Risk of brainstem necrosis in pediatric patients with central nervous system malignancies after pencil beam scanning proton therapy.

Background: Radiation therapy (RT) plays an important role in management of pediatric central nervous system (CNS) malignancies. Centers are increasingly utilizing pencil beam scanning proton therapy (PBS-PT). However, the risk of brainstem necrosis has not yet been reported. In this study, we evaluate the rate of brainstem necrosis in pediatric patients with CNS malignancies treated with PBS-PT.Material and methods: Pediatric patients with non-hematologic CNS malignancies treated with PBS-PT who received dose to the brainstem were included. All procedures were approved by the institutional review board. Brainstem necrosis was defined as symptomatic toxicity. The actuarial rate was analyzed by the Kaplan Meier method.Results: One hundred and sixty-six consecutive patients were reviewed. Median age was 10 years (range 0.5-21 years). Four patients (2.4%) had prior radiation. Median maximum brainstem dose in the treated course was 55.4 Gy[RBE] (range 0.15-61.4 Gy[RBE]). In patients with prior RT, cumulative median maximum brainstem dose was 98.0 Gy [RBE] (range 17.0-111.0 Gy [RBE]). Median follow up was 19.6 months (range, 2.0-63.0). One patient who had previously been treated with twice-daily radiation therapy and intrathecal (IT) methotrexate experienced brainstem necrosis. The actuarial incidence of brainstem necrosis was 0.7% at 24 months (95% CI 0.1-5.1%).Conclusion: The rate of symptomatic brainstem necrosis was extremely low after treatment with PBS-PT in this study. Further work to clarify clinical and dosimetric parameters associated with risk of brainstem necrosis after PBS-PT is needed.

An investigation of fingerstick blood collection for point-of-care HIV-1 viral load monitoring in South Africa.

BACKGROUND: Viral load (VL) quantification is an important tool in determining newly developed drug resistance or problems with adherence to antiretroviral therapy (ART) in HIV-positive patients. VL monitoring is becoming the standard of care in many resource-limited settings. Testing in resource-limited settings may require sampling by fingerstick because of general shortages of skilled phlebotomists and the expense of venepuncture supplies and problems with their distribution. OBJECTIVE: To assess the feasibility and ease of collecting 150 µL capillary blood needed for the use of a novel collection device following a classic fingerstick puncture. METHODS: Patients were recruited by the study nurse upon arrival for routine ART monitoring at the Themba Lethu Clinic in Johannesburg, South Africa. Each step of the fingerstick and blood collection protocol was observed, and their completion or omission was recorded. RESULTS: One hundred and three patients consented to the study, of whom three were excluded owing to the presence of callouses. From a total of 100 patients who consented and were enrolled, 98% of collection attempts were successful and 86% of participants required only one fingerstick to successfully collect 150 µL capillary blood. Study nurse adherence to the fingerstick protocol revealed omissions in several steps that may lower the success rate of capillary blood collection and reduce the performance of a subsequent VL assay. CONCLUSION: The findings of this study support the feasibility of collecting 150 µL of capillary blood via fingerstick for point-of-care HIV-1 VL testing in a resource-limited setting.

Advancing pharmacovigilance through academic-legal collaboration: the case of gadolinium-based contrast agents and nephrogenic systemic fibrosis-a Research on Adverse Drug Events and Reports (RADAR) report.

