthogonal array design (L18) was used to optimize the spray drying conditions. The optimal conditions for microencapsulation were inlet drying air temperature of 185 °C, feed rate of 6 mL/min and HI-CAP 100 as wall material. The moisture content, encapsulation efficiency and bulk density at these conditions were 4.65%, 82.42% and 358.40 kg/m3, respectively. The spray-dried microcapsules were spherical-shaped with folds and vacuoles. The yellowness index and a* value of curcumin decreased after microencapsulation. FTIR spectroscopy indicated that the curcumin after microencapsulation presumably retained its chemical structure. DSC thermograms confirmed that the microcapsules were heat stable up to 200 °C. The microcapsules had better heat stability and sustained in-vitro release as compared to that of pure curcumin. The DPPH free radical scavenging activity of curcumin was 61.43%, which was largely unaffected after microencapsulation. Fortification of milk with HI-CAP 100-based microcapsules at the selected dose had no adverse effect on organoleptic properties as compared to normal milk. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13197-021-05142-0.

Association between distance from the radiation source and radiation exposure: A phantom-based study.

OBJECTIVES: The study evaluated the association between distance from radiation source and radiation exposure. BACKGROUND: Radiation exposure during medical procedures is associated with increased risk of cancer and other adverse effects. METHODS: An American National Standards Institute phantom was used to study the relationship between measured entrance surface exposure (MESE) and distance from the X-ray source in postero-anterior, left anterior oblique, and right anterior oblique projections. Three distance settings for table height were evaluated with "low" defined as 52 cm, "mid" 66 cm, and "high" 80 cm from the focal point of the X-ray source. Air-kerma and dose-area product measurements were recorded. Operator exposure with each of these conditions was measured, in a short operator (150 cm) as well as in a tall operator (190 cm). RESULTS: Aggregate results for the three projections were as follows. MESE (µGy/frame) significantly decreased as table-height increases (median, interquartile range, p-value) (low table-height 192.5 [122.4-201.2], mid table-height 105.8 [82.7-115.8], and high table-height 71.7 [58.4-75], p < .0005). The operator exposure (µGy/frame), significantly increased as the table-height increased (low table-height 0.0943 [0.0598-0.1157], medium table-height 0.1128 [0.0919-0.1397], and high table-height 0.158 [0.1339-0.2165], p < .0005). A shorter operator received higher radiation exposure compared to a taller operator (short operator 0.1405 [0.1155-0.1758] and tall operator 0.0995 [0.0798-0.1212], p < .0005). CONCLUSIONS: Increasing table-height is associated with a significant decrease in MESE. Operator radiation exposure increases with increasing table-height and shorter operators receive greater radiation exposure compared to taller operators.

Distinctive and common features of moderate aplastic anaemia.

The therapy algorithm for severe aplastic anaemia (sAA) is established but moderate AA (mAA), which likely reflects a more diverse pathogenic mechanism, often represents a treatment/management conundrum. A cohort of AA patients (n = 325) was queried for those with non-severe disease using stringent criteria including bone marrow hypocellularity and chronic persistence of moderately depressed blood counts. As a result, we have identified and analyzed pathological and clinical features in 85 mAA patients. Progression to sAA and direct clonal evolution (paroxysmal nocturnal haemoglobinuria/acute myeloid leukaemia; PNH/AML) occurred in 16%, 11% and 1% of mAA cases respectively. Of the mAA patients who received immunosuppressive therapy, 67% responded irrespective of time of initiation of therapy while conservatively managed patients showed no spontaneous remissions. Genomic analysis of mAA identified evidence of clonal haematopoiesis with both persisting and remitting patterns at low allelic frequencies; with more pronounced mutational burden in sAA. Most of the mAA patients have autoimmune pathogenesis similar to those with sAA, but mAA contains a mix of patients with diverse aetiologies. Although progression rates differed between mAA and sAA (P = 0·003), cumulative incidences of mortalities were only marginally different (P = 0·095). Our results provide guidance for diagnosis/management of mAA, a condition for which no current standard of care is established.

Nebivolol-Loaded Microsponge Gel for Healing of Diabetic Wound.

