The A1 adenosine receptor as a new player in microglia physiology.

The purinergic system is highly involved in the regulation of microglial physiological processes. In addition to the accepted roles for the P2 X4,7 and P2 Y12 receptors activated by adenosine triphosphate (ATP) and adenosine diphosphate, respectively, recent evidence suggests a role for the adenosine A2A receptor in microglial cytoskeletal rearrangements. However, the expression and function of adenosine A1 receptor (A1AR) in microglia is still unclear. Several reports have demonstrated possible expression of A1AR in microglia, but a new study has refuted such evidence. In this study, we investigated the presence and function of A1AR in microglia using biomolecular techniques, live microscopy, live calcium imaging, and in vivo electrophysiological approaches. The aim of this study was to clarify the expression of A1AR in microglia and to highlight its possible roles. We found that microglia express A1AR and that it is highly upregulated upon ATP treatment. Moreover, we observed that selective stimulation of A1AR inhibits the morphological activation of microglia, possibly by suppressing the Ca(2+) influx induced by ATP treatment. Finally, we recorded the spontaneous and evoked activity of spinal nociceptive-specific neuron before and after application of resting or ATP-treated microglia, with or without preincubation with a selective A1AR agonist. We found that the microglial cells, pretreated with the A1AR agonist, exhibit lower capability to facilitate the nociceptive neurons, as compared with the cells treated with ATP alone.

Nicotinamide adenine dinucleotide based therapeutics.

Nicotinamide adenine dinucleotide (NAD), generally considered a key component involved in redox reactions, has been found to participate in an increasingly diverse range of cellular processes, including signal transduction, DNA repair, and post-translational protein modifications. In recent years, medicinal chemists have become interested in the therapeutic potential of molecules affecting interactions of NAD with NAD-dependent enzymes. Also, enzymes involved in de novo biosynthesis, salvage pathways, and down-stream utilization of NAD have been extensively investigated and implicated in a wide variety of diseases. These studies have bolstered NAD-based therapeutics as a new avenue for the discovery and development of novel treatments for medical conditions ranging from cancer to aging. Industrial and academic groups have produced structurally diverse molecules which target NAD metabolic pathways, with some candidates advancing into clinical trials. However, further intensive structural, biological, and medical studies are needed to facilitate the design and evaluation of new generations of NAD-based therapeutics. At this time, the field of NAD-therapeutics is most likely at a stage similar to that of the early successful development of protein kinase inhibitors, where analogs of ATP (a more widely utilized metabolite than NAD) began to show selectivity against target enzymes. This review focuses on key representative opportunities for research in this area, which extends beyond the scope of this article.

Synthesis and antitumor activity of a heterodinucleotide of BVDU and gemcitabine.

A heterodinucleotide comprising BVDU and Gemcitabine bound together by a 5',5'-pyrophospate bridge (BVDUp(2)dFdC) has been synthesized and evaluated as antitumor agent against AH13 rat sarcoma cells. BVDUp(2)dFdC showed a cytotoxicity similar to that of Gemcitabine.

Inhibition of HIV-1 replication in macrophages by red blood cell-mediated delivery of a heterodinucleotide of lamivudine and tenofovir.

Homo- and heterodimers of nucleoside/nucleotide analogues as reverse transcriptase inhibitors are effective on HIV-1-infected human monocyte-derived macrophages (M/M) compared to the single drugs or their combination. Since the combined treatment of lamivudine (3TC) and tenofovir ((R)PMPA) has an antiretroviral efficacy and a synergic effect respect to separate drugs, the heterodinucleotide 3TCpPMPA was synthesized. A single administration of the dimer as free drug or 3TCpPMPA-loaded RBC selectively targeted to M/M was able to almost completely protect macrophages from "de novo" infection.

Synthesis and biological evaluation of NAD analogs as human pyridine nucleotide adenylyltransferase inhibitors.

NAD analogs modified at the ribose adenylyl moiety, named N-2'-MeAD and Na-2'-MeAD, were synthesized as ligands of pyridine nucleotide (NMN/NaMN) adenylyltransferase (NMNAT). Both dinucleotides resulted selective inhibitors against human NMNAT-3 isoenzyme.

Nicotinamide Adenine Dinucleotide Based Therapeutics, Update.

