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Well characterised novel catalysts consisting of TiO2 modified with very small amounts of gold nanoparticles have been applied to the photocatalytic degradation of two important pollutants, methyl tert-butyl ether (MTBE) and 4-chlorophenol, in dilute aqueous solution using a fixed bed flow-through photocatalytic reactor. Although the thermal processing that was necessary for coating the reactor walls with the photocatalysts did lead to some loss of performance, the net gains in activity relative to unmodified TiO2 were nevertheless substantial and in excess of anything previously reported. Improvements in reaction rate by 50% and 100% for the removal of 4-chlorophenol and MTBE, respectively, were achieved. It was also found that effective removal of both pollutants could be achieved at water flow rates that are relevant to field applications involving the photocatalytic clean-up of contaminated groundwater. Due to their very small Au content, the cost of these materials is compatible with large scale use.

In the absence of the use of prevention methods, AlGaN layers on GaN are known to form an array of cracks if a critical thickness is exceeded. In this study growth of AlGaN–GaN structures was carried out by metalorganic vapour phase epitaxy using sapphire substrates. Under optical and atomic force microscopy two distinct crack populations have been obseved. In thin, highly strained films an initial high density population of microcracks are found propagating from threading dislocations. This crack array extends as the thickness increases, before contracting with the onset of large cracks whick extend over many mm across the wafer. The formation of the microcrack array is very dependent on the stain in the epilayer and does not follow the classic critical thickness dependence with lattice mismatch. Avoiding stresses high enough to prevent the microcracking phenomenon may be critical in the use of highly tensile strained layers in nitride devices. (© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

GaN low temperature nucleation and high temperature buffer layers have been grown by metalorganic vapour phase epitaxy. The effect of nucleation layer annealing temperature and buffer layer growth temperature on their microstructure and morphology has been examined by atomic force microscopy and X-ray diffraction and correlated to the in-situ reflectivity obtained from the growing layers. For the nucleation layer, the anneal was observed to lead to the formation of GaN nucleites on the substrate surface, the properties of which changed markedly with temperature. Surface pits resulting from dislocations with a screw component have been observed and the variation of the density with growth temperature ascertained.

A new series of potent, linearly-minimized, orally active, selective GPIIb/IIIa inhibitors is identified. Thus 15 (L-750,034) achieves interaction via a constrained, non-turned conformation that maintains the proper distance between its charged termini and full sulfonamide exosite interaction. The diminutive stature and the proposed linear conformation of L-750,034 define a new paradigm for the conceptualization of RGD mimics.

The synthesis and pharmacological evaluation of 5 (L-738, 167), a potent, selective non-peptide fibrinogen receptor antagonist is reported. Compound 5 inhibited the aggregation of human gel-filtered platelets with an IC50 value of 8 nM and was found to be33000-fold less effective at inhibiting the attachment of human endothelial cells to fibrinogen, fibronectin, and vitronectin than it was at inhibiting platelet aggregation. Ex vivo platelet aggregation was inhibited by85% 24 h after the oral administration of 5 to dogs at 100 micrograms/kg. The extended pharmacodynamic profile exhibited by 5 appears to be a consequence of its high-affinity binding to GPIIb/IIIa on circulating platelets and suggests that 5 is suitable for once-a-day dosing.

Centrally constrained thieno[2,3- b ]thiophene sulfonamides have provided a potent, selective, orally active series of platelet aggregation inhibitors. Compound 21 showed excellent activity in the dog after a single oral dose of 200 μg/kg.

Potency enhancing features of two series of fibrinogen receptor antagonists were combined to give analogs with improved potency and oral activity. Antagonists containing either alkyl or aryl sulfonamides and a central isoindolinone structural constraint demonstrate high affinity for both activated and unactivated platelet receptors.