An attempt was made to formulate nebivolol-loaded microsponge gel to access drug at wound area, incorporated into gel that possess optimum moist wound management environment during later stages of wound closure. Nebivolol, antihypertensive drug, exhibits vasodilating effects via nitric oxide pathway, slows diabetic neuropathy, and restores endothelial function in diabetic wounds. Microsponges were prepared by optimizing independent variables; drug to polymer ratio and internal phase volume and their effects on production yield, entrapment efficiency, and particle size. Formulations of microsponges were evaluated for drug content. Differential scanning calorimetry indicated reduction in crystallinity of NB during the formation of microsponges. In vitro study (drug to polymer 1:4 and 10 ml internal phase volume acetone) showed 80% drug released within 8 h. Spherical and porous microsponges confirmed by scanning electron microscopy were incorporated in the carbopol 934 (2%) gel base. Gel was characterized for pH, viscosity, and drug content. Less spreadability determined by texture analyzer demonstrated viscous nature of gel. In vitro diffusion study revealed entrapped drug in porous microsponges with slow release to heal wound. In vivo study performed using streptozotocin-induced diabetic rats and excision wound model showed wound healing and closure activity within day 10. Histology revealed inflammatory cell infiltrations and neovascularization in granulation tissues, ultimately healing wound. Microsponge gel prolonged drug release due to entrapped form in porous structure of microsponges with significant and fast wound healing and closure in diabetic rats. Microsponges with loaded drug fulfilled accessibility at wound area, while gel provided optimum moist wound management environment during later stages of wound closure.

Acid exposure induces multiplication of Salmonella enterica serovar Typhi.

Salmonella enterica serovar Typhi faces several environmental stresses while going through the stomach (acidic pH) to the small intestine (basic pH) and intracellularly in macrophages (acidic pH) in humans. The acidic pH followed by alkaline pH in the small intestine might be responsible for expression of certain stress-induced genes, resulting in not only better survival but also induction of multiplication and invasion of the bacterium in the small intestine. Based on this hypothesis, we developed a process wherein we exposed the blood, urine, and stool specimens from 90 acute typhoid fever patients and 36 chronic typhoid carriers to acidic pH to see the effect on isolation rate of S. Typhi. About 5 g of freshly passed unpreserved stool, a centrifuged deposit of 15 ml of urine, and 5 ml of blood clot were subjected to 5 ml of Luria-Bertani (LB) broth (pH 3.5) for 20 min, followed by enrichment in bile broth-selenite F broth. When the combined isolation from all 3 specimens, i.e., blood, urine, and stool, after acid exposure was considered, a total of 77.7% of the acute typhoid patients were observed to be positive for the isolation of the S. Typhi serotype, compared to 8.8% by the conventional method. Similarly, 42% (15/36) of chronic carriers yielded positive for S. Typhi growth after acid exposure, compared to 5.5% (2/36) by the conventional method. It therefore can be concluded that acid shock triggers the multiplication of the bacteria, resulting in better isolation rates from blood clot, stool, and urine specimens.

Plasmodium falciparum merozoite surface antigen, PfRH5, elicits detectable levels of invasion-inhibiting antibodies in humans.

Plasmodium falciparum is an intracellular protozoan parasite that infects erythrocytes and hepatocytes. The blood stage of its life cycle causes substantial morbidity and mortality associated with millions of infections each year, motivating an intensive search for potential components of a multi-subunit vaccine. In this study, we present data showing that antibodies from natural infections can recognize a recombinant form of the relatively conserved merozoite surface antigen, PfRH5. Furthermore, we performed invasion inhibition assays on clinical isolates and laboratory strains of P. falciparum in the presence of affinity purified antibodies to RH5 and show that these antibodies can inhibit invasion in vitro.

Deciphering the Neuropsychiatric Lupus Enigma: Navigating the Intersection of Acute Inflammatory Demyelinating Polyneuropathy (AIDP), Infection, and Flare.