About 500 NAD (P)-dependent enzymes in the cell use NAD (P) as a cofactor or a substrate. This family of broadly diversified enzymes is crucial for maintaining homeostasis of all living organisms. The NAD binding domain of these enzymes is conserved and it was believed that NAD mimics would not be of therapeutic value due to lack of selectivity. Consequently, only mycophenolic acid which selectively binds at the cofactor pocket of NAD-dependent IMP-dehydrogenase (IMPDH) has been approved as an immunosuppressant. Recently, it became clear that the NAD (P)-binding domain was structurally much more diversified than anticipated and numerous highly potent and selective inhibitors of NAD (P) dependent enzymes have been reported. It is likely, that as in the case of protein kinases inhibitors, inhibitors of NAD (P)-dependent enzymes would find soon their way to the clinic. In this review, recent developments of selective inhibitors of NAD-dependent human IMPDH, as well as inhibitors of IMPDHs from parasites, and from bacterial sources are reported. Therapies against Cryptosporidium parvum and the development of new antibiotics that are on the horizon will be discussed. New inhibitors of bacterial NAD-ligases, NAD-kinases, NMN-adenylyl transferases, as well as phosphoribosyl transferases are also described. Although none of these compounds has yet to be approved, the progress in revealing and understanding crucial factors that might allow for designing more potent and efficient drug candidates is enormous and highly encouraging.

Surgical repair of prolapsed lacrimal glands.

Herniation of the lacrimal gland is a condition that occurs unilaterally or bilaterally. Either or both lobes of the lacrimal gland may prolapse. Orbital lobe prolapse may be associated with blepharochalasis, a disease of puberty. We developed a surgical technique for the repair of prolapsed lacrimal glands. It is important to have adequate hemostasis and closure of the orbital septum.

Dermis-fat graft as a movable implant within the muscle cone.

A 31-year-old woman had an extruding ocular implant in her right orbit. After surgically removing the implant, we transferred an autogenous dermis-fat graft from the hip region to the freshly prepared socket. The graft was sutured to the conjunctiva, and a conformer was placed in the socket. Eight weeks postoperatively, the dermis-fat graft was covered with conjunctival epithelium and a prosthesis was fitted successfully. No evidence of infection has occurred. This technique of using composite dermis-fat grafts in enophthalmos avoids recurrent extrusions and corrects the cosmetic problems produced by migrating or extruding implants.

Orbital hemorrhage with loss of vision.

A 58-year-old woman had the sudden onset of unilateral painful proptosis, ophthalmoplegia, vomiting, and loss of vision. Computed axial tomography showed a mass that was greatly attenuated in the orbit. The initial reading of the internal carotid angiogram was normal, but a subtraction study showed a hypervascular lesion within the orbit with features indicating a hemangioma. Orbital decompression failed to restore the vision as intraorbital hemorrhage had irreparably damaged the optic nerve.

NMN/NaMN adenylyltransferase (NMNAT) and NAD kinase (NADK) inhibitors: chemistry and potential therapeutic applications.

Nicotinamide adenine dinucleotide (NAD(+)) has a crucial role in many cellular processes, both as a coenzyme for redox reactions and as a substrate to donate ADP-ribose units. Thus, enzymes involved in NAD(+) metabolism are attractive targets for drug discovery against a variety of human diseases. Herein we focus on two of them: NMN/NaMN adenylyltransferase (NMNAT) and NAD kinase (NADK). NMNAT is a key enzyme in all organisms catalyzing coupling of ATP and NMN or NaMN yielding NAD or NaAD, respectively. NADKs are ubiquitous enzymes involved in the last step of the biosynthesis of NADP. They phosphorylate NAD to produce NADP using ATP (or inorganic polyphosphates) in the presence of Mg(2+). No other pathway of NADP biosynthesis has been found in prokaryotic or eukaryotic cells. In this review we provide a comprehensive summary of NMNAT and NADK inhibitors highlighting their chemical modifications by different synthetic approaches, and structure-activity relationships depending on their potential therapeutic applications.

The treatment of lacrimal gland prolapse in blepharoplasty.

