Distal radius fracture fixation using WALANT versus general and regional anesthesia: A systematic review and meta-analysis.

BACKGROUND: WALANT (wide-awake local anaesthetic no tourniquet) has become a popular technique in upper limb surgery including distal radius fracture fixation. The purpose of this systematic review and meta-analysis is to assess the effectiveness of the WALANT technique in distal radius fracture fixation, and to compare it to both general and regional anaesthesia. METHODS: Pubmed, Embase, and Scopus databases were searched on 26/06/21 according to the PRISMA guidelines with the following search terms: radius, WALANT, "local anesthetic", wide-awake surgery. All studies comparing WALANT with other forms of anaesthesia for distal radius fracture fixation were included. RESULTS: 110 articles were identified, six studies (410 patients) were included, 164 of these patients were in the WALANT group. Two patients (1.2%) in the WALANT group and seven (6.5%) in the regional anaesthesia group required conversion to general anaesthesia. There was no statistically significant difference in post-operative complications, intra-operative VAS pain scores, operative times, functional or radiological outcomes. A statistically significant 8.6 mls increase in pooled mean blood loss in the WALANT group was noted (p = 0.02) although the clinical significance of this is doubtful. CONCLUSION: The WALANT technique for distal radius fracture fixation is non-inferior to regional and general anaesthesia. It is a safe and effective technique that surgeons may consider utilising, especially for patients not suitable for general anaesthetic or in centres in which there is a lack of access to specialist anaesthetic equipment and care.

Liquid crystalline assembly for potential combinatorial chemo-herbal drug delivery to lung cancer cells.

BACKGROUND: Lung cancer is the most common cancer and the leading cause of total deaths worldwide. Its classified into two major types including non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC) based on the origin of abnormal lung cells as well as the smoking status of the patient. NSCLC is the most common and aggressive type of lung cancer representing 80%-85% of all cases. PURPOSE: The aim of the study was to present lyotropic liquid crystalline nanoparticles (LCNPs) as promising carriers for co-delivery of the chemotherapeutic agent, pemetrexed (PMX) and the herbal drug, resveratrol (RSV) for effective lung cancer management. METHODS: The proposed PMX-RSV-LCNPs were prepared by hydrotrope method. Hydrophobic ion pairing with cetyl trimethyl ammonium bromide (CTAB) was implemented to increase the encapsulation efficiency of the hydrophilic PMX up to 95%±3.01%. RESULTS: The tailored PMX-RSV-LCNPs exhibited a particle size of 173±0.26 nm and biphasic release pattern with a relatively initial burst release within first 3-4 hour followed by sustained release up to 24 hours. Moreover, PMX-RSV-LCNPs manifested superior concentration and time dependent cytotoxicity profile against A549 lung cancer cells with IC50 4.0628 µg/mL. Besides, the enhanced cellular uptake profile based on bioadhesive properties of glyceryl monoolein (GMO) as well as energy independent (cholesterol dependent) pattern. In-vivo evaluations against urethane induced lung cancer bearing mice demonstrated the potentiality of PMX-RSV-LCNPs in tumor growth inhibition via inhibition of angiogenesis and induction of apoptosis. The results were supported by histopathological analysis and immunohistochemical Ki67 staining. Moreover, PMX-RSV-LCNPs displayed a promising safety profile via attenuating nephro- and hepatotoxicity. CONCLUSION: PMX-RSV-LCNPs elaborated in the current study hold a great promise for lung cancer treatment.

Self-assembled phospholipid-based phytosomal nanocarriers as promising platforms for improving oral bioavailability of the anticancer celastrol.

Celastrol (CST) is a promising natural drug of herbal origin that gained a great interest in the recent years by virtue of its wide variety of pharmacological actions. Nowadays, CST is extensively studied as a natural anticancer surrogate with a potential activity against various types of cancers. However, CST suffers from many limitations that handicapped its clinical utility such as limited aqueous solubility and poor gastrointestinal absorption which resulted into its low oral bioavailability. This work spotlights, for the first time, development of self-assembled phytosomal nanocarriers (CST-PHY) for improving CST solubility and oral bioavailability. First CST-phospholipid complex was prepared by a simple solvent evaporation technique. Formation of CST-phospholipid complex was confirmed by differential scanning calorimetry (DSC), infrared spectroscopy (IR), powder X-ray diffraction (XRD) and partition coefficient determination. After dispersion into deionized water, CST-phospholipid complex was self-assembled to form CST-PHY. The optimized CST-PHY demonstrated a nanometric particle size of 178.4±7.07nm and a negative zeta potential of -38.7±3.61mV. Comparative in-vitro release study showed the ability of phytosomes to significantly enhance CST release compared with crude drug and physical mixture. Pharmacokinetic studies in rabbits revealed significant improvement in CST-PHY oral bioavailability compared with crude CST evidenced by 4-fold increase in AUC0-8 and 5-fold increase in Cmax of CST-PHY compared with crude CST. Conclusively, the results confirmed the potential of phytosomal nanocarriers to improve CST oral delivery paving the way for its use for oral cancer therapy.

Prospective Assessment of Virtual Screening Heuristics Derived Using a Novel Fusion Score.

High-throughput screening (HTS) is a widespread method in early drug discovery for identifying promising chemical matter that modulates a target or phenotype of interest. Because HTS campaigns involve screening millions of compounds, it is often desirable to initiate screening with a subset of the full collection. Subsequently, virtual screening methods prioritize likely active compounds in the remaining collection in an iterative process. With this approach, orthogonal virtual screening methods are often applied, necessitating the prioritization of hits from different approaches. Here, we introduce a novel method of fusing these prioritizations and benchmark it prospectively on 17 screening campaigns using virtual screening methods in three descriptor spaces. We found that the fusion approach retrieves 15% to 65% more active chemical series than any single machine-learning method and that appropriately weighting contributions of similarity and machine-learning scoring techniques can increase enrichment by 1% to 19%. We also use fusion scoring to evaluate the tradeoff between screening more chemical matter initially in lieu of replicate samples to prevent false-positives and find that the former option leads to the retrieval of more active chemical series. These results represent guidelines that can increase the rate of identification of promising active compounds in future iterative screens.

Yin Yang 1-mediated epigenetic silencing of tumour-suppressive microRNAs activates nuclear factor-κB in hepatocellular carcinoma.

Enhancer of zeste homolog 2 (EZH2) catalyses histone H3 lysine 27 trimethylation (H3K27me3) to silence tumour-suppressor genes in hepatocellular carcinoma (HCC) but the process of locus-specific recruitment remains elusive. Here we investigated the transcription factors involved and the molecular consequences in HCC development. The genome-wide distribution of H3K27me3 was determined by chromatin immunoprecipitation coupled with high-throughput sequencing or promoter array analyses in HCC cells from hepatitis B virus (HBV) X protein transgenic mouse and human cell models. Transcription factor binding site analysis was performed to identify EZH2-interacting transcription factors followed by functional characterization. Our cross-species integrative analysis revealed a crucial link between Yin Yang 1 (YY1) and EZH2-mediated H3K27me3 in HCC. Gene expression analysis of human HBV-associated HCC specimens demonstrated concordant overexpression of YY1 and EZH2, which correlated with poor survival of patients in advanced stages. The YY1 binding motif was significantly enriched in both in vivo and in vitro H3K27me3-occupied genes, including genes for 15 tumour-suppressive microRNAs. Knockdown of YY1 reduced not only global H3K27me3 levels, but also EZH2 and H3K27me3 promoter occupancy and DNA methylation, leading to the transcriptional up-regulation of microRNA-9 isoforms in HCC cells. Concurrent EZH2 knockdown and 5-aza-2'-deoxycytidine treatment synergistically increased the levels of microRNA-9, which reduced the expression and transcriptional activity of nuclear factor-κB (NF-κB). Functionally, YY1 promoted HCC tumourigenicity and inhibited apoptosis of HCC cells, at least partially through NF-κB activation. In conclusion, YY1 overexpression contributes to EZH2 recruitment for H3K27me3-mediated silencing of tumour-suppressive microRNAs, thereby activating NF-κB signalling in hepatocarcinogenesis.