A 17-year-old male diagnosed with systemic lupus erythematosus (SLE), showing poor compliance with medication, presented to our facility with a 20-day history of fever, polyarthritis, and cough. Additionally, he had experienced a seizure episode, followed by a one-day history of altered mentation. Subsequently, he developed pneumonia, respiratory distress, and shock, necessitating ventilator and inotropic support. Neuropsychiatric lupus (NP-lupus) was suspected, and hence high-dose steroids, hydroxychloroquine, and broad-spectrum antibiotics were initiated. Following successful extubation, he manifested ascending flaccid paralysis. The presence of albumin-cytological dissociation and axonal neuropathy confirmed the diagnosis of acute inflammatory demyelinating polyneuropathy (AIDP). He underwent further management with pulse steroids and plasmapheresis. Upon recovery, he was discharged on a regimen of steroids, cyclophosphamide, and hydroxychloroquine. During follow-up, he maintained ambulatory status with no residual neurological sequelae.

Real-world experience with clinical management of talquetamab in relapsed/refractory multiple myeloma: a qualitative study of US healthcare providers.

OBJECTIVE: Talquetamab is the first-in-class GPRC5DxCD3 bispecific antibody for relapsed/refractory multiple myeloma. Given limited real-world data, this study was conducted with US healthcare providers (HCPs) to understand real-world talquetamab dosing and symptom management. METHODS: In February/March 2024, individual in-depth interviews (IDIs; n = 10) were conducted with HCPs administering talquetamab in real-world settings. A subsequent expert panel (n = 6) further discussed current practices. RESULTS: The IDIs reported a variety of settings for step-up dosing (SUD), including inpatient (n = 5), outpatient (n = 3), and hybrid models (n = 2), with a trend toward shorter SUD length to reduce healthcare resource utilization. Most HCPs used a biweekly (Q2W) schedule in SUD (n = 7) and treatment phases (n = 8). Six participants explored reducing dose frequency to every 4 weeks (Q4W) in patients following positive disease response to treatment, considering patient convenience and relieving GPRC5D-related symptoms. Panelists recommended symptom management and prophylactic strategies, such as dexamethasone and nystatin mouthwash or zinc and vitamin B complex for oral symptoms, and topical steroids and cosmetic products for skin and nail symptoms. CONCLUSION: This study outlines current real-world practices for talquetamab. Findings indicate variation in the SUD care setting. The 0.8 mg/kg Q2W dosing schedule was most common, although switching to Q4W is a real-world symptom management strategy for some patients with responses to therapy. GPRC5D-related symptom management approaches are evolving; prophylactic use of dexamethasone and nystatin mouthwash or zinc and vitamin B complex may be effective strategies to alleviate oral symptoms. Further real-world evidence is needed to inform optimal dosing schedules while mitigating symptom impact.

Talquetamab is a new treatment that was approved in the United States in 2023 for a type of blood cancer called multiple myeloma. This drug is administered at one of two doses, each of which includes a defined step-up dosing schedule where patients first receive smaller amounts of the drug to help avoid serious side effects. Because talquetamab is new and associated with treatment-related symptoms not normally seen with other multiple myeloma treatments, doctors and patients need more guidance on drug administration and symptom management. In this study, we describe findings from interviews and an expert panel discussion with healthcare professionals who have experience using talquetamab. This study found that most healthcare professionals administered step-up dosing with patients staying overnight in the hospital, while other providers administered these doses during outpatient visits. Most providers administered talquetamab once every 2 weeks after utilizing the associated step-up dosing schedule. Additionally, healthcare providers described transitioning some patients, who had responded positively to treatment, to a less frequent dosing schedule of once per month to help reduce the effect of treatment-related symptoms. Participants in the expert panel described approaches for managing or preventing these symptoms, such as dexamethasone and nystatin mouthwashes or zinc and vitamin B complex for oral symptoms, and topical steroids and cosmetic products for skin and nail symptoms. In summary, this study provides valuable real-world information from healthcare providers who have experience treating patients with multiple myeloma with talquetamab.

Nursing Considerations for the Clinical Management of Adverse Events Associated with Talquetamab in Patients with Relapsed or Refractory Multiple Myeloma.