Careful evaluation of the patient undergoing blepharoplasty should include an assessment of lacrimal gland position. Lacrimal gland prolapse, if uncorrected at the time of surgery, will result in lid asymmetry. The purpose of this article is to review the anatomy of the lacrimal gland, the causes of herniation, and the surgical management in conjunction with blepharoplasty.

Naso-orbital fractures: management and complications.

The term naso-orbital fracture refers to the backward displacement of the nasal bones into the interorbital space. The fracture is most commonly the result of traumatic contact with the dashboard in automobile accidents. The trauma results in soft tissue eyelid deformities, which may also involve nasolacrimal disruption and life-threatening intracranial injury. Early management consists of closed reduction of the nasal fracture when feasible. Late management, which is more common, consists of transnasal wiring, restoration of the nasolacrimal apparatus, and contouring of the nasal bones.

Use of autogenous materials in reconstructing the anophthalmic socket.

A variety of autogenous materials may be used for orbital implantation in the anophthalmic socket. An understanding of the pathology of the socket is necessary to treat the problem correctly. Autogenous grafts have been used successfully to treat the superior sulcus deformity, extruding implant, and the contracting socket. The major advantages of autogenous material are its minimal inflammatory reaction and its total compatibility with the host.

Management of the contracted eye socket.

The approach to the surgical management of the contracted eye socket requires a good patient history and preliminary evaluation. Upon assessing the extent of socket contraction, the surgeon has at his disposal several procedures. For moderate socket contraction, a mucous membrane graft may be employed. For severe contraction, split thickness skin graft and a socket mold wired to the orbital rim is advocated. For the extruding or exposed implant, a dermal-far graft is recommended.

Herniation of the lacrimal glands.

Herniation of the lacrimal gland is an unusual condition which has a predilection for blacks and is associated with blepharochalasis. It is benign and tends to become progressive. Either or both lobes of the lacrimal gland can herniate and must be differentiated from dermolipoma and orbital fat. A surgical treatment is described, and three cases are presented.

Adenoid cystic carcinoma with orbital and cranial metastases: case report.

Adenoid cystic carcinoma of the paranasal sinuses was demonstrated in a patient who subsequently developed a metastatic lesion to both orbits resulting in total blindness. While there are reports of extension of adenoid cystic carcinoma of the lacrimal gland to the adjacent orbit, this patient is an example of orbital extension of an adenoid cystic carcinoma of minor salivary gland originating in a paranasal sinus. The frequency and classification of this tumor also is reviewed.

Dinitrochlorobenzene immunotherapy of recurrent squamous papilloma of the conjunctiva.

Dinitrochlorobenzene (DNCB) immunotherapy of a recurrent conjunctival papilloma was employed successfully in a 24-year-old man. Previous attempts at electrocautery, surgical excision, and cryosurgery met without success. The tumor response to DNCB therapy resulted in total eradication of the tumor and represents a more successful modality than previous treatments. Poor patient compliance, variable patient immune mechanisms, and tumor size may influence the variable patient immune mechanisms, and tumor size may influence the fate and type of response to DNCb immunotherapy. DNCB therapy should be considered in the treatment of conjunctival papillomas refractory to conventional modes of therapy.

Single-dose kinetics of primidone in acute viral hepatitis.

The pharmacokinetics of primidone (PRM) after oral administration of a single 500 mg dose was studied in 7 patients with acute viral hepatitis and 7 healthy control subjects. The elimination half-life and the apparent clearance of unchanged PRM in the patients were 18.0 +/- 3.1 h and 42 +/- 14 ml X h-1 X kg-1, respectively (mean +/- SD) and did not differ significantly from the values in the controls (half-life 17.0 +/- 2.4 h; clearance 35 +/- 8 ml X h-1 X kg-1). The metabolite phenylethylmalonamide (PEMA) was detected in the serum of all normal subjects within 2-24 h. By contrast, serum levels of this metabolite were undetectable (less than 2 mumol/1) in all but one of the patients. Serum levels of phenobarbital (PB) remained below the limit of detection (less than 2 mumol/1) in all subjects. The findings indicate that accumulation of PRM with its attendant toxicity is unlikely to occur in epileptic patients who develop acute viral hepatitis, despite evidence that the metabolism of the drug is affected by this condition. The possibility of impaired conversion to PB and its implications are discussed.