Cyclizations of substituted benzylidene-3-alkenylamines: synthesis of the tricyclic core of the martinellines.

The martinellines (1 and 2) are natural products that possess both interesting biological activity and chemical structure. During the investigation of a hetero Diels-Alder route to these molecules, alternate Lewis acid-dependent cyclizations of (2'-amino-N'-tert-butoxycarbonyl-5'-chlorobenzylidene)-3-butenylamine (10) were observed. The reaction of a variety of imines with TMSOTf or TiCl(4) led to the formation of different heterocycles including iminodibenzo[b,f][1,5]diazocines, hexahydropyrido[1, 2-c]quinazolin-6-ones, tetrahydropyrrolo[1,2-c]quinazolin-5-ones, 2-arylpiperidines, and 2-arylpyrrolidines. Tetