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At least 1,189 records · Page 66Linked to original sources
PubMed2003

What type of eye drops should be given to a toddler with conjunctivitis?

This mini-review describes a parent's search for evidence on the relative merits of two commonly used treatments for conjunctivitis. It was conducted in a very limited period of time with access to free databases (Pub Med, Cochrane Library) and only the abstracts of papers. Five relevant studies were identified that compared fusidic acid eye drops to chloramphenicol. Three of the five studies reported no difference in effectiveness between the two preparations with both drugs performing equally well. Two studies undertaken in less-developed countries showed fusidic acid to be far more effective but the cure rate with chloramphenicol was low, suggesting resistance or different causal agents. However, there was some evidence that chloramphenicol was less well tolerated and so fusidic acid may be the drug of choice. The review illustrates that evidence for practice can be found rapidly with access to limited facilities by an appropriately skilled practitioner.

Administration, Topical↗
PubMed1988

Structure, turnover, and heme-mediated suppression of the level of mRNA encoding rat liver delta-aminolevulinate synthase.

lambda gt11 cDNA libraries were constructed with poly(A)+ RNA preparations from both porphyric chicken and rat livers. A cDNA which encodes chicken hepatic delta-aminolevulinate synthase was cloned by screening with an anti-chicken liver delta-aminolevulinate synthase antibody. Using this cDNA as a probe, cDNAs encoding the entire protein coding sequence of rat hepatic delta-aminolevulinate synthase were then cloned. The complete nucleotide sequences of the cDNAs have been determined. The result predicts that the rat hepatic pre-delta-aminolevulinate synthase comprises 642 amino acids. We measured the half-life of the hepatic delta-aminolevulinate synthase mRNA by RNA blot hybridization analysis using allylisopropylacetamide-induced porphyric rats as an experimental model and the rat cDNA as a hybridization probe. The half-life of the mRNA determined by the injection of alpha-amanitin is as short as 20 min. This value is significantly shorter than the estimated half-lives of most other mRNAs in the differentiated tissues of animals. The effect of hemin administration on the level of hepatic delta-amino-levulinate synthase mRNA was also examined. The half-disappearance time of the mRNA after the hemin administration was essentially the same as that determined by alpha-amanitin or actinomycin D, and no additive effect was observed between alpha-amanitin and hemin on the half-life determination. The results provide convincing evidence that heme inhibits the transcription of delta-aminolevulinate synthase mRNA.

5-Aminolevulinate Synthetase↗
PubMed1997

Gonadotropin alpha-subunit glycoprotein from channel catfish (Ictalurus punctatus) and its expression during hormone-induced ovulation.

Complementary DNA (cDNA) encoding the channel catfish (Ictalurus punctatus) gonadotropin (GTH) alpha-subunit glycoprotein was cloned by polymerase chain reaction (PCR) from a plasmid library made from pituitary RNA. Complete cDNA cloning was achieved by carrying out two PCR reactions: one with an upstream sense primer plus the universal sequencing primer, located downstream of the poly(A) sequence of the cDNA in the plasmid vector, to amplify the downstream portion of the cDNA; the other with a downstream antisense primer plus the reverse-sequencing primer, located upstream of the very 5' end of the cDNA sense strand in the plasmid vector, to amplify the upstream portion of the cDNA. The two amplified fragments overlapping about 70 bp. Nucleotide sequence analysis revealed that the catfish GTH alpha-subunit was 658 bp encoding 116 amino acids and harboring a 5' nontranslated region (NTR) of 42 bp and a 3' NTR of 265 bp. The deduced amino acid sequence of the catfish GTH alpha-subunit is highly conserved with those from other cloned teleost GTH alpha-subunits. The GTH alpha-subunit was highly expressed even before induction for ovulation in females during spawning season. Administration of carp pituitary extract (a spawning-inducing reagent) induced only 1.4-fold higher expression of the GTH alpha-subunit RNA, but included very rapid egg maturation and ovulation. This unexpected result indicated that the GTH alpha-subunit may not be the limiting factor for ovulation and spawning, which may be regulated by the change of proportional coupling of the GTH alpha-subunit with specific beta-subunit during hormone-induced ovulation.

Amino Acid Sequence↗
PubMed2001

Characterization of the rodent genes for arylacetamide deacetylase, a putative microsomal lipase, and evidence for transcriptional regulation.