OBJECTIVES: Talquetamab is a newly approved bispecific antibody targeting the CD3 receptor on T cells and a receptor, G protein-coupled receptor family C group 5 member D (GPRC5D), highly expressed on multiple myeloma (MM) cells. In addition to immune therapy-related adverse events (AEs) associated with bispecific antibody therapies, talquetamab is associated with unique skin/nail and oral GPRC5D-related side effects that require additional supportive care. This review provides clinical management strategies for talquetamab based on oncology nurses' experience during the MonumenTAL-1 (NCT03399799/NCT04634552) clinical trial. The objective of this review is to raise awareness among nurses and patients to better understand and manage the side effects associated with talquetamab treatment in order to optimize patient outcomes. DATA SOURCES: MonumenTAL-1 is a phase 1/2 clinical trial of talquetamab in patients with relapsed/refractory MM who are triple-class exposed. Details on overall response, safety, and AE incidence and occurrence were previously published. Management strategies for the T-cell-related and unique GPRC5D-related AEs were collected from oncology nurses from different study sites. CONCLUSION: Talquetamab has shown overall response rates of >71% in patients with relapsed/refractory MM in the MonumenTAL-1 study. AEs were low grade and predictable; few led to study discontinuation. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses have specialized knowledge of treatment administration monitoring based on their participation in the MonumenTAL-1 trial. This review provides information for nurses in both the academic and community settings on how to monitor, counsel, and support patients, which will in turn improve patients' quality of life and overall survival.

Patient perspectives on BCMA-targeted therapies for multiple myeloma: a survey conducted in a patient advocacy group.

Background: Advances in multiple myeloma (MM) treatment have shifted the therapeutic landscape. Understanding patients' perspectives can assist physicians in helping patients make informed decisions. This study aimed to understand the patient decision-making process and gain insights into patient perspectives on B-cell maturation antigen (BCMA)-targeted therapies for MM. Methods: An 18-question survey was completed by patients with MM enrolled in HealthTree® Cure Hub, an online portal helping patients with plasma cell dyscrasias navigate their disease. Results: From October 28, 2022, to January 12, 2023, 325 patients with MM participated in the survey. The mean age (standard deviation) of the respondents was 66 (8) years; 54% were female and 90% were White. Among 218 patients with complete clinical records in the database, the median (min, max) lines of therapy (LOT) was 2 (1,16). Among 61 (28%) patients who had received ≥4 LOTs, 55 (90%) were triple-class exposed. Of the 290 patients who responded to the question about openness to new therapies, 76 (26%) were open to trying a new therapy immediately and 125 (43%) wanted more information on safety and efficacy. Most respondents reported likely or very likely to try a BCMA CAR T-cell therapy (60%) or a bispecific antibody (74%) and some needed more information to decide (16% for CAR T-cell therapy and 13% for bispecific antibody). The most requested information included efficacy, side effects (SEs), eligibility, and administration process for both CAR T-cell and bispecific therapies. When 2 therapies with the same efficacy and duration of response were offered, 69% of respondents would prefer the therapy with a lower risk of severe SEs but requires continuous dosing with no treatment-free interval, and 31% preferred a therapy given once followed by a treatment-free interval but with a potentially higher risk of severe SEs. To receive an effective therapy, the top acceptable trade-offs included frequent monitoring of SEs and initiating a new therapy in a hospital setting, and the least acceptable compromise was caregiver burden. Conclusions: This study found a high level of openness in patients with MM to try BCMA-targeted therapies. Information on efficacy, safety, availability, and eligibility may assist patients on decision-making.

Hybrid Endovascular and Surgical Treatment of a Traumatic Scalp Arteriovenous Fistula.

Traumatic scalp arteriovenous fistula (AVF) is a relatively rare complication of scalp trauma. Patients most commonly present with a growing pulsatile head mass. History of trauma, clinical presentation, and diagnostic imaging, including digital subtraction angiography, aid in establishing the diagnosis. Endovascular embolization is the preferred treatment modality which may be combined with surgical excision for larger complex lesions. In this case, we report the clinical and radiological features of a traumatic scalp AVF in a middle-aged man with a remote history of trauma that was treated with a two-step hybrid approach combining transarterial embolization with surgical resection. We also present a brief overview of the various treatment modalities currently employed to treat scalp AVFs.

Acute amnesia caused by left fornix infarction: A case report of an unusual entity.

Cerebral infarction is an uncommon and unusual cause of acute amnesia. The fornix is a white matter tract bundle that plays an important function in memory. We present the case of a 60-year-old male presenting with altered mental status and acute onset amnesia with CT and MR imaging demonstrating an acute left fornix infarct. This case serves to further illuminate the findings associated with this uncommon clinical event. In addition, it highlights the importance for physicians across multiple subspecialities to maintain an index of suspicion for fornix infarct in the evaluation of acute onset amnesia.