The structure-activity relationship of a series of orally active glycoprotein IIb/IIIa antagonists containing a nitrogen heterocycle grafted onto a 3,4-dihydro-1 (1H)-isoquinolinone core is described. These compounds are structurally novel analogs of the progenitor compound 1 (L-734,217,[[3(R)-[2-(piperidin-4-yl)ethyl]-2-oxopiperidinyl ]acetyl]-3(R)- methyl-beta-alanine) in which the lactam chiral center has been removed. The 4-piperazinyl- and 4-piperidinyl-substituted 3,4-dihydro-1(1H)-isoquinolinones were found to be optimal for in vitro potency. In addition, substitution at the 3-position of the beta-amino acid enhanced potency with the 3-pyridyl and 3-ethynyl analogs being the most potent prepared. Attempts to improve the in vivo profile of these compounds focused on modification of the physical properties. Ester prodrugs were prepared to increase the lipophilicity and remove the zwitterionic nature of the antagonists. The prodrug approach, coupled with the arylpiperazine terminus (pKa = approximately 9.0), afforded moderately basic and relatively nonpolar compounds. The acid N-[[7-(piperazin-1-yl)-3,4-dihydro-1(1H)-oxoisoquinolin-2-yl ]acetyl]-3(S)- ethynyl-beta-alanine, 6d (L-767,679), is a potent fibrinogen receptor antagonist able to inhibit the ADP-induced aggregation of human gel-filtered platelets with an IC50 of 12 nM. Although 6d is orally active based on the results of an ex vivo dog assay at 0.3 mg/kg, the ethyl ester prodrug of this compound, 19 (L-767,685), is better absorbed at this dose than 6d. Upon oral dosing, the ester 19 is converted to 6d in vivo in dog with an estimated oral systemic availability of > 17% (0-8 h, AUC19po/AUC6div). In addition, studies in monkey at an oral dose of 1 mg/kg show that 19 affects the complete inhibition of the ex vivo platelet aggregation in response to ADP between 2 and 8 h postdose with the level of inhibition remaining at 40% at 12 h postdose. This level of activity was superior to that observed for 6d and 1 at the same dose. Using ex vivo ADP-induced aggregation data from rhesus monkey (n = 2, 0-8 h using the AUC19po/AUC6div), the estimated systemic oral availability of 6d when dosed as 19 is 32%.

Al0.49Ga0.51N∕Al0.16Ga0.84N distributed Bragg reflectors (DBRs), designed for the ultraviolet spectral region, are reported. The crack-free structures are grown on sapphire substrates by metalorganic chemical vapor deposition. A peak reflectivity of 91% at 353nm with a stop-band width of 17nm was obtained at 300K using a 25pair DBR. Structures at 6nm shorter wavelength show asymmetric spectra, a narrower stop band, and slightly decreased peak reflectivity. By studying the spectra as a function of temperature, the degradation is shown to arise from internal absorption at short wavelengths. Simulations based on transfer matrix theory agree well with the experimental data.

Low molecular weight non-peptide inhibitors of platelet aggregation based on rigid bicyclic scaffolds are described. Consideration of the reported conformational preferences of 1-alkyl-3-carbonyl pyrroles led to the synthesis of pyrrolopiperazinone 2a which was shown to be a potent, selective antagonist.

Analysis of platelet aggregation inhibition results and rotational isomer preferences has provided an understanding of inhibitory potency for m-phthalic acid analogs 7–7. Constraint of the N-terminal amide led to compound 9, which is potent, selective, and orally active.

Potent non-peptidic alpha(v)beta(3) antagonists have been prepared where deletion of an amide bond from an earlier series of linear RGD-mimetics provides a novel series of chain-shortened alpha(v)beta(3) antagonists with significantly improved oral pharmacokinetics. These chain-shortened alpha(v)beta(3) antagonists represent structurally novel integrin inhibitors.

Investigations linking sudden infant death syndrome (SIDS) and type II intrauterine growth retardation (IUGR) have thus far failed due in part to technical limitations. Recently developed stereological methods for the unbiased estimation of total nephron number in the human kidney are capable of detecting deviations from normal values of greater than 10%. We compared the total number of nephrons in the kidneys of 24 SIDS victims with those from 16 controls with the same age range. Mean nephron number was significantly (P < 0.001) reduced in ex-IUGR SIDS cases (birthweight under the 10th centile, n = 9, mean number 635,000, range 327,000-1,010,000) in comparison with controls (903,000, 740,000-1,060,000). A similarly significant (P < 0.01) reduction in the "normal birthweight" SIDS group (birthweight over 10th centile, n = 15, 690,000, 361,000-1,040,000) was found. This hitherto unreported renal developmental arrest may be only one manifestation of a general, somatic developmental defect, reflecting adverse intrauterine conditions; other organ systems, similarly critical to homeostasis may be comparably affected. The findings, although not proposed as direct cause of SIDS, may represent a potential explanation for the recognized association of IUGR and SIDS, and provide--we believe--the first quantitative evidence of intrauterine growth retardation in, at least a number of, children of average birthweight.

