Optimizing metabolic stability of phosphodiesterase 5 inhibitors: Discovery of a potent N-(pyridin-3-ylmethyl)quinoline derivative targeting synaptic plasticity.

Phosphodiesterase 5 (PDE5) is a cyclic guanosine monophosphate-degrading enzyme involved in numerous biological pathways. Inhibitors of PDE5 are important therapeutics for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD). We previously reported the first generation of quinoline-based PDE5 inhibitors for the treatment of AD.

Dropped Gallstone Mimicking Retroperitoneal Tumor 5 Years After Laparoscopic Cholecystectomy Posing a Diagnostic Challenge.

Laparoscopic cholecystectomy is the standard treatment for cholecystitis. The major complications associated with laparoscopic cholecystectomy include bleeding, abscess formation, biliary injury with bile leakage, and bowel injury. Gallbladder perforation and subsequent stone spillage are not uncommon in laparoscopic cholecystectomy.

Development of novel phosphodiesterase 5 inhibitors for the therapy of Alzheimer's disease.

Nitric oxide (NO) is a gaseous molecule that plays a multifactorial role in several cellular processes. In the central nervous system, the NO dual nature in neuroprotection and neurotoxicity has been explored to unveil its involvement in Alzheimer's disease (AD). A growing body of research shows that the activation of the NO signaling pathway leading to the phosphorylation of the transcription factor cyclic adenine monophosphate responsive element binding protein (CREB) (so-called NO/cGMP/PKG/CREB signaling pathway) ameliorates altered neuroplasticity and memory deficits in AD animal models.

Prevalence of Cerebrotendinous Xanthomatosis Among Patients Diagnosed With Acquired Juvenile-Onset Idiopathic Bilateral Cataracts.

Importance: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive bile acid synthesis disorder caused by mutations in CYP27A1, the gene encoding sterol 27-hydroxylase, which results in elevated levels of plasma cholestanol and urinary bile alcohols. Clinical symptoms and signs may include early-onset chronic diarrhea, juvenile-onset bilateral cataracts, cholestatic jaundice, tendon xanthomas, and progressive neurological deterioration. Although initiation of treatment at a young age can prevent disease complications, diagnosis often occurs after the onset of permanent neurologic damage.

Long-Term Carriage of Medicopsis romeroi, an Agent of Black-Grain Mycetoma, Presenting as Phaeohyphomycosis in a Renal Transplant Patient.

Medicopsis species are rare fungal pathogens that frequently resist common antifungal therapies and are difficult to identify morphologically as conidia are produced in pycnidia, a key feature of coelomycetes. Immunocompromised patients are at risk of these infections, even after remote exposure, and typically present with phaeohyphomycoses without dissemination. We present the case of a renal transplant recipient 6.

Synaptic and memory dysfunction induced by tau oligomers is rescued by up-regulation of the nitric oxide cascade.

Background: Soluble aggregates of oligomeric forms of tau protein (oTau) have been associated with impairment of synaptic plasticity and memory in Alzheimer's disease. However, the molecular mechanisms underlying the synaptic and memory dysfunction induced by elevation of oTau are still unknown.

Methods: This work used a combination of biochemical, electrophysiological and behavioral techniques.

Identification of a Novel 1,2,3,4-Tetrahydrobenzo[b][1,6]naphthyridine Analogue as a Potent Phosphodiesterase 5 Inhibitor with Improved Aqueous Solubility for the Treatment of Alzheimer's Disease.

Phosphodiesterase 5 (PDE5) hydrolyzes cyclic guanosine monophosphate (cGMP) leading to increased levels of the cAMP response element binding protein (CREB), a transcriptional factor involved with learning and memory processes. We previously reported potent quinoline-based PDE5 inhibitors (PDE5Is) for the treatment of Alzheimer's disease (AD). However, the low aqueous solubility rendered them undesirable drug candidates.

Antiangiogenic Effect of (±)-Haloperidol Metabolite II Valproate Ester [(±)-MRJF22] in Human Microvascular Retinal Endothelial Cells.