Cross-sectional comparison of point-of-care with laboratory HbA1c in detecting diabetes in real-world remote Aboriginal settings.

OBJECTIVES: To determine if point-of-care (POC) glycated haemoglobin (HbA1c) is sufficiently accurate in real-world remote settings to predict or exclude the diagnosis of diabetes based on laboratory HbA1c measurements. DESIGN: Cross-sectional study comparing POC capillary HbA1c results with corresponding venous HbA1c levels measured in a reference laboratory. PARTICIPANTS: Aboriginal patients ≥15 years old who were due for diabetes screening at the participating clinics were invited to participate. Two hundred and fifty-five Aboriginal participants were enrolled and 241 were included in the analysis. SETTING: 6 primary healthcare sites in the remote Kimberley region of Western Australia from September 2011 to November 2013. MAIN OUTCOME MEASURES: Concordance and mean differences between POC capillary blood HbA1c measurement and laboratory measurement of venous blood HbA1c level; POC capillary blood HbA1c equivalence value for screening for diabetes or a high risk of developing diabetes; sensitivity, specificity and positive-predictive value for diagnosing and screening for diabetes; barriers to conducting POC testing. RESULTS: Concordance between POC and laboratory results was good (ρ=0.88, p<0.001). The mean difference was -0.15% (95% limits of agreement, -0.67% to 0.36%). POC HbA1c measurements ≥6.5%, 48 mmol/mol had a specificity of 98.2% and sensitivity of 73.7% for laboratory measurements ≥6.5%. The POC equivalence value for screening for diabetes or a high risk of developing diabetes was ≥5.7%, 39 mmol/mol (sensitivity, 91%; specificity, 76.7% for laboratory measurements ≥6.0%, 42 mmol/mol). Staff trained by other clinic staff 'on the job' performed as well as people with formal accredited training. Staff reported difficulty in maintaining formal accreditation. CONCLUSIONS: POC HbA1c testing is sufficiently accurate to be a useful component in screening for, and diagnosing, diabetes in remote communities. Limited local training is adequate to produce results comparable to laboratory results and accreditation processes need to reflect this.

Structure of a shear-thickening polysaccharide extracted from the New Zealand black tree fern, Cyathea medullaris.

A shear-thickening water-soluble polysaccharide was purified from mucilage extracted from the fronds of the New Zealand black tree fern (Cyathea medullaris or 'mamaku' in Maori) and its structure characterised. Constituent sugar analysis by three complementary methods, combined with linkage analysis (of carboxyl reduced samples) and 1H and 13C nuclear magnetic resonance spectroscopy (NMR) revealed a glucuronomannan comprising a backbone of 4-linked methylesterified glucopyranosyl uronic acid and 2-linked mannopyranosyl residues, branched at O-3 of 45% and at both O-3 and O-4 of 53% of the mannopyranosyl residues with side chains likely comprising terminal xylopyranosyl, terminal galactopyranosyl, non-methylesterified terminal glucopyranosyl uronic acid and 3-linked glucopyranosyl uronic acid residues. The weight-average molecular weight of the purified polysaccharide was ∼1.9×10(6) Da as determined by size-exclusion chromatography coupled with multi-angle laser light scattering (SEC-MALLS). The distinctive rheological properties of this polysaccharide are discussed in relation to its structure.

Host immune defense peptide LL-37 activates caspase-independent apoptosis and suppresses colon cancer.