In the current study, we have determined the cDNA and the genomic sequences of the arylacetamide deacetylase (AADA) gene in mice and rats. The AADA genes in the rat and mouse consist of five exons and have 2.4 kilobases of homologous promoter sequence upstream of the initiating ATG codon. AADA mRNA is expressed in hepatocytes, intestinal mucosal cells (probably enterocytes), the pancreas and also the adrenal gland. In mice, there is a diurnal rhythm in hepatic AADA mRNA concentration, with a maximum 10 h into the light (post-absorptive) phase. This diurnal regulation is attenuated in peroxisome proliferator-activated receptor alpha knockout mice. Intestinal but not hepatic AADA mRNA was increased following oral administration of the fibrate, Wy-14,643. The homology of AADA with hormone-sensitive lipase and the tissue distribution of AADA are consistent with the view that AADA plays a role in promoting the mobilization of lipids from intracellular stores and in the liver for assembling VLDL. This hypothesis is supported by parallel changes in AADA gene expression in animals with insulin-deficient diabetes and following treatment with orotic acid.

Acyl-CoA Oxidase↗
PubMed2000

Phage display technology: a tool to explore the diversity of inhibitors to blood coagulation factor VIII.

Hemophilia A is a X-linked bleeding disorder that is caused by the functional absence of blood coagulation factor VIII. The bleeding tendency in hemophilia A patients can be corrected by the administration of plasma-derived or recombinant factor VIII concentrates. A serious complication in hemophilia care is the development of factor VIII neutralizing antibodies (inhibitors) that arise as a consequence of factor VIII replacement therapy. The majority of factor VIII inhibitors are directed toward epitopes located within the A2, A3, and C2 domains of factor VIII. In this article, we summarize current knowledge on the epitope specificity of factor VIII inhibitors. In addition, we will discuss recent information on the molecular characteristics of human anti-factor VIII antibodies generated by phage display technology.

Base Sequence↗
PubMed2004

An intravenous medication safety system: preventing high-risk medication errors at the point of care.

Improving medication safety at the point of care--particularly for high-risk drugs--is a major concern of nursing administrators. The medication errors most likely to cause harm are administration errors related to infusion of high-risk medications. An intravenous medication safety system is designed to prevent high-risk infusion medication errors and to capture continuous quality improvement data for best practice improvement. Initial testing with 50 systems in 2 units at Vanderbilt University Medical Center revealed that, even in the presence of a fully mature computerized prescriber order-entry system, the new safety system averted 99 potential infusion errors in 8 months.

Academic Medical Centers↗
PubMed2004

Oral immunoglobulin for preventing necrotizing enterocolitis in preterm and low birth-weight neonates.

BACKGROUND: Necrotizing enterocolitis (NEC) is the most common emergency of the gastrointestinal tract occurring in the neonatal period. There have been published reports which suggest that oral immunoglobulins IgA and IgG produce an immunoprotective effect in the gastrointestinal mucosa. This systematic review was undertaken to clarify the issue. OBJECTIVES: To assess whether oral immunoglobulin administered to preterm and low birth-weight neonates reduces the incidence of necrotizing enterocolitis without adverse effects. SEARCH STRATEGY: The databases MEDLINE, CINAHL, EMBASE (1966 to October 26, 2003) and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2003) were searched. Proceedings of the Perinatal Society of Australia and New Zealand were hand searched. The computer neonatal discussion site 'Nicu Net' was also used. Additionally, all references in the identified trials were checked and authors were contacted to request any additional published or unpublished data. No new trials were identified. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials where oral immunoglobulins were used as prophylaxis against necrotizing enterocolitis in preterm (<37 weeks gestation) and/or low birth-weight (<2500 gms) neonates. DATA COLLECTION AND ANALYSIS: The procedures of the Cochrane Neonatal Review Group (CNRG) were used. The two reviewers independently assessed the trials for their methodological quality and subsequent inclusion in the review. Relative risk (RR), risk difference (RD), and number needed to treat (NNT) were used in the analysis. MAIN RESULTS: Five studies on oral immunoglobulin for the prevention of necrotizing enterocolitis were identified of which three met the inclusion criteria. In this review of the three eligible trials (including a total of 2095 neonates) the oral administration of IgG or an IgG/IgA combination did not result in a significant reduction in the incidence of definite NEC [RR 0.84 (95% CI 0.57, 1.25), RD -0.01 (95% CI -0.03, 0.01)], suspected NEC [RR 0.84 (95% CI 0.49, 1.46), RD -0.01 (95% CI -0.02, 0.01)], need for surgery [RR 0.21 (95% CI 0.02, 1.75), RD -0.03 (95% CI -0.06, 0.00)] or death from NEC [RR 1.10 (95% CI 0.47, 2.59), RD 0.00 (95% CI -0.01, 0.01)]. REVIEWER'S CONCLUSIONS: Based on the available trials, the evidence does not support the administration of oral immunoglobulin for the prevention of NEC. There are no randomised controlled trials of oral IgA alone for the prevention of NEC.