(±)-MRJF22 [(±)-2], a novel prodrug of haloperidol metabolite II (sigma-1 receptor antagonist/sigma-2 receptor agonist ligand) obtained by conjugation to valproic acid (histone deacetylase inhibitor) via an ester bond, exhibits antiangiogenic activity, being able to reduce human retinal endothelial cell (HREC) viability in a comparable manner to bevacizumab. Moreover, (±)-2 was able to significantly reduce viable cells count, endothelial cell migration, and tube formation in vascular endothelial growth factor A (VEGF-A) stimulated HREC cultures.

Effect of MRJF4 on C6 Glioma Cells Proliferation and Migration.

Background: MRJF4, a novel haloperidol metabolite II prodrug, was obtained through the esterification of the secondary hydroxyl group of haloperidol metabolite II with 4-phenylbutyric acid. The activities of (±)-MRJF4 and its two enantiomers [(+)-MRJF4 and (-)-MRJF4] as tumor specific inducers of pro-apoptotic genes were evaluated on malignant C6 glioma cells. In particular, changes in Nf-κB signaling pathway, activity of nitric oxide synthases (NOS), metalloproteinases (MMPs), and membrane adhesion proteins were investigated.

PDE5 Exists in Human Neurons and is a Viable Therapeutic Target for Neurologic Disease.

Phosphodiesterase 5 (PDE5) is a critical component of the cGMP-PKG axis of cellular signaling in neurons, and inhibition of PDE5 has been shown to be therapeutic in a wide range of neurologic conditions in animal models. However, enthusiasm for PDE5 inhibitors in humans is limited by data suggesting that PDE5 may not exist in human neurons. Here, we first show that past attempts to quantify PDE5 mRNA were flawed due to the use of incorrect primers, and that when correct primers are used, PDE5 mRNA is detectable in human brain tissue.

MRJF4, a novel histone deacetylase inhibitor, induces p21 mediated autophagy in PC3 prostate cancer cells.

Autophagy is a cellular defense mechanism which occurs through degradation and recycling of cytoplasmic constituents and represents a caspase—independent alternative to cell death by apoptosis. It is generally accepted that the suppression of autophagy in many cancer cells is directly correlated to malignancy; hence, the control of autophagy genes could represent a target for cancer therapy. The inhibition of cell proliferation through autophagy activation could be an important mechanism for many anti—tumor drugs.

Synaptic therapy in Alzheimer's disease: a CREB-centric approach.

Therapeutic attempts to cure Alzheimer's disease (AD) have failed, and new strategies are desperately needed. Motivated by this reality, many laboratories (including our own) have focused on synaptic dysfunction in AD because synaptic changes are highly correlated with the severity of clinical dementia. In particular, memory formation is accompanied by altered synaptic strength, and this phenomenon (and its dysfunction in AD) has been a recent focus for many laboratories.

Haloperidol metabolite II prodrug: asymmetric synthesis and biological evaluation on rat C6 glioma cells.

In a previous work we reported the antiproliferative effects of (±)-MRJF4, a novel haloperidol metabolite II (HP-mII) (a sigma-1 antagonist and sigma-2 agonist) prodrug, obtained through conjugation to 4-phenylbutyric acid (PhBA) [a histone deacetylase inhibitor (HDACi)] via an ester bond. As a continuation of this work, here we report the asymmetric synthesis of compounds (R)-(+)-MRJF4 and (S)-(-)-MRJF4 and the evaluation of their biological activity on rat C6 glioma cells, derived from glioblastoma multiforme (GBM), which is the most common and deadliest central nervous system (CNS) invasive malignancy. Favourable physicochemical properties, high permeability in the parallel artificial membrane permeability assay (PAMPA), good enzymatic and chemical stability, in vivo anticancer activity, associated with the capacity to reduce cell viability and to increase cell death by apoptosis, render compound (R)-(+)-MRJF4 a promising candidate for the development of a useful therapeutic for gliomas therapy.

Synthesis of quinoline derivatives: discovery of a potent and selective phosphodiesterase 5 inhibitor for the treatment of Alzheimer's disease.

Phosphodiesterase type 5 (PDE5) mediates the degradation of cGMP in a variety of tissues including brain. Recent studies have demonstrated the importance of the nitric oxide/cGMP/cAMP-responsive element-binding protein (CREB) pathway to the process of learning and memory. Thus, PDE5 inhibitors (PDE5Is) are thought to be promising new therapeutic agents for the treatment of Alzheimer's disease (AD), a neurodegenerative disorder characterized by memory loss.