Cathelicidins are a family of bacteriocidal polypeptides secreted by macrophages and polymorphonuclear leukocytes (PMN). LL-37, the only human cathelicidin, has been implicated in tumorigenesis, but there has been limited investigation of its expression and function in cancer. Here, we report that LL-37 activates a p53-mediated, caspase-independent apoptotic cascade that contributes to suppression of colon cancer. LL-37 was expressed strongly in normal colon mucosa but downregulated in colon cancer tissues, where in both settings its expression correlated with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive apoptotic cells. Exposure of colon cancer cells to LL-37 induced phosphatidylserine externalization and DNA fragmentation in a manner independent of caspase activation. Apoptogenic function was mediated by nuclear translocation of the proapoptotic factors, apoptosis-inducing factor (AIF) and endonuclease G (EndoG), through p53-dependent upregulation of Bax and Bak and downregulation of Bcl-2 via a pertussis toxin-sensitive G-protein-coupled receptor (GPCR) pathway. Correspondingly, colonic mucosa of cathelicidin-deficient mice exhibited reduced expression of p53, Bax, and Bak and increased expression of Bcl-2 together with a lower basal level of apoptosis. Cathelicidin-deficient mice exhibited an increased susceptibility to azoxymethane-induced colon tumorigenesis, establishing pathophysiologic relevance in colon cancer. Collectively, our findings show that LL-37 activates a GPCR-p53-Bax/Bak/Bcl-2 signaling cascade that triggers AIF/EndoG-mediated apoptosis in colon cancer cells.

Derangement of the temporomandibular joint; a case study using Mechanical Diagnosis and Therapy.

Mechanical Diagnosis and Therapy (MDT) is widely used for spinal problems, and more recently the principles and mechanical syndromes have been applied to extremity musculoskeletal problems. One of the most common classifications is derangement syndrome, which describes a presentation in which repeated movements causes a decrease in symptoms and a restoration of restricted range of movement. The case study describes the application of repeated movements to a patient with a 7-year history of non-specific temporomandibular pain and reduced function, who had had lots of previous failed treatment. Examination using repeated movements resulted in a classification of derangement, and the patient rapidly responded in 4 treatment sessions, with an abolition of pain and full restoration of function, and remained improved after many years. The case study demonstrates the application of Mechanical Diagnosis and Therapy principles to a patient with a temporomandibular problem.

First Report of Leaf Curl on Celery Caused by Colletotrichum acutatum in the United States.

In June 2010 and July 2011, celery (Apium graveolens) samples cv. Tango were submitted to the Penn State Plant Disease Clinic from Franklin and Dauphin Counties, PA, respectively. Plants exhibited curling and twisting of leaves and petioles and dark, brownish-black necrotic lesions at the base of the plant, extending up the petioles. A fungal organism with morphology consistent to Colletotrichum acutatum J.H. Simmonds was isolated from plant lesion tissue excised from the Dauphin Co. sample. Grown on half strength potato dextrose agar (PDA), the colony had gray aerial mycelium and a pink reverse. Conidia were 5.1 to 14.5 × 2.6 to 5.1 µm, aseptate, hyaline, elliptical, with one or both ends slightly pointed, and formed from the mycelium or in dense orange masses of acervuli on the aerial surface of the culture. Setae were not present. To test pathogenicity, five 23-week-old plants of the cv. Sonora and five 11-week-old plants each of the cvs. Tango and Tall Utah were sprayed until runoff with a conidial suspension (1.3 × 106 conidia/ml and 1.4 × 106 conidia/ml, respectively) and 0.025% Tween. One plant of each cv. was sprayed with milliQ water and 0.025% Tween as a control. Plastic bags were sprayed with the conidial suspension (milliQ water for the control), and secured over the individual plants for 24 h to create a humidity chamber. Plants were incubated in a growth chamber with a 16-h photoperiod, 25°C day/18°C night temperatures, and 70% humidity. Post-inoculation, all of the cv. Tango plants exhibited leaf cupping and curling after 7 days and most plants had dark stem lesions after 3 weeks, consistent with celery leaf curl symptoms. Plants of cvs. Tall Utah and Sonora developed malformed leaves and leaf curl symptoms 16 days and 10 days post-inoculation, respectively. None of the control plants developed symptoms. Infected tissue was excised from diseased plants, surface disinfested in 0.5% sodium hypochlorite for 45 s and plated on half strength PDA. Fungal colonies consistent with C. acutatum were recovered from all inoculated celery tissues (except two of the five inoculated cv. Tall Utah plants and the negative controls). To verify morphological identification, the internal transcribed spacer (ITS) rDNA region was amplified and sequenced for our original isolate and those recovered from the inoculated plants using ITS1 and ITS4 primers (2) (GenBank Accession No. JQ794875). Sequence homology revealed 99 to 100% similarity to accessioned isolates of C. acutatum, which included the holotype and a paratype of C. acutatum (Accession Nos. AF411700 and AF411701, respectively). Celery leaf curl has been reported to have caused devastating crop losses on celery in Australia (1, 3) and to our knowledge, C. acutatum causing leaf curl of celery has not been officially reported in the United States. Infected celery plants are unmarketable because of the leaf malformation and eventual plant necrosis caused by C. acutatum. As such, this disease could have serious negative implications for celery growers in the United States. References: (1) J. B. Heaton and S. R. Dullahide. Australas. Plant Pathol. 22:152, 1993. (2) T. J. White et al. Page 315 in: PCR Protocols: A Guide to Methods and Applications. Academic Press, San Diego, CA, 1990. (3) D. G Wright and J. B. Heaton. Australas. Plant Pathol. 20:155, 1991.