New transition-state analogues bearing C-termini derived from alpha-mercaptoalkanoic acids, esters, and amides were prepared and evaluated as inhibitors of human renin. Addition of alpha-mercaptoalkanoate esters to a chiral Boc-amino epoxide intermediate led ultimately to the target [(2R,3S)-3-(BocPheHis-amino)-4-cyclohexyl-2-hydroxy-1-butyl]thio derivatives. The corresponding sulfoxide and sulfone analogues were also investigated. Some of these derivatives, including one with a stable BocPhe replacement, were relatively potent inhibitors of human plasma renin, having IC50 values below 10 nM. When selected compounds were administered intravenously to sodium-deficient rhesus monkeys (Macaca mulatta) at 0.06-1 mg/kg, they reduced plasma renin activity by 87-94%. However, the accompanying drop in blood pressure was of short duration.

A series of transition-state analogues having heterocyclythio C-termini has been synthesized and evaluated for inhibition of human renin. Addition of mercaptoheterocycles to a chiral Boc-amino epoxide intermediate led, after several steps, to the target [(2R,3S)-3-(BocPheHis-amino)-4-cyclohexyl-2-hydroxy-1-butyl]thio derivatives. Oxidation of the thioether to sulfone was also investigated. Several of the compounds, especially those derived from N1-substituted-5-mercaptotetrazoles or N4-substituted-3-mercapto-5-(trifluoromethyl)-1,2,4-triazoles, were moderately potent inhibitors of human plasma renin, having IC50 values of 30-40 nM. When selected compounds were administered intravenously to sodium-deficient rhesus monkeys at 0.3-1.2 mg/kg, they reduced plasma renin activity by 75-98%. However, this inhibition and the accompanying drop in blood pressure were of short duration.

OBJECTIVE To investigate the effect of Type II (asymmetrical) intrauterine growth retardation (IUGR) on renal development. DESIGN A prospective descriptive study. SETTING Department of Fetal and Infant Pathology, Liverpool Children's Hospital. SUBJECTS Six (severely) affected IUGR stillbirths of known gestational age with a control group of stillbirths with birthweight greater than 10th centile, and eight liveborn IUGR infants who died within a year of birth with a control group of appropriately grown infants who died within a year of birth (postnatal groups). TECHNIQUES The kidneys from all the groups studied were analysed using unbiased, reproducible and objective design-based stereological techniques. MAIN OUTCOME MEASURES Total renal nephron (glomerular) numbers and average volumes of total nephron and cortical and medullary nephron segments. RESULTS Nephron number estimates lay below the control group's 5% prediction limit in five out of the six growth-retarded stillbirths, and were significantly (P less than 0.005, IUGR at 65% of the control mean) reduced in the postnatal group. Estimates of nephron (segment) volume did not differ between control and IUGR groups. CONCLUSIONS Type II intrauterine growth retardation may exert a profound effect on renal development. The reduced nephron number at birth, together with the lack of any early postnatal compensation in either nephron number or nephron size, emphasizes the need for vigorous antenatal surveillance for IUGR and consideration of elective preterm delivery of affected fetuses. A systematic review of other organs, which develop in a similarly rapid fashion during the late intrauterine period, is indicated by this work. With one exception, all birthweights in the growth-retarded groups were below the third centile, thus the precise quantitative relation between progressive IUGR and renal function requires further assessment.