Administration, Oral↗
PubMedDate not supplied

Corneal crystals in nephropathic cystinosis: natural history and treatment with cysteamine eyedrops.

Although renal disease is the most prominent feature of the lysosomal storage disease cystinosis, corneal cystine crystal formation remains a major complication, leading to photophobia, corneal erosions, and keratopathies. Moreover, the extent of corneal crystal accumulation reflects the course and severity of the disease itself, and the cornea is accessible to direct examination. Therefore, we employed a scoring system, based on a library of slit-lamp photographs of corneas with increasing crystal densities (0.00-3.00), to assess the degree of crystal accumulation in 170 patients with nephropathic cystinosis examined at the National Institutes of Health between 1976 and 2000. None of the patients had received topical cystine-depleting therapy at the time of the evaluation. In this natural history study, infants in the first year of life had absent or minimal corneal crystals, i.e., a corneal cystine crystal score (CCCS) of 0 or 0.25. However, the CCCS increased linearly with age, such that every patient had visible crystals by 16 months of age, and plateaued at approximately 3.00 by early adolescence. Longitudinal studies in representative patients support the cross-sectional results. Individuals homozygous for the common 57-kb deletion involving the cystinosis gene (CTNS) displayed the same course of corneal crystal accumulation as did individuals not bearing the large deletion. Patients with ocular or nonnephropathic cystinosis had CCCSs that were, in general, half those expected for patients with nephropathic cystinosis of the same age. Administration of 0.55% cysteamine eyedrops, given 6 to 12 times per day, dissolved corneal cystine crystals in 10 representative patients with nephropathic cystinosis aged 1 to 32 years within 8 to 41 months.

Adolescent↗
PubMed2005

Medical eligibility criteria for new contraceptive methods: combined hormonal patch, combined hormonal vaginal ring and the etonogestrel implant.

To review evidence on the combined hormonal patch, combined hormonal vaginal ring and the etonogestrel implant, with a focus on safety and effectiveness of use among women with special health conditions, we searched MEDLINE, Pre-MEDLINE and the Cochrane Library for reports published from 1980 through March 2005. Articles eligible for review included 11 on the hormonal patch, nine on the hormonal ring, and 11 on the etonogestrel implant. Limited evidence suggests patch efficacy is lower among women>90 kg. No evidence was identified for vaginal ring use among women with medical conditions. A single small study found that etonogestrel implants had no adverse effects on bone mineral density among women 18-40 years old. Limited evidence also suggests no adverse effects of the etonogestrel implant on lactation parameters or infant development among users enrolled 28 to 56 days postpartum and followed for 4 months.

Administration, Cutaneous↗
PubMed1997

Information needs of rural health professionals: a retrospective use study.

To explore the information needs of rural health professionals, a retrospective study was undertaken of 1,224 document delivery requests made during the course of three outreach projects in west and central Illinois. The 547 unique journals from which the articles were requested were analyzed for frequency of request, subject content, and inclusion on core lists. These rural health professionals were found to request current information on a wide range of topics in clinical medicine, nursing, health administration, allied health, social sciences, and basic sciences. While 10% of the titles filled 37% of the requests, 58% of the titles were requested once and filled 26% of the requests. A high correlation with Abridged Index Medicus and Brandon/Hill list titles was found, but titles from either of these lists could fill no more than 30% of the total requests. Besides demonstrating the complex information needs of rural health professionals and depicting the difficulty of building a collection to support them, the study exemplifies a method for need-based journal collection development and begins to identify titles commonly requested in a rural health setting.

Community-Institutional Relations↗
PubMed2001

Opioids for the palliation of breathlessness in terminal illness.