OBJECTIVE: To compare and contrast three databases, that is, The International Centre for Nephrogenic Systemic Fibrosis Registry (ICNSFR), the Food and Drug Administration Adverse Event Reporting System (FAERS) and a legal data set, through pharmacovigilance and to evaluate international nephrogenic systemic fibrosis (NSF) safety efforts. METHODS: The Research on Adverse Drug events And Reports methodology was used for assessment-the FAERS (through June 2009), ICNSFR and the legal data set (January 2002 to December 2010). Safety information was obtained from the European Medicines Agency, the Danish Medicine Agency and the Food and Drug Administration. RESULTS: The FAERS encompassed the largest number (n = 1395) of NSF reports. The ICNSFR contained the most complete (n = 335, 100%) histopathological data. A total of 382 individual biopsy-proven, product-specific NSF cases were analysed from the legal data set. 76.2% (291/382) identified exposure to gadodiamide, of which 67.7% (197/291) were unconfounded. Additionally, 40.1% (153/382) of cases involved gadopentetate dimeglumine, of which 48.4% (74/153) were unconfounded, while gadoversetamide was identified in 7.3% (28/382) of which 28.6% (8/28) were unconfounded. Some cases involved gadobenate dimeglumine or gadoteridol, 5.8% (22/382), all of which were confounded. The mean number of exposures to gadolinium-based contrast agents (GBCAs) was gadodiamide (3), gadopentetate dimeglumine (5) and gadoversetamide (2). Of the 279 unconfounded cases, all involved a linear-structured GBCA. 205 (73.5%) were a non-ionic GBCA while 74 (26.5%) were an ionic GBCA. CONCLUSION: Clinical and legal databases exhibit unique characteristics that prove complementary in safety evaluations. Use of the legal data set allowed the identification of the most commonly implicated GBCA. ADVANCES IN KNOWLEDGE: This article is the first to demonstrate explicitly the utility of a legal data set to pharmacovigilance research.

fdg-pet in two cases of neurofibromatosis type 1 and atypical malignancies.

Patients with neurofibromatosis type 1 (nf1) are at increased risk for both benign and malignant tumours, and distinguishing the malignant potential of an individual tumour is a common clinical problem in these patients. Here, we review two cases of uncommon malignancies (Hodgkin lymphoma and mediastinal germ-cell tumour) in patients with nf1. Although (18)F-fluorodeoxyglucose positron-emission tomography (fdg-pet) has been used to differentiate benign neurofibromas from malignant peripheral nerve sheath tumours, fdg-pet characteristics for more rare tumours have been poorly described in children with nf1. Here, we report the role of pet imaging in clinical decision-making in each case. In nf1, fdg-pet might be useful in the clinical management of unusual tumour presentations and might help to provide information about the malignant potential of uncommon tumours.

Parent-of-origin in individuals with familial neurofibromatosis type 1 and optic pathway gliomas.

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant cancer syndromes worldwide. Individuals with NF1 have a wide variety of clinical features including a strongly increased risk for pediatric brain tumors. The etiology of pediatric brain tumor development in NF1 is largely unknown. Recent studies have highlighted the contribution of parent-of-origin effects to tumorigenesis in sporadic cancers and cancer predisposition syndromes; however, there is limited data on this effect for cancers arising in NF1. To increase our understanding of brain tumor development in NF1, we conducted a multi-center retrospective chart review of 240 individuals with familial NF1 who were diagnosed with a pediatric brain tumor (optic pathway glioma; OPG) to determine whether a parent-of-origin effect exists overall or by the patient's sex. Overall, 50 % of individuals with familial NF1 and an OPG inherited the NF1 gene from their mother. Similarly, by sex, both males and females were as likely to inherit the NF1 gene from their mother as from their father, with 52 % and 48 % of females and males with OPGs inheriting the NF1 gene from their mother. In conclusion, in contrast to findings from other studies of sporadic cancers and cancer predisposition syndromes, our results indicate no parent-of-origin effect overall or by patient sex for OPGs in NF1.

Legal, financial, and public health consequences of transfusion-transmitted hepatitis C virus in persons with haemophilia.

BACKGROUND: Since the first cases of acquired immunodeficiency syndrome in persons with haemophilia were reported in 1982, much has been written about the consequences of human immunodeficiency virus (HIV) contamination of the blood supply. Relatively little attention has been paid to similar hepatitis C virus (HCV) concerns since the first cases of HCV-infected persons with haemophilia were identified in 1989. METHODS: We review the history, public health, policy, and financial consequences of blood supply policy decisions made for persons with haemophilia who received HCV-contaminated blood products in eight countries that were severely impacted by viral contamination of the blood supply during the 1980s, contrasting these findings with those reported previously for HIV contamination of the blood supply during the same time-period. A Medline search and a hand search of retrieved bibliographies of English-language articles on HCV concerns in haemophilia patients published from 1989 to 2006 were performed. RESULTS: Our review identified that two- to eightfold more persons with haemophilia in the eight countries contracted HCV vs. HIV from contaminated blood products during the 1980s. Opportunistic infections and immunosuppression-related complications among persons with haemophilia developed shortly after these patients received HIV-infected blood products whereas hepatic complications among HCV-infected persons with haemophilia are just now being diagnosed two decades after these individuals received HCV-contaminated blood products. Policy makers in four countries conducted official public inquiries into blood safety decisions related to HIV- and/or HCV-contamination of the blood supply. More than 20 countries allocated compensation funds for HIV-infected persons with haemophilia (mean award ranging from $37 000 to 400 000) whereas only the UK, Canada, and Ireland allocated compensation funds for HCV-infected persons with haemophilia (mean award ranging from $37 000 to 50 000). CONCLUSION: While the clinical impact among persons with haemophilia of HCV contamination of the blood supply in the 1980s was larger than the impact of HIV contamination of the blood supply during this time-period, the policy response was smaller. Consideration should be given to adopting support programmes for HCV-infected persons with haemophilia in countries that do not have these programs.