The design of P2-P3 conformational restrictions in renin inhibitors by the use of a renin computer graphic model led to the synthesis of inhibitors containing N-Boc, N-acetyl, and N-phthalyl derivatives of 3(S)-amino-4(R,S)-2-piperidones and 4(S)-amino-2-benzazepinones in place of phenylalanine in the control compound N-acetyl-L-phenylalanyl-N-[4(S)-[(butylamino)carbonyl]-1(S)- (cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl]-L-norleuci namide (32). The piperidone inhibitors were prepared by utilization of the Evans chiral auxilliary to introduce the amino group with enantioselectivity and also to act as a leaving group in an intramolecular cyclization to the piperidone. The most potent inhibitor, 3(S)-(acetylamino)-alpha(S)-butyl-N-[4(S)- [(butylamino)carbonyl]-1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5- methylhexyl]-2-oxo-4(R)-phenyl-1-piperidineacetamide (18, IC50 = 21 nM), was 25-fold less potent than the acyclic control 32. Considerable dependence of potency with the size of the P4 derivative was observed as had been expected based on the presynthetic modeling studies. Attempts to rationalize the observed potencies on the basis of further molecular modeling studies suggested that the loss in inhibitor potency was due to the conformational restrictions distorting the 3S center from the geometry present in the putative extended conformation present when the inhibitor is bound within the renin active site.

Using a computer model of the active site of human renin developed at Merck, we designed a series of novel P2-P1'-linked, macrocyclic renin inhibitors 3-10. These unique inhibitors incorporate a transition-state isostere within a 13- or 14-membered ring. The three most active compounds in this family were 13-membered-ring glutamine-derived inhibitor 3, 14-membered-ring diaminopropionic acid derived inhibitor 6, and 13-membered-ring diol 9 (IC50 0.61, 0.59, 0.65 microM, respectively). Modification of inhibitor 3 at P4 led to 56 nM macrocyclic renin inhibitor 39. This study shows the viability of renin inhibitor designs which incorporate a scissile-bond replacement within a macrocycle.

The voltage-gated potassium channel Kv1.5 is one of the key regulators of membrane potential repolarization in human atrial myocytes and is considered a potential drug target to treat atrial fibrillation. In this study we sought to determine molecular mechanism of action of DPO-1, a diphenylphosphine oxide derivative recently shown to terminate experimental atrial arrhythmia without affecting ventricular refractory period. In addition, we provided similar analysis for additional two small molecule blockers, representing different structural classes: cyclohexanones (PAC) and nor-triterpenoids (correolide). To rapidly identify the residues within the Kv1.5 channel critical for blocking activity of these molecules, two functional high-throughput ion channel assays were employed together with site-directed mutagenesis. Our study revealed that the residues critical for blocking activity of for DPO-1 include T480, localized at the outer mouth of the pore, and two residues along S6 helix: V505 and I508. The overlapping site was identified for PAC and included residues T480 and V505. In contrast to DPO-1, the I508A mutation resulted in only a modest reduction in the block of Kv1.5 by PAC (9-fold). Correolide, the largest molecule examined, made widespread interactions along the entire length of the pore (from T480 to V516). In summary, we have identified multiple residues involved in forming high affinity binding site for Kv1.5 blockers. Similar approaches of high-throughput ion channel technologies, combined with site-directed mutagenesis, may allow for parallel, rapid and accurate analysis of ion channel interactions with multiple compounds and could facilitate the design of more potent and selective ion channel blockers.

Temperature-dependent measurements of the pulsed light-current characteristics of InGaN light-emitting diodes that were thermally annealed at different temperatures have been investigated. A distinct light output, at a fixed current density, with operating temperature arises where the light output increases as the operating temperature is reduced from 300 K, reaches a maximum, and then decreases with subsequent reductions of the operating temperature. We observe that light-emitting diodes thermally annealed at higher temperatures, which is believed to increase the number of electrically activated acceptors in the p layers, have a lower light output below 300 K and the maximum light output shifts to higher operating temperatures. Measured absorption and emission spectra show that the thermal anneal process has not affected the structure of the quantum wells within these samples. The light output, for a fixed current density, has been simulated as a function of operating temperature, and we find that by changing the concentration of acceptor atoms, compensating donor atoms, and the hole mobility in the p layers, the trends observed experimentally can be reproduced. On the basis of the simulations we find that the distinct behavior of the light output with operating temperature is due to the combination of Shockley-Reed-Hall recombination, at operating temperatures around 300 K, and electron drift leakage, at operating temperature below 300 K, and the increase of the acceptor concentration results in an increased electron drift leakage due to the change of the concomitant hole mobility. The simulations support the view that the experimental observations can be explained through changes of the acceptor concentration in the p layers when the thermal anneal temperature is increased.