BACKGROUND: Breathlessness is a common symptom in people with advanced disease. The most effective treatments are aimed at treating the underlying cause of the breathlessness but this may not be possible and symptomatic treatment is often necessary. Strategies for the symptomatic treatment of breathlessness have never been systematically evaluated. Opioids are commonly used to treat breathlessness: the mechanisms underlying their effectiveness are not completely clear and there have been few good-sized trials in this area. OBJECTIVES: To determine the effectiveness of opioid drugs given by any route in relieving the symptom of breathlessness in patients who are being treated palliatively. SEARCH STRATEGY: An electronic search was carried out of Medline, Embase, Cinahl, the Cochrane library, Dissertation Abstracts, Cancercd and SIGLE. Review articles and reference lists of retrieved articles were hand searched. Date of most recent search: May 1999 SELECTION CRITERIA: Randomised double-blind, controlled trials comparing the use of any opioid drug against placebo for the relief of breathlessness were included. Patients with any illness suffering from breathlessness were included and the intervention was any opioid, given by any route, in any dose. DATA COLLECTION AND ANALYSIS: Studies identified by the search were imported into a reference manager database. The full texts of the relevant studies were retrieved and data were independently extracted by two reviewers. Studies were quality scored according to the Jadad scale. The primary outcome measure used was breathlessness and the secondary outcome measure was exercise tolerance. Studies were divided into non-nebulised and nebulised and were analysed both separately and together. A qualitative analysis was carried out of adverse effects of opioids. Where appropriate, meta-analysis was carried out. MAIN RESULTS: Eighteen studies were identified of which nine involved the non-nebulised route of administration and nine the nebulised route. A small but statistically significant positive effect of opioids was seen on breathlessness in the analysis of studies using non-nebulised opioids. There was no statistically significant positive effect seen for exercise tolerance in either group of studies or for breathlessness in the studies using nebulised opioids. REVIEWER'S CONCLUSIONS: There is evidence to support the use of oral or parenteral opioids to palliate breathlessness although numbers of patients involved in the studies were small. No evidence was found to support the use of nebulised opioids. Further research with larger numbers of patients, using standardised protocols and with quality of life measures is needed.

Apnea↗
PubMed2005

P-glycoprotein-independent apoptosis induction by a novel synthetic compound, MMPT [5-[(4-methylphenyl)methylene]-2-(phenylamino)-4(5H)-thiazolone].

To develop new anticancer agents that are effective for treatment of chemoresistant tumors, we screened a chemical library for compounds that can effectively kill both paclitaxel-sensitive lung cancer cell H460 and P-glycoprotein-overexpressing paclitaxel-resistant cell H460/TaxR. A synthetic compound, MMPT (5-[(4-methylphenyl)methylene]-2-(phenylamino)-4(5H)-thiazolone), was identified to induce cytotoxic effects in both H460 and H460/TaxR cells but not in normal fibroblasts. MMPT effectively inhibited the growth of several human lung cancer cell lines in a dose-dependent manner, with 50% inhibitory concentrations ranging from 4.9 to 8.0 microM. The inhibitory effect on cancer cells is independent of the status of p53 and P-glycoprotein. Moreover, MMPT had no obvious toxic effects on normal human fibroblasts and mesenchymal stem cells at the 50% inhibitory concentration for lung cancer cell lines. Treating lung cancer cells with MMPT-induced apoptosis with caspase-3, -8, -9, and poly(ADP-ribose) polymerase cleavage and cytochrome c release from mitochondria. MMPT-induced apoptosis was abrogated when c-Jun N-terminal kinase (JNK) activation was blocked with a specific JNK inhibitor, SP600125. Furthermore, in vivo administration of MMPT suppressed human H460 xenograft tumor growth in nude mice. Our results suggest that MMPT may induce tumor-selective cell killing in both P-glycoprotein-negative and -positive cancer cells and could be a new anticancer agent for treatment of refractory tumors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1984

Induction by cAMP of the mRNA encoding the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) from the chicken. Identification and characterization of a cDNA clone for the enzyme.