Defining optic nerve tortuosity.

BACKGROUND AND PURPOSE: Optic nerve tortuosity is one of several nonmalignant abnormalities documented on MR imaging in patients with neurofibromatosis type 1 and may be related to the development of optic pathway gliomas. This study seeks an operational definition for optic nerve tortuosity. MATERIALS AND METHODS: A focus group of 3 pediatric neuroradiologists reviewed 20 MR images of the brain and orbits of patients suspected to have optic nerve tortuosity in the absence of optic pathway glioma and found 6 radiographic factors that occurred frequently. Subsequently, 28 MR images were assessed for the presence of optic nerve tortuosity, using a global assessment question that reflects a neuroradiologist's confidence in the presence of optic nerve tortuosity, and for the presence of the 6 radiographic factors, to identify a combination of these factors that best predicted a diagnosis of optic nerve tortuosity. RESULTS: We found perfect inter-rater agreement between 3 readers on the presence/absence of tortuosity in 75% of cases. Lack of congruity of the optic nerves, in more than 1 coronal section and dilation of the subarachnoid space surrounding the optic nerves, when found together are sensitive (89%) and specific (93%) for a diagnosis of tortuosity on the global scale. The absence of these 2 factors, along with absence of deviation of the optic nerve within the axial plane, provides a reliable test to exclude tortuosity. CONCLUSION: Lack of congruity of the optic nerves in more than 1 coronal section and dilation of the subarachnoid space surrounding the optic nerves together provide an operational radiographic definition of optic nerve tortuosity.

Evaluation of perennial ryegrass straw as a forage source for ruminants.

Two experiments were conducted to evaluate perennial ryegrass straw as a forage source for ruminants. Experiment 1 evaluated digestion and physiological variables in steers offered perennial ryegrass straw containing increasing levels of ergot alkaloid, lolitrem B. Sixteen ruminally cannulated Angus x Hereford steers (231+/-2 kg BW) were blocked by weight and assigned randomly to one of four treatments. Steers were provided perennial ryegrass straw at 120% of the previous 5-d average intake. Before straw feeding, soybean meal was provided (0.1% BW; CP basis) to meet the estimated requirement for degradable intake protein. Low (L) and high (H) lolitrem B straws (<100 and 1,550 ppb, respectively; DM basis) were used to formulate treatment diets: 100% L; 67% L:33% H; 33% L:67% H; 100% H (DM basis). Intake and digestibility of DM and OM, and ruminal pH, total VFA, and NH3-N were not affected by increasing lolitrem B concentration. Ruminal indigestible ADF (IADF) fill increased linearly (P = 0.01) and IADF passage rate decreased linearly (P = 0.04) as lolitrem B increased. Experiment 2 evaluated performance and production by 72 Angus x Hereford cows (539+/-5 kg BW) consuming perennial ryegrass straw containing increasing lolitrem B during the last third of gestation. Cows were blocked by body condition score and randomly assigned to one of three treatments. Cows were provided perennial ryegrass straw ad libitum and supplemented with soybean meal (0.1% BW; CP basis) to meet the estimated requirement for degradable intake protein. Mixtures of a L and H lolitrem B straw (467 and 2,017 ppb, respectively) were used to formulate treatment diets: 100% L, 50% L:50% H, 100% H (DM basis). Thirteen of 24 cows on the 100% H treatment exhibited signs of ryegrass staggers and were removed from the study; nevertheless, lolitrem B concentration did not influence pre- or postcalving weight or body condition score change. These data suggest that feeding perennial ryegrass straw containing up to 1,550 ppb lolitrem B (DM basis) did not adversely affect nutrient digestion or physiological response variables in steers. However, providing straw with a lolitrem B concentration of approximately 2,000 ppb (DM basis) resulted in 54% of cows exhibiting signs of ryegrass staggers. These data suggest that blending straws with a high (>2,000 ppb) and low (<500 ppb) concentration of lolitrem B can be a successful management practice.