Kidney disease and COVID-19 disease severity-systematic review and meta-analysis.

We aimed to identify prevalence and association of comorbid chronic kidney disease (CKD), acute kidney injury (AKI) and utilization prevalence of continuous renal replacement therapy (CRRT) in COVID-19-hospitalized patients as a function of severity status. With the ongoing struggle across the globe to combat COVID-19 disease, published literature has described the role of kidney disease in COVID-19 patients based on single/multicenter experiences across the globe. We extracted data from observational studies describing comorbid CKD, AKI and CRRT and outcomes and severity of COVID-19-hospitalized patients from December 1, 2019-August 20, 2020 following PRISMA guidelines. Severity of COVID-19 includes intensive care unit admission, oxygen saturation < 90%, invasive mechanical ventilation utilization, in-hospital admission and mortality. Meta-analysis was performed using a random-effects model to calculate pooled estimates, and forest plots were created. In total, 29 studies with 15,017 confirmed COVID-19 patients were included. The overall prevalence of AKI was 11.6% [(430/3693)], comorbid CKD 9.7% [(1342/13,728)] and CRRT 2.58% [(102/3946)] in our meta-analysis. We also found higher odds of comorbid CKD (pooled OR: 1.70; 95%CI: 1.21-2.40; p = 0.002), AKI (8.28; 4.42-15.52; p < 0.00001) and utilization of CRRT (16.90; 9.00-31.74; p < 0.00001) in patients with severe COVID-19 disease. Conclusion Our meta-analysis suggests that comorbid CKD, AKI and utilization of CRRT were significantly associated with COVID-19 disease severity. Clinicians should focus on early triaging of COVID-19 patients with comorbid CKD and at risk for AKI to prevent complication and mortality.

Structure-guided insights into potential function of novel genetic variants in the malaria vaccine candidate PfRh5.

The recent stall in the global reduction of malaria deaths has made the development of a highly effective vaccine essential. A major challenge to developing an efficacious vaccine is the extensive diversity of Plasmodium falciparum antigens. While genetic diversity plays a major role in immune evasion and is a barrier to the development of both natural and vaccine-induced protective immunity, it has been under-prioritized in the evaluation of malaria vaccine candidates. This study uses genomic approaches to evaluate genetic diversity in next generation malaria vaccine candidate PfRh5. We used targeted deep amplicon sequencing to identify non-synonymous Single Nucleotide Polymorphisms (SNPs) in PfRh5 (Reticulocyte-Binding Protein Homologue 5) in 189 P. falciparum positive samples from Southern Senegal and identified 74 novel SNPs. We evaluated the population prevalence of these SNPs as well as the frequency in individual samples and found that only a single SNP, C203Y, was present at every site. Many SNPs were unique to the individual sampled, with over 90% of SNPs being found in just one infected individual. In addition to population prevalence, we assessed individual level SNP frequencies which revealed that some SNPs were dominant (frequency of greater than 25% in a polygenomic sample) whereas most were rare, present at 2% or less of total reads mapped to the reference at the given position. Structural modeling uncovered 3 novel SNPs occurring under epitopes bound by inhibitory monoclonal antibodies, potentially impacting immune evasion, while other SNPs were predicted to impact PfRh5 structure or interactions with the receptor or binding partners. Our data demonstrate that PfRh5 exhibits greater genetic diversity than previously described, with the caveat that most of the uncovered SNPs are at a low overall frequency in the individual and prevalence in the population. The structural studies reveal that novel SNPs could have functional implications on PfRh5 receptor binding, complex formation, or immune evasion, supporting continued efforts to validate PfRh5 as an effective malaria vaccine target and development of a PfRh5 vaccine.

Erythrocyte CD55 mediates the internalization of Plasmodium falciparum parasites.