Previous work from our laboratory (Hod, Y., Utter, M. F., and Hanson, R. W. (1982) J. Biol. Chem. 257, 13787-13794) has demonstrated that chicken kidney contains both mitochondrial and cytosolic forms of phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) and that the two forms are distinct proteins. Using poly(A+) RNA from chicken kidney, a double-stranded cDNA library was constructed. DNA clones containing sequences complementary to the mRNA for the cytosolic form of phosphoenolpyruvate carboxykinase were initially identified by colony hybridization with 32P-labeled cDNA transcribed from an RNA fraction enriched for the enzyme mRNA. The identity of plasmids containing phosphoenolpyruvate carboxykinase cDNA was confirmed by hybrid-selected translation. Mature mRNA for cytosolic phosphoenolpyruvate carboxykinase of the chicken is 2.8 kilobases in length, similar to that previously noted for mRNA coding for the same enzyme in the rat. The cDNA for the chicken enzyme hybridizes with several restriction fragments of the corresponding cDNA for the rat cytosolic phosphoenolpyruvate carboxykinase, indicating conservation of nucleotide sequences during evolution. Wide spread conservation of sequence homology is also demonstrated by the hybridization of the cDNA for the rat phosphoenolpyruvate carboxykinase with a 2.8-kilobase RNA from the livers of a variety of vertebrates including amphibian, avian, and primate species. Specific mRNA coding for the cytosolic form of phosphoenolpyruvate carboxykinase was present in chicken kidney but absent from the liver, even in animals starved for 48 h. However, the administration of cAMP to normal fed chickens caused a rapid induction of phosphoenolpyruvate carboxykinase mRNA. These findings suggest that the gene for the cytosolic enzyme in chicken liver can be expressed if the proper hormonal stimuli are present.

Animals↗
PubMed2006

Longterm efficacy of topical nonsteroidal antiinflammatory drugs in knee osteoarthritis: metaanalysis of randomized placebo controlled clinical trials.

OBJECTIVE: To evaluate the longterm efficacy of topical therapies for pain control in primary knee osteoarthritis (OA). METHODS: Systematic literature search was carried out from January 1, 1966, to December 31, 2004, in Pubmed, Medline, Embase, and Cochrane database. Manual searches of related journals in the National Medical Library (New Delhi, India), the library of our institute, and conference abstracts were also carried out. We included randomized controlled clinical trials of 4 weeks or more comparing any topical nonsteroidal antiinflammatory drug (NSAID) with placebo or vehicle. Effect size for pain control was estimated. RESULTS: Out of 172 citations, 4 studies fulfilled all the specified criteria. Four of them compared topical NSAID with placebo or vehicle. Pooled effect of topical NSAID measured at 4 weeks or beyond was superior to placebo/vehicle in pain relief (mean effect size -0.28, 95% CI -0.42 to -0.14). CONCLUSION: Topical NSAID are effective for pain relief in knee OA for a longer duration; however, this may not hold true for all the preparations.

Administration, Topical↗
PubMed1992

Cloning and characterization of a novel CYP3A1 allelic variant: analysis of CYP3A1 and CYP3A2 sex-hormone-dependent expression reveals that the CYP3A2 gene is regulated by testosterone.

A clone was isolated from a cDNA library constructed from phenobarbital-treated Wistar rat liver and proven to correspond to the full-length mRNA of a polymorphic variant of Sprague-Dawley CYP3A1. Eight nucleotide differences were detected in a single 76-nucleotide stretch and confirmed to be present in the genomic clone. They are seated in a region implicated in the definition of a substrate binding domain of the native P450. Three out of the eight nucleotide changes are nonconservative, implicating the replacement of Thr/Ala 207, Phe/Ile 213, and Ile/Val 232. This is the first report of an allelic variant of CYP3A1, a new example of interstrain P450 variability. The CYP3A subfamily is composed of several genes coding for active testosterone 6 beta-hydroxylases which are expressed in the liver. CYP3A genes are under strong and distinct developmental regulation. Conversely to CYP3A1, transiently expressed in immature animals, CYP3A2 is constitutively expressed in the liver early after birth and characterized by an extinction in the adult females. Castration of 90-day-old male rats causes a drastic reduction (80%) of CYP3A2 mRNA relative abundance. Administration of testosterone propionate restores the physiological levels of CYP3A2 mRNA characteristic of the male rat liver. Our results demonstrate the existence of a direct relationship between the male hormonal status and the constitutive expression of rat liver CYP3A2.

Age Factors↗
PubMed2005

Discovery of novel and potent small-molecule inhibitors of NO and cytokine production as antisepsis agents: synthesis and biological activity of alkyl 6-(N-substituted sulfamoyl)cyclohex-1-ene-1-carboxylate.

To develop a new therapeutic agent for sepsis, screening of the Takeda chemical library was carried out using mouse macrophages stimulated with lipopolysaccharide (LPS) to identify a new class of small-molecule inhibitors of inflammatory mediator production. The lead compound 5a was discovered, from which a series of novel cyclohexene derivatives I bearing a sulfamoyl and ester group were designed, synthesized and tested for their inhibitory activity against nitric oxide (NO) production. Derivatives I were synthesized by the coupling of sulfonyl chlorides and anilines with concomitant double bond migration in the presence of triethylamine, and phenyl ring substitution and modification of the ester and cyclohexene moieties were carried out. Among the compounds synthesized, ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate [(R)-(+)-5n, TAK-242] was found to exhibit the most potent suppressive activity for the production of not only NO but also inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) induced by LPS-stimulated mouse macrophages with IC50 values of 1.8, 1.9 and 1.3 nM, respectively. It shows marked beneficial effects in vivo also. Intravenous administration of (R)-(+)-5n at doses of 0.1 mg/kg or more suppressed the production of NO and various cytokines [TNF-alpha, IL-6 and IL-1beta] in the mouse endotoxin shock model. Furthermore, it protected mice from death dose-dependently and all mice survived at a dose of 3 mg/kg. The minimum effective dose to protect mice from lethality in this model was 0.3 mg/kg, which was consistent with those for inhibitory effects on the production of NO and cytokines. Compound (R)-(+)-5n is currently undergoing clinical trials for the treatment of sepsis.

Animals↗
PubMed2001

The effects of an increase of central blood volume before spinal anesthesia for cesarean delivery: a qualitative systematic review.

UNLABELLED: We evaluated in this qualitative systematic review the efficacy of increasing central blood volume on the incidence of hypotension after spinal anesthesia for elective cesarean delivery. Randomized controlled trials investigating any method of increasing central blood volume before the initiation of obstetric spinal anesthesia were sought by using MEDLINE (1966-2000), Embase (January 1988-April 2000), and the Cochrane Library (Issue 1, 2000). Additional reports from retrieved and review articles, hand searching of non-MEDLINE journals, and abstracts of major anesthesia meetings (1994-1999) were located. The primary outcome was the incidence of hypotension. Secondary outcomes included: ephedrine use, Apgar scores, umbilical cord pH values, and maternal nausea and vomiting. Twenty-three articles met our inclusion criteria with the use of crystalloid preload, colloid preload, and mechanical methods of increasing central volume. Crystalloid preload was inconsistent in preventing hypotension, whereas colloid appeared to be effective in all but one study. Leg wrapping and thromboembolic stockings decreased the incidence of hypotension compared with leg elevation or control. Few differences in fetal outcomes or maternal nausea and vomiting were reported. Increasing central blood volume by using colloid and leg wrapping decreases but does not abolish the incidence of hypotension before spinal anesthesia for elective cesarean delivery. IMPLICATIONS: We performed a systematic review to determine whether fluid loading reduced the incidence of low blood pressure after spinal anesthesia for cesarean delivery. Although no technique totally eliminates the occurrence of hypotension, colloid administration (starch or gelatin containing fluids) and leg wrapping were the most effective.

Adult↗
PubMed2000

Discovering novel ligands for macromolecules using X-ray crystallographic screening.

The need to decrease the time scale for clinical compound discovery has led to innovations at several stages in the process, including genomics/proteomics for target identification, ultrahigh-throughput screening for lead identification, and structure-based drug design and combinatorial chemistry for lead optimization. A critical juncture in the process is the identification of a proper lead compound, because a poor choice may generate costly difficulties at later stages. Lead compounds are commonly identified from high-throughput screens of large compound libraries, derived from known substrates/inhibitors, or identified in computational prescreeusing X-ray crystal structures. Structural information is often consulted to efficiently optimize leads, but under the current paradigm, such data require preidentification and confirmation of compound binding. Here, we describe a new X-ray crystallography-driven screening technique that combines the steps of lead identification, structural assessment, and optimization. The method is rapid, efficient, and high-throughput, and it results in detailed crystallographic structure information. The utility of the method is demonstrated in the discovery and optimization of a new orally available class of urokinase inhibitors for the treatment of cancer.

Administration, Oral↗