Adenoviral-mediated transfer of tissue plasminogen activator gene into brain capillary endothelial cells in vitro.

Tissue plasminogen activator (tPA) has a critical role in fibrinolysis, converting plasminogen into active protease plasmin. Because intravenous tPA has only limited effectiveness as acute stroke therapy, enhancement of endogenous tPA represents a potential alternative to stroke treatment. Adenoviral-mediated gene transfer was used to enhance production of tPA in bovine brain capillary endothelial cells (BEC). Antigen and activity levels of tPA and plasminogen activator inhibitor-1 (PAI-1) in media from BEC infected with AdCMVtPA were analyzed. Conditioned media were analyzed for thrombomodulin, the integral membrane antithrombotic molecule that co-activates protein C. BEC infected with AdCMVtPA demonstrated enhanced expression of tPA antigen (40.2 +/- 0.4 ng/mL vs 1.1 +/- 1.5 ng/mL [p<0.001] and 0.3 +/- 0.5 ng/mL [p<0.0001], respectively) and increased tPA enzymatic activity (27.4 +/- 5.7 IU/mL vs 8.3 +/- 1.7 IU/mL [p<0.05] and 13.3 +/- 3.2 IU/mL [p<0.05], respectively) compared to BEC infected with the control adenovirus (Adl327) or uninfected BEC. There was a moderate increase in PAI-1 protein 4 days after transfection with AdCMVtPA, and the integral membrane protein thrombomodulin was released into media by transfected BEC. These results demonstrate that adenoviral-mediated delivery in vitro of the human tPA gene resulted in high levels of expression of tPA in BEC. Transient overexpression of tPA by gene transfer might be a useful strategy to protect against thrombotic occlusion during the period of risk of acute stroke.

Nucleotide substitution in the ectodomain of trail receptor DR4 is associated with lung cancer and head and neck cancer.

Allelic loss of chromosome 8p21-22 occurs frequently in cancer, including lung and head and neck squamous cell cancer. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors, including proapoptotic DR4 and KILLER/DR5, are located on 8p21-22. TRAIL receptors are candidate tumor suppressor genes, because their inactivation would be expected to result in deficient apoptotic signaling. To investigate the involvement of DR4 in human cancer, we have determined the genomic structure of DR4 and screened 31 lung cancer cell lines [14 small cell lung cancer and 17 non-small cell lung cancer (NSCLC)], many with deletions at 8p21-22, and 21 primary NSCLC samples for mutations in DR4. We found two missense alterations in the ectodomain of DR4. One, at nucleotide 626, changes a cytosine to a guanine (C626G) and results in a substitution of an arginine for threonine. The other, at nucleotide 422, changes a guanine to adenine (G422A) and results in a substitution of a histidine for arginine. Using genomic DNA sequencing and RFLP analysis, we show that these two alterations cosegregated in 96% of all of the samples (n = 243) evaluated (tumor and normal). The frequency of being homozygous for both altered alleles was 35% in the lung cancer cell lines but only 13% in age- and race-matched controls, which was a significant increase (chi(2) = 5.2, P = 0.023). The frequency of homozygosity for both alleles was also significantly increased in the primary NSCLC samples (chi(2) = 9.2, P = 0.002) as compared with the age- and race-matched controls. To determine whether the altered alleles are specific for lung cancer, we evaluated 19 head and neck squamous cell cancer and 25 gastric adenocarcinoma samples. Forty-seven % of the former and 44% of the latter were homozygous for both the C626G and G422A alterations, and this was significantly elevated relative to age- and race-matched controls (chi(2) = 8.6, P = 0.003 and chi(2) = 8.2, P = 0.004). These alterations result in amino acid changes in or near the ligand-binding domain of DR4 and, based on the crystal structure of DR5 and its homology with DR4, have the potential to affect TRAIL binding to DR4. Our results suggest that the altered DR4 alleles may be associated with, and should be investigated additionally as potential markers for, predisposition to common malignancies.