Invasion of human erythrocytes by the malaria parasite Plasmodium falciparum is a multi-step process. Previously, a forward genetic screen for P. falciparum host factors identified erythrocyte CD55 as essential for invasion, but its specific role and how it interfaces with the other factors that mediate this complex process are unknown. Using CRISPR-Cas9 editing, antibody-based inhibition, and live cell imaging, here we show that CD55 is specifically required for parasite internalization. Pre-invasion kinetics, erythrocyte deformability, and echinocytosis were not influenced by CD55, but entry was inhibited when CD55 was blocked or absent. Visualization of parasites attached to CD55-null erythrocytes points to a role for CD55 in stability and/or progression of the moving junction. Our findings demonstrate that CD55 acts after discharge of the parasite's rhoptry organelles, and plays a unique role relative to all other invasion receptors. As the requirement for CD55 is strain-transcendent, these results suggest that CD55 or its interacting partners may hold potential as therapeutic targets for malaria.

Structural Basis of Antibody Conformation and Stability Modulation by Framework Somatic Hypermutation.

Accumulation of somatic hypermutation (SHM) is the primary mechanism to enhance the binding affinity of antibodies to antigens in vivo. However, the structural basis of the effects of many SHMs remains elusive. Here, we integrated atomistic molecular dynamics (MD) simulation and data mining to build a high-throughput structural bioinformatics pipeline to study the effects of individual and combination SHMs on antibody conformation, flexibility, stability, and affinity. By applying this pipeline, we characterized a common mechanism of modulation of heavy-light pairing orientation by frequent SHMs at framework positions 39H, 91H, 38L, and 87L through disruption of a conserved hydrogen-bond network. Q39LH alone and in combination with light chain framework 4 (FWR4L) insertions further modulated the elbow angle between variable and constant domains of many antibodies, resulting in improved binding affinity for a subset of anti-HIV-1 antibodies. Q39LH also alleviated aggregation induced by FWR4L insertion, suggesting remote epistasis between these SHMs. Altogether, this study provides tools and insights for understanding antibody affinity maturation and for engineering functionally improved antibodies.

Quantitative Determination and Characterization of a Kashmir Saffron (Crocus sativus L.)-Based Botanical Supplement Using Single-Laboratory Validation Study by HPLC-PDA with LC-MS/MS and HPTLC Investigations.

Food ingredients hold a higher nutritional value as a botanical supplement playing a vital role in modifying and maintaining the physiological conditions that improve human health benefits. The Kashmir saffron (Crocus sativus L; KCS) obtained from dried stigmas is known for its aroma precursors and apocarotenoid derivatives, imparting a wide range of medicinal values and therapeutic benefits. In the present study, a simultaneous determination of apocarotenoids and flavonoids in stigma-based botanical supplements was carried out using analytical investigations. The high-performance thin-layer chromatography-based qualitative analysis of the raw material (stigmas, stamens, and tepals) and stigma extract has been carried out to identify apocarotenoids and flavonoids. The rapid HPLC-PDA method for the simultaneous quantification of KCS apocarotenoids was robust, precise (<5.0%), linear (R 2 > 0.99), and accurate (80-110%) as per the single-laboratory validation data. Furthermore, the combined-expanded uncertainty (95%; K = 2) was calculated and found as 0.0035-0.007% (<5.0%) as per the EURACHEM guide for this HPLC analysis. Additionally, an untargeted identification of 36 compounds in the botanical supplement was based on the elution order, UV-vis spectra, mass fragmentation pattern, and standards by ESI-MS/MS analysis with comprehensive chromatographic fingerprinting. Thus, these analytical approaches enable a composite profile of the stigma-based extract as a potential supplement for human health benefits.

Bernthsen synthesis, antimicrobial activities and cytotoxicity of acridine derivatives.

The condensation reaction of diphenylamine with 2-oxo-2H-(substituted chromen)-4-yl acetic acid in presence of anhydrous zinc chloride afford 4-(acridine-9-ylmethyl)-2H-(substituted chromen)-2-one. The synthesized compounds were characterized by spectral studies and elemental analysis and screened for their in vitro antibacterial activity against Staphylococcus aureus, Staphylococcus pyogenes (gram +ve), Escherichia coli, Pseudomonas aeruginosa (gram -ve) and antifungal activity against Aspergillus niger and anticancer activity (HL-60, Hep-2 & HEK293T) by MTT assay. Chloro substituted compounds showed antimicrobial and anticancer activity with IC(50) values in the low micromolar range.