A tale of two soles: sociomechanical and biomechanical considerations in diabetic limb salvage and amputation decision-making in the worst of times.

Foot ulcerations complicated by infection are the major cause of limb loss in people with diabetes. This is especially true in those patients with severe sepsis. Determining whether to amputate or attempt to salvage a limb often requires in depth evaluation of each individual patient's physical, mental, and socioeconomic status.

Clinical efficacy of the pan metatarsal head resection as a curative procedure in patients with diabetes mellitus and neuropathic forefoot wounds.

Objective: To evaluate the safety and efficacy of the pan metatarsal head resection (PMHR) compared with nonsurgical management of wounds in the forefoot in people with diabetes.

Methods: The authors evaluated 92 patients with diabetes (66.3% male), with ulcers classified as University of Texas grade 1A or 2A at the plantar aspect of the forefoot using a case-control model.

Adventitious bursae underlying chronic wounds: another possible deterrent to healing.

Adventitious bursae typically develop in areas of chronic frictional irritation, usually under bony prominences. Although adventitious bursae are generally well understood, there is a paucity of data on effects of bursae underlying chronic wounds in neuropathic patients. This manuscripts reviews 4 clinical cases, each with a neuropathic patient with adventitious bursae underlying chronic nonhealing wound and strategies for treatment.

Antiproliferative activity of phenylbutyrate ester of haloperidol metabolite II [(±)-MRJF4] in prostate cancer cells.

Complex mechanisms of prostate cancer progression prompt to novel therapeutic strategies concerning a combination of drugs or of single molecules able to interact with more crucial targets. Histone deacetylase inhibitors and sigma ligands with mixed σ(1) antagonist and σ(2) agonist properties were proposed as new potential tools for treatment of prostate cancer. (±)-MRJF4 was synthesized as phenylbutyrate ester of haloperidol metabolite II, which is a molecule consisting of a histone deacetilase inhibitor (4-phenylbutyric acid) and a sigma ligand (haloperidol metabolite II).

Pseudo-obstruction associated with colonic ischemia: successful management with colonoscopic decompression.

Colonic pseudo-obstruction has been associated with colonic ischemia in only 7-10% of cases. When both conditions are present, most authors recommend immediate laparotomy because of the additional weakening of the bowel wall induced by the presence of ischemia and the resultant increased risk of perforation. We report on three patients with pseudo-obstruction and right-sided colonic ischemia who were successfully managed with colonoscopic decompression with tube placement.

Colonic ischemia complicating immunotherapy with interleukin-2 and interferon-alpha.

Colonic ischemia (CI) is a rare complication of high-dose interleukin-2 (IL-2) immunotherapy. This complication occurred in three of 141 patients (2.1%) with metastatic cancer treated with high-dose IL-2 therapy; CI only developed in patients receiving interferon-alpha (IFN) with IL-2 (three of 21, 14%) compared with none of 120 in those patients receiving IL-2 alone (P equals 0.

The diagnostic yield of superior mesenteric angiography: correlation with the pattern of gastrointestinal bleeding.

In an attempt to evaluate the usefulness of mesenteric angiography in relation to the nature and rate of gastrointestinal bleeding, we reviewed the records of all patients hospitalized at Montefiore Medical Center between 1983 and 1986 who had mesenteric angiography as part of their diagnostic evaluation for gastrointestinal bleeding. Fifty-eight patients were classified according to the pattern of blood loss: 14 patients with chronic occult, 28 patients with recurrent acute, and 16 patients with acute bleeding. The sensitivity and specificity of mesenteric angiography for each group was: chronic occult, 40% sensitivity and 100% specificity; recurrent acute, 30% sensitivity and 100% specificity; acute, 47% sensitivity and 100% specificity.

Identical genetic profiles in primary and metastatic bladder tumors.

Transitional cell carcinoma of the bladder has been shown repeatedly to possess abnormal genetic profiles. During long periods recurrent tumors in the bladder consistently show the same type of genetic profile with each recurrence. We report on a patient with metastatic bladder cancer who had similar genetic profiles of the primary lesion and thoracocentesis fluid from the metastatic site.