We have measured the pulsed light-current characteristics of a series of InGaN/GaN quantum well light-emitting diodes which were annealed post-growth at different temperatures as a function of their operating temperature. The light output at a fixed current density increases with the temperature of measurement, reaches a maximum and then decreases for all the diodes. The measurement temperature at which the maximum light output occurs and the magnitude of the light output depend on the post-growth thermal anneal temperature. The thermal anneal temperature is thought to affect the acceptor concentration in the p-doped cap layer, which also changes the carrier mobility. A simulation, incorporating carrier leakage, is used to reproduce the experimental behavior where the acceptor concentration is changed to represent the effects of the different anneal temperatures.

To investigate the effect of tea polyphenol (TP) on the mineralization behaviour of enamel in two sterile, in vitro systems.In the demineralization study, sound enamel sections were pH-cycled. Treatments were 2000 mg/L TP, 200 mg/L TP, 2000 mg/L TP + 100 mg/L fluoride, 100 mg/L fluoride, and deionized water. In the remineralization study, surface-softened enamel was used and pH-cycled as above. Test treatments were 2000 mg/L TP, 2000 mg/L TP + 250 mg/L fluoride, 250 mg/L fluoride, and deionized water. The acidic buffers were retained for calcium analysis. The enamel was analysed before and after pH-cycling by microhardness.In the demineralization study, the calcium depletion rates(CDR) were (0.43 +/- 0.05), (0.49 +/- 0.006), (0.21 +/- 0.02), (0.21 +/- 0.03) and (0.50 +/- 0.11) microgram/(mm2.h) respectively. The Knoop hardness values(KHV) percent reduction were 94.19 +/- 3.50, 96.62 +/- 0.63, 74.74 +/- 4.09, 77.79 +/- 3.11 and 97.32 +/- 4.03 respectively. There were no significant differences within either the TP-only groups or the fluoride groups, but the fluoride groups were significantly more efficacious than the TP-only groups (P0.05). In the remineralization study, the KHV percent increase were -11.96 +/- 10.1, -21.32 +/- 11.3, -49.52 +/- 24.6 and -4.24 +/- 8.51 respectively. Notably more remineralization was observed in the fluoride group. There were no significant differences between the other groups (P0.05).The data of this in vitro study suggest that TP has no effect on de/remineralization of enamel blocks and there is no synergetic action of TP and fluoride in a sterile system. This finding supports the proposition that tea polyphenols exert an anti-caries effect via an anti-microbial mode-of-action.

The mammalian testis contains high levels of a protein, L-isoaspartyl (D-aspartyl) O-methyltransferase (PIMT), postulated to play a role in the repair of age-damaged proteins. To examine the regulation of PIMT concentrations during the development of spermatozoa, poly(A)+ RNA was isolated from purified populations of pachytene spermatocytes and round spermatids. Northern blot analysis revealed that a unique 1.1-1.3 kb PIMT transcript is present in preparations of round spermatid and pachytene spermatocyte poly (A)+ RNA. The concentration of this small PIMT transcript is at least four times higher in mRNA isolated from round spermatids than in mRNA isolated from pachytene spermatocytes, indicating that the PIMT gene is actively transcribed during the haploid phase of spermatogenesis. The germ cell-specific PIMT transcripts are distributed between the polysomal fraction and the nonpolysomal fractions of testis RNA, suggesting that translational controls also contribute to the high concentrations of PIMT in mammalian sperm. PIMT function is not essential for spermatogenesis because the testes from transgenic mice lacking PIMT activity have normal levels of protamine transcripts, and because functional sperm can be recovered from the cauda epididymis. The protein repair function of the PIMT may be more important in maintaining the fertilization competence of translationally-inactive mature sperm during the prolonged period of epididymal transit and storage in the male reproductive tract.

The synthesis and biological activity of a series of 3,6-substituted quinazolinediones and quinazolinones are described. The potent activity of these compounds as platelet aggregation inhibitors demonstrates the utility of these structures as central templates for nonpeptide RGD mimics.