The principle of homologous groups in regulatory affairs of allergen products--a proposal.

Among other legal regulations, the Note for Guidance on Allergen Products CPMP/BWP/243/96 released by the European Medicines Agency provides regulatory instructions regarding the quality of allergen extracts for diagnostic or therapeutic purposes. The current revision of this guideline intends to transform the so-called 'principle of taxonomic families' to the 'principle of homologous groups'. According to this concept, the data of one allergen extract demonstrating stability, efficacy and safety can, to a limited extent, be extrapolated to other allergen extracts belonging to the same homologous groups. The present work proposes the formation of homologous groups for pollen species and animal-derived materials on the basis of similar biochemical composition and homology/cross-reactivity of allergens or allergen sources. Some tree pollen species could be assigned to three different homologous groups, some weed pollen species to one homologous group and numerous grass pollen species to one homologous group on condition that data rely on single defined representative species. A homologous group for mites is limited to the Dermatophagoides species and the grouping of vertebrate-derived materials such as dander could be possible under restrictions. The criteria for the formation of the proposed homologous groups are illustrated in detail to provide an opportunity for extending existing homologous groups by further species in case of new insights in allergens and cross-reactivity of allergen sources. In this way, the concept of homologous groups could serve as a dynamic tool in the regulation of allergen products.

Development of a data collecting tool to explore the consuming patterns of Chinese and Western medicines in Hong Kong.

Chinese and Western medicines are both consumed by citizens in Hong Kong. Safe medication practice, however, whether or not it is conducted by Hong Kong citizens, remains unknown. A data collecting tool was developed to explore the consuming patterns of medicines adopted by Hong Kong citizens. It is hoped that by using this tool, baseline information about the ways in which Hong Kong citizens consume their medicines can be explored. It is also hoped that the information will contribute to the educational planning of community-based safe medication practice. The objectives of this paper were thus to report the development of this data collecting tool and to discuss the use of the tool for the promotion of community-based safe medication practice.

Comparison of methods for point of care preparation of autologous platelet gel.