Sequence analysis of the rat phenylalanine hydroxylase gene promoter.

We have characterized the 5'-end (3218 bp) of the rat phenylalanine hydroxylase (PAH) gene. Within this PAH promoter sequence, we have identified a number of putative regulatory sites analogous to those present in the human and murine PAH promoters. In particular, potential HNF 1 binding sites and a CRE have been identified. These sequences respectively bind HNF1 and CREB transcription factors present in rat nuclear extracts and may be significant in the tissue-specific and hormonal control of PAH expression.

Stroke precipitated by moderate blood pressure reduction.

Rapid lowering of blood pressure can precipitate or worsen ischemic strokes. This usually has been observed in the setting of profoundly lowered pressure and hypotension. We report on six patients in whom ischemic neurologic injury ensued or worsened after moderate reduction of blood pressure by pharmacological treatment. The 6 patients suffered new or worsened ischemic neurologic deficits after receiving oral or intravenous antihypertensive medications, mostly after relatively small doses. Mean arterial blood pressure in these patients was decreased by 25 +/- 7.7%, or 37 +/- 16 mm Hg (mean +/- SD) without resultant hypotension. These cases emphasize the potential hazards of moderate blood pressure reduction by antihypertensive medications in the setting of an acute ischemic stroke or transient ischemic attack (TIA), as well as rapidly treated hypertension even in those who have not yet manifested ischemic symptoms.

1,2-Disubstituted indole, azaindole and benzimidazole derivatives possessing amine moiety: a novel series of thrombin inhibitors.

A novel series of 1,2-disubstituted indole, azaindole and benzimidazole derivatives possessing an amine moiety was identified as thrombin inhibitors. An indole with basic diamine moieties (12a) was the most potent thrombin inhibitor in the series with Kass= 197 x 10(6) L/mol.

Retrograde venous perfusion with hypothermic saline and adenosine for protection of the ischemic spinal cord.

PURPOSE: Spinal cord injury and the resultant postoperative paraplegia are devastating complications of thoracic aortic surgery, for which no widely accepted protective interventions exist. We hypothesized that retrograde venous perfusion-cooling of the spinal cord with a hypothermic saline and adenosine solution would protect it from ischemic injury caused by thoracic aortic occlusion. METHODS: Adult domestic swine of either sex (weight range, 20 to 30 kg) were intubated and ventilated. A left thoracotomy was performed. The accessory hemiazygous vein was divided, and a catheter was inserted distally. The aorta was clamped at the left subclavian artery. The venous catheter was not used in the animals in the control group (n = 7); in the animals in the experimental group (n = 7), a cold (4 degrees C) saline and adenosine solution was infused into the accessory hemiazygous vein. After 30 minutes, the clamp and catheter were removed, and the chest was closed. A blinded observer evaluated the animals' hind-leg motor activity 24 hours later. The Tarlov scale was used: 0, complete paralysis; 1, minimal movement; 2, stands with assistance; 3, stands alone; 4, weak walk; 5, normal gait. The animals' rectal temperatures were measured at the end of the experiment, and blood pressure was measured throughout. Two other groups were studied to assess the effect of the intervention on spinal cord temperature. RESULTS: The animals in the control group had a mean Tarlov score of 1.7 +/- 0.6; the animals in the experimental group had a mean Tarlov score of 4.9 +/- 0.1 (P <.01). The animals in the experimental group had a significantly greater drop in spinal cord temperature than those in the control group (4. 05 +/- 0.6 degrees C vs 0.58 +/- 0.12 degrees C; P <.01). No significant difference in rectal temperatures was found, nor did any arrhythmias or hypotensive episodes occur in either group. Perfusion of the spinal cord was confirmed with angiography by using this approach. CONCLUSION: Retrograde venous perfusion-cooling of the spinal cord with a hypothermic saline and adenosine solution protects the cord from ischemic injury caused by clamping of the thoracic aorta.

Characterization of ecdysteroid 26-hydroxylase: an enzyme involved in molting hormone inactivation.