The antiaggregatory and antithrombotic actions of MK-0383, a low molecular weight, nonpeptide antagonist of the platelet glycoprotein IIb/IIIa, were evaluated in a variety of canine models. Inhibition of ex vivo platelet aggregation responses to ADP and collagen were observed after the acute sequential i.v. administrations of 10 to 500 micrograms/kg or 360-min continuous i.v. infusions of 1 to 10 micrograms/kg/min of MK-0383. Hemostatic function normalized within 30 (platelet response to collagen, template bleeding times) to 90 min (platelet response and sensitivity to ADP) after the termination of 360-min i.v. MK-0383 infusions, suggesting no protracted, direct effects on platelet function. With acute sequential i.v. administrations of MK-0383, platelet response to ADP was abolished without significant extension of bleeding time. In a model of platelet-dependent cyclic flow reductions in injured, stenosed left circumflex coronary artery, the bolus i.v. administrations of 300 and 1000 micrograms/kg of MK-0383 totally abolished cyclic flow reductions for periods of 18 +/- 1 and 37 +/- 5 min, respectively. In a model of electrically induced left circumflex coronary artery occlusive thrombosis, 10 micrograms/kg/min i.v. of MK-0383 initiated 15 min before electrical injury prevented occlusive thrombosis in three of six preparations despite continued electrical stimulation of the vessel for 300 min, delayed occlusion in three of six preparations (160.3 +/- 5.5 min) and reduced thrombus mass (5.1 +/- 1.3 mg), compared to the development of occlusive thrombosis in six of six saline-treated preparations (50.5 +/- 8.7 min; 19.1 +/- 3.0 mg). When administered as an adjunct to thrombolytic agents in the presence of background heparin for lysis of electrically induced left circumflex coronary artery occlusive thrombus, 10 micrograms/kg/min i.v. of MK-0383 initiated 15 min before tissue-type plasminogen activator or streptokinase increased the incidence of (tissue-type plasminogen activator: eight of nine MK-0383 vs. three of eight saline; streptokinase: eight of eight MK-0383 vs. two of eight saline) and accelerated reperfusion, and reduced the incidence of acute thrombotic reocclusion during continued MK-0383 infusion. These findings indicate significant antithrombotic potential for MK-0383 alone or as an adjunct to thrombolytic therapy in the treatment of coronary artery ischemic syndromes.

Inhibitors of platelet-fibrinogen binding offer an opportunity to interrupt the final, common pathway for platelet aggregation. Small molecule inhibitors of the platelet fibrinogen receptor GPIIb/IIIa were prepared and evaluated for their ability to prevent platelet aggregation. Compound 23m (L-700,462/MK-383) inhibited in vitro platelet aggregation with an IC50 of 9 nM and demonstrated a selectivity of > 24,000-fold between platelet and human umbilical vein endothelial cell fibrinogen receptors. Dose-dependent inhibition of ex vivo platelet aggregation induced by ADP was achieved with i.v. infusions of 0.1-10 micrograms/kg/min of 23m in anesthetized dogs, with 10 micrograms/kg/min completely inhibiting platelet aggregation during the entire 6 h infusion protocol. Platelet aggregatability returned rapidly after the termination of the 23m infusions. These features suggest that 23m may be useful in the treatment of arterial occlusive disorders.

Iron-rich Fe-Al alloys have been tensile tested in moist air and dry oxygen at a strain rate of 3.3×10−4 s−1. Moist air did not cause embrittlement until the composition reached 18-20% Al. Alloys with lower aluminum contents were embrittled when tested in hydrogen gas. The environmental sensitivity of these alloys was further investigated by examining the effects of strain rate on the ductility. For the most part, no significant strain rate effects were observed in the low aluminum alloys; strain rates of up to 3.3×10−1 s−1 were not fast enough to prevent embrittlement. In contrast, the ductility of Fe-35 at.% Al did increase with increasing strain rate in air and hydrogen; at a strain rate of 3.3×10−1 s−1 the elongations approached that of vacuum.