A platelet gel (PG) is produced by the addition of calcium chloride and thrombin to a platelet concentrate (PC). PG releases multiple growth factors, which have the ability to initiate and stimulate one growth factor's function in the presence of others. This finding has resulted in the use of PG in orthopedic, plastic, and reconstructive surgery. The study compared the commercial systems available for the preparation of PG. All procedures were performed according to the manufacturers directions. The devices were evaluated with respect to ease of use, collection efficiency, platelet quality, and growth factor release. The SmartPReP requires only four processing steps compared to 12 to 24 required by other devices. The SmartPReP and the CATS were the most reproducible, as evidenced by their low coefficient of variation of 13% and 16%. The mean platelet yield was 72% for the SmartPReP, 58% for the 3iPCCS, 54% for the Sequestra, 31% for the Secquire, 31% for the CATS, 27% for the Interpore Cross, and 42.6% for the Biomet GPS. The mean total amount of PDGF-AB and TGF-B1 obtained from the SmartPReP is greater than other systems evaluated. The SmartPReP produced a consistent PC with a yield that was four times baseline range with the lowest coefficient of variation.

An in vitro and in vivo evaluation of autologous platelet concentrate in oral reconstruction.

A platelet concentrate, when combined with calcified thrombin, produces a platelet gel that has been used to achieve hemostasis and modulate bone growth and wound healing. The recovery of high concentrations of viable platelets and their resulting growth factor levels represents the most important factor in the clinical utility of a platelet concentrate because only functional platelets can release the growth factors that are necessary to induce tissue growth and bone regeneration. The SmartPReP system's efficiency in recovery of platelets from a sample of whole blood averaged 70.6%, almost twice that of various manual techniques using laboratory centrifuges. Platelet concentrates prepared by the SmartPReP system had a viability equal to platelet concentrates prepared for transfusion as measured by hypotonic stress, platelet aggregation, and p-selectin. A series of clinical case studies demonstrates the use of autologous platelet gel in oral surgery.

Living-related liver transplantation for Crigler-Najjar syndrome in Saudi Arabia.

OBJECTIVE: To analyse the outcome of six children with Crigler-Najjar syndrome type I (CNS-I) and report the first three living-related liver transplants for this syndrome in Saudi Arabia and the Middle East. SETTINGS: To review the medical records of six children suffering from CNS-I, three of whom underwent living-related liver transplantation (LRLT) between 22 November 1998 and January 2001. MAIN RESULTS: Living-related liver transplantation was performed in three children with a pre-transplant unconjugated bilirubin level of 362, 381 and 502 micromol/L, respectively, despite daily phototherapy of >or= 12 h. Two of the transplanted children developed acute hepatocellular rejection, which was successfully treated with methylprednisolone pulse therapy. One tested cytomegalovirus positive (using the PP65 method), but showed no signs of clinical infection and was treated with ganciclovir. One patient had a biliary leak at the cut surface of the graft which was surgically repaired. Post-operative bilirubin levels returned to normal in all three transplanted children and no further phototherapy was required. One patient, who was not transplanted but received phototherapy, developed severe neurological damage prior to the start of our living-related liver transplant programme with a bilirubin level of 450 micromol/L, her sister is still awaiting transplantation. A 14-yr-old child with a bilirubin level of 420 micromol/L is presently undergoing phototherapy whilst awaiting orthotopic liver transplantation because of the lack of a suitable living-related donor. Six siblings of the six children in our series were reported dead by the families. CONCLUSION: Crigler-Najjar syndrome type I is a relatively common disease in Saudi Arabia for which LRLT is a curative treatment when performed at an early age before the development of kernicterus and neurological deficiency. In countries where there is a severe shortage of cadaveric organs, as is the case in Saudi Arabia, LRLT is the optimum treatment modality for this syndrome.

Determination of the allergenic activity of birch pollen and apple prick test solutions by measurement of beta-hexosaminidase release from RBL-2H3 cells. Comparison with classical methods in allergen standardization.