Insect molting hormone (ecdysteroid) inactivation occurs by several routes, including 26-hydroxylation and further oxidation to the 26-oic acids. Thus, the ecdysteroid 26-hydroxylase is a critical enzyme involved in precise regulation of ecdysteroid titers during insect development. Administration of the ecdysteroid agonist, RH-5849 (1,2-dibenzoyl, 1-tert-butyl hydrazone), or 20-hydroxyecdysone to the tobacco hornworm, Manduca sexta, results in induction of ecdysteroid 26-hydroxylase activity in midgut mitochondria and microsomes. The biochemical and kinetic properties of the ecdysteroid 26-hydroxylase were investigated. The mitochondrial enzyme was found to have optimal activity at a pH of 7. 5 in a Hepes or sodium phosphate buffer at 30-37 degrees C. The apparent K(m) of the microsomal 26-hydroxylase for 20-hydroxyecdysone substrate was lower than that of the mitochondrial enzyme for either 20-hydroxyecdysone or ecdysone substrate. The V(max) of the 26-hydroxylase in both subcellular fractions was slightly higher using 20-hydroxyecdysone as substrate compared to ecdysone. Demonstration that activity of the mitochondrial 26-hydroxylase was inhibited by incubation in a CO (or N(2)) atmosphere, taken together with the requirement for reducing cofactor and the efficacy of the P450 inhibitors, ketoconazole and fenarimol, provided strong evidence that the hydroxylase is cytochrome P450-dependent. Indirect evidence suggested that the mitochondrial and microsomal ecdysteroid 26-hydroxylase(s) could exist in a less active dephosphorylated state or more active phosphorylated state. Using Escherichia coli alkaline phosphatase to remove covalently bound phosphate groups, the activity of the 26-hydroxylase was decreased and, conversely, activity was enhanced using a cAMP-dependent protein kinase with appropriate cofactors. In addition, the protein kinase was shown to reactivate the 26-hydroxylase activity in alkaline phosphatase-treated fractions.

Homozygous deletion of the death receptor DR4 gene in a nasopharyngeal cancer cell line is associated with TRAIL resistance.

The family of tumor necrosis factor related apoptosis inducing ligand (TRAIL) receptors, including the pro-apoptotic DR4 and p53-regulated KILLER/DR5, as well as the decoys TRID and TRUNDD, are all located on human chromosome 8p21-22. This region of the genome is frequently altered in head and neck cancer. We previously reported that KILLER/DR5 can be mutationally inactivated in head and neck cancer. Here, we report that the FaDu nasopharyngeal cancer cell line contains an abnormal chromosome 8p21-22 region. In addition, there appears to be a homozygous deletion involving DR4 but not KILLER/DR5 in FaDu cells. The homozygous loss within the DR4 gene encompasses its death domain, which is required for apoptotic signaling. The deletion of DR4 in FaDu cells is associated with resistance to the cytotoxic effects of TRAIL. Re-introduction of wild-type DR4 leads to apoptosis and restores TRAIL sensitivity of FaDu cells. These observations suggest that the death inducing DR4 receptor gene may be a rare target for inactivation in human cancer and that DR4 loss may contribute to resistance to TRAIL therapy.

Spatio-logical processes in intracellular signalling.

Classical models of intracellular signalling describe how small changes in a cell's external environment can bring about major changes in cellular activity. Recent findings from experimental biology indicate that many intracellular signalling systems show a high level of spatial organisation. This permits the modification, by protein kinase or protein phosphatase action, of specific subsets of intracellular proteins - an attribute that is not addressed in classical signalling models. Here we use ideas and concepts from computer science to describe the information processing nature of intracellular signalling pathways and the impact of spatial heterogeneity of their components (e.g. protein kinases and protein phosphatases) on signalling activity. We argue that it is useful to view the signalling ecology as a vast parallel distributed processing network of agents operating in heterogeneous microenvironments, and we conclude with an overview of the mathematical and semantic methodologies that might help clarify this analogy between biological and computational systems.

Fused bicyclic Gly-Asp beta-turn mimics with potent affinity for GPIIb-IIIa. Exploration of the arginine isostere.

6-[4-Amidinobenzoyl]amino]-tetralone-2-acetic acid is a potent antagonist of GPIIb-IIIa. Substitution in the meta position of the benzamidine, or replacement with a heteroaryl amidine was tolerated in this series. Use of an acyl-linked 4-alkyl piperidine as an arginine isostere also provided active compounds. Compounds from this series provided substantial systemic exposure in the rat following oral administration.