The antiaggregatory and antithrombotic actions of MK-0852, a cyclic heptapeptide antagonist of the platelet GP IIb/IIIa, were evaluated in a variety of canine models. In vitro, MK-0852 inhibited the aggregation of canine platelet-rich plasma induced by 10 microM ADP in the presence of 1 microM epinephrine with an IC50 value of 0.10 microM. The i.v. infusion of 1.0 and 3.0 micrograms/kg/min MK-0852 to anesthetized dogs significantly inhibited ex vivo platelet aggregation responses to ADP and collagen, with the 3.0 micrograms/kg/min infusion completely inhibiting ex vivo aggregation responses to both agonists. The i.v. administrations of 100 and 300 micrograms/kg MK-0852 suppressed platelet-dependent cyclic flow reductions in stenosed canine left circumflex (LCX) coronary artery for periods of 24 +/- 3 and 64 +/- 4 min, respectively. In a canine model of copper coil-induced femoral arterial thrombosis, i.v. MK-0852 (100 micrograms/kg + 1 microgram/kg/min), initiated 15 min before coil placement, reduced the incidence of occlusive thrombosis during the 45-min post-coil time period of continued therapy (1/5 MK-0852 vs. 7/7 saline; P.01). MK-0852 was administered as an adjunctive therapy with tPA to evaluate its effects on thrombolysis after copper coil-induced femoral arterial thrombus formation. MK-0852 (i.v.; 100 micrograms/kg + 1 microgram/kg/min), initiated 15 min before tPA, reduced the incidence of post-thrombolysis reocclusion. During the 60-min period of continued drug infusion after the termination of tPA, 0 of 5 animals receiving MK-0852 reoccluded vs. 7/8 saline (P.01). In a canine model of electrically induced LCX coronary artery thrombosis, i.v. MK-0852 (100 micrograms/kg + 3 micrograms/kg/min), initiated 15 min before the initiation of electrical injury, prevented occlusive thrombosis in 4 of 6 preparations despite the continued electrical stimulation of the vessel for 180 min. Thrombotic occlusion was delayed in the remaining two preparations (99 and 100 min), compared with occlusion in 4 of 4 saline-treated preparations (69.3 +/- 6.3 min). When administered as an adjunct to thrombolytic agents for lysis of electrically induced LCX coronary artery thrombi, i.v. MK-0852 (300 micrograms/kg + 3 micrograms/kg/min), initiated 15 min before tPA or streptokinase, both increased the incidence of reperfusion (tPA: 8/8 MK-0852 vs. 3/8 saline; streptokinase: 5/8 MK-0852 vs. 2/8 saline) and accelerated reperfusion. The incidence of reocclusion during continued adjunctive therapy was reduced.(ABSTRACT TRUNCATED AT 400 WORDS)

A series of renin inhibitors containing lactam-bridged P1-P1' dipeptide mimetics based on the ACHPA (4(S)-amino-5-cyclohexyl-3(S)-hydroxypentanoic acid) design was studied. The inhibitors were obtained by aldol addition of various lactams with N alpha-Boc-L-cyclohexylalaninal, followed by Boc group removal and acylation with Boc-Phe-His. The aldol diastereomer having the S configuration at the two newly generated stereogenic centers gave optimal enzyme inhibition. Potency was further enhanced in the gamma-lactam ring series by substitution with small hydrophobic groups to mimic the P1' side chain of the renin substrate. Thus, 2(S)-[(Boc-L-phenylalanyl-L-histidyl)amino]-3-cyclohexyl-1(S)-hydroxyl-1 - (1,5,5-trimethyl-2-oxopyrrolidin-3(S)-yl)propane (34) has an IC50 of 1.3 nM in the human plasma renin assay. A variety of substituents on the lactam nitrogen are tolerated and can be used to vary the physical properties of the inhibitor. By using a model of the human renin active site, the conformation of 34 in the enzyme-inhibitor complex is proposed. This modeled conformation is very similar to the solid-state conformation of 2(S)-[(Boc-L-phenylalanyl-L-histidyl)amino]-3-cyclohexyl-1(S)-hydroxyl- 1-(1-methyl-2-oxopyrrolidin-3(S)-yl)propane (36), the structure of which was determined by single-crystal X-ray diffraction analysis. The most potent ACH-PA-lactam renin inhibitors show good selectivity when assayed against other types of aspartic proteinases. By varying the lactam ring substituents, potent and selective inhibitors of cathepsin D and cathepsin E can be obtained.