BACKGROUND: A murine in vitro model of the allergic type I reaction was set up to determine the biologic activity of extracts without involvement of human beings. It is based on beta-hexosaminidase release from passively sensitized RBL cells after allergen challenge. The intended application of this RBL cell assay in the field of quality control of allergenic extracts requires its comparison with established methods. METHODS: The activity of five standardized birch-pollen prick test solutions was determined in parallel by RBL assay, direct IgE binding, IgE-binding inhibition, major allergen content, histamine-release assay, and skin testing. RESULTS: The RBL cell-release assay corresponded well to other methods if a reagin raised against natural birch-pollen extract was used for passive sensitization. However, in the case of a reagin against recombinant Bet v 1, only a decreased activity was observed, presumably because a reduced number of epitopes were recognized by the monospecific reagin. In contrast to standardized birch-pollen extracts, nonstandardized apple extracts showed poor activity in all assays. CONCLUSIONS: This murine model might be a useful tool in the quality control of allergenic extracts. It combines properties of assays based on standardized antisera and of assays that consider IgE cross-linking properties.

Selenium-based drug design: rationale and therapeutic potential.

The wide media coverage given recently to a study correlating higher selenium levels with a reduced risk of advanced prostate cancer is but the latest addition to a growing body of epidemiological findings which link dietary selenium deficiency to diseases as diverse as cancer, heart disease, arthritis and AIDS. Indeed, selenium has a long history of association with human health and disease. Moreover, direct evidence is now emerging for specific beneficial effects of dietary selenium supplementation. Thus, the pharmacology, biology and biochemistry of selenium metabolism have become subjects of intense current interest. At the molecular level, selenium (as selenocysteine) is an essential component of the active sites of the enzymes glutathione peroxidase, iodothyronine 5'-deiodinase and mammalian thioredoxin reductase, and is also present in several other mammalian selenoproteins. Both glutathione peroxidase and thioredoxin reductase catalyse reactions essential to the protection of cellular components against oxidative and free radical damage. As a consequence of the growing recognition of the important biological role of selenium, a number of novel pharmaceutical agents, either selenium-based or which target specific aspects of selenium metabolism, are under development. Among these are orally active selenium-based antihypertensive agents, anticancer, antiviral, immunosuppressive and antimicrobial agents, and organoselenium compounds which reduce oxidative tissue damage and oedema. It can be anticipated that as our understanding of the basic biology and biochemistry of selenium increases, future efforts will uncover even more sophisticated approaches for the rational development of new selenium-based pharmaceutical agents.

Selenium-based antihypertensives. Rationale and potential.

Selenium, long recognised as an important 'dietary antioxidant', is now known to be an essential component of the active sites of a number of enzymes, including the glutathione peroxidase selenoenzyme family which scavenge hydroperoxides to prevent cellular damage. Dietary selenium deficiency has been linked to diseases as diverse as cancer, heart disease, arthritis and AIDS, and epidemiological evidence is now emerging for the beneficial effects of selenium supplementation. Thus, the pharmacology, biology and biochemistry of selenium metabolism have become subjects of considerable interest, which are spurring efforts to develop synthetic selenium-containing compounds as potential therapeutic agents. Phenylaminoalkyl selenides were developed in the authors' laboratories as novel, selenium-based pharmacological agents. We demonstrated that these compounds exhibited dose-dependent antihypertensive activity in spontaneously hypertensive rats. Biochemical studies established that as a consequence of the redox properties of their selenium moieties, these phenylaminoalkyl selenides possessed the remarkable property of propagating a cycle of turnover-dependent local depletion of reduced ascorbate when processed by the key enzyme of catecholamine metabolism, dopamine-beta-monooxygenase. On the basis of inductively coupled plasma/mass spectroscopic analyses, corroborated by operant behaviour and locomotor activity investigations, an orally-active phenylaminoalkyl selenide with restricted CNS permeability was successfully developed. To our knowledge, this compound--4-hydroxy-alpha-methyl-phenyl-2-aminoethyl selenide--is the first orally active, selenium-based anti-hypertensive compound ever reported. In the future, we anticipate more widespread efforts to incorporate selenium into rationally designed pharmaceutical agents, with the goal of developing novel compounds which may be of therapeutic benefit toward a variety of human diseases.