The synthesis and pharmacology of 4, a potent thienothiophene non-peptide fibrinogen receptor antagonist, are reported. Compound 4 inhibited the aggregation of human gel-filtered platelets with an IC50 of 8 nM and demonstrated an 8-fold improvement in affinity for isolated GPIIb/IIIa receptors over analogues possessing an isoindolinone backbone. Flow cytometry studies revealed that the binding of 4 to resting platelets is a diffusion-controlled process (kon = 3.3 x 10(6) M-1 s-1) and that 4 binds to dog and human platelets with comparable affinity (Kd = 0.04 and 0.07 nM, respectively). Ex vivo platelet aggregation in dogs was completely inhibited by an iv dose of 5 microg/kg [corrected], and an oral dose of 50-90 microg/kg [corrected] followed by low daily doses of 10 microg/kg [corrected] was sufficient to maintain approximately 80% inhibition of ex vivo platelet aggregation over several days. Inhibition of ADP-induced platelet aggregation in anesthetized dogs at 77 +/- 7% resulted in a moderate 2.5-fold increase in bleeding time, while complete inhibition (100%) resulted in an approximately 10-min bleeding time. Additional doses were required to increase the bleeding time to the maximum time allowed in the protocol (15 min), thus indicating a potentially useful and safe separation of efficacy and bleeding time.

The relative contributions of macrophages and lymphocytes to the induction of resistance to primary herpes simplex virus type 1 (HSV-1) infection by polyriboinosinic-polyribocytidylic acid complex [poly (I:C)] were investigated in C58 mice. The induction of resistance was found to be strongly dependent on macrophages compared to lymphocytes. Macrophage-deficient (silica-treated) mice produced less interferon and were not as responsive to prophylactic treatment of HSV-1 infections with poly (I:C) as were either normal, lymphocyte-deficient (cyclophosphamide-treated), or T-lymphocyte-deficient (anti-thymocyte serum-treated, adult-thymectomized) mice. Silica and cyclophosphamide treatments reduced the therapeutic activity of poly (I:C), whereas T-cell depletion did not have a significant effect. Similarly, the protection of mice with exogenous interferon was markedly reduced in silica-treated mice and moderately reduced in cyclophosphamide-treated mice, but unaffected in T-cell-deficient mice. Furthermore, suppression of HSV-1 plaque formation was obtained by cocultivation of infected mouse fibroblast monolayers with peritoneal (macrophage-rich) cells, but not with splenic (lymphocyte-rich) cells, from poly (I:C)-treated mice. Peritoneal cells did not protect heterologous (human) fibroblasts, suggesting that the protection of mouse embryo fibroblasts is mediated by interferon. Collectively, the data indicate that macrophages are required for the production of poly (I:C)-induced interferon and that macrophages and perhaps B-lymphocytes are important for mediating the protection against HSV-1 infection after interferon has been produced.

We performed experiments with mice to determine the nature of the immune response(s) that prevents primary infections of the skin and the trigeminal ganglia with herpes simplex virus. Immunization with infectious herpes simplex virus, inactivated virus, or material enriched for viral glycoproteins protected hairless mice against primary facial and ganglionic infections. Live and inactivated viruses induced neutralizing antibodies, whereas glycoprotein material did not. Instead, glycoprotein material induced antibodies that were largely directed against two glycopolypeptides with molecular weights of 120,000 to 130,000. Hairless mice immunized with glycoprotein material responded faster than control mice in the synthesis of neutralizing antibodies after challenge with infectious virus. Congenital athymic BALB/c (nu/nu) mice were protected against primary facial infections after immunization with glycoprotein material, but glycoprotein-specific antibodies were not induced.

Addition of aluminum as a cation substituent in GaAs improves the relative radiation hardness of the GaAs light emitting diode, as deduced from both gamma and neutron irradiation experiments to 108 rads (Si) and 3.5t1013 neutrons/cm2, respectively. The gamma damage coefficient, K y , shows a marked and unexpected decrease from 52 (rads (Si) .s)−1 to ∼ 2 (rads(Si) .s)−1 in the composition range from GaAs to ∼ Ga .90 Al 10 AS. Above 10 percent Al content, the damage coefficient changes only slightly. On the other hand, the neutron damage coefficient K n shows a gradual change over the entire compositional range from 0 to 34 percent aluminum. Annealing of the gamma-irradiated samples indicates that the 240° C stage noted for GaAs and attributed to an arsenic vacancy is reduced with addition of aluminum. On the other hand the annealing of the Ga 1−x Al x As samples following neutron irradiation indicates that the annealing characteristics are virtually independent of the aluminum composition. For both types of irradiation there is a shift of the peak emission wavelength to shorter wavelengths following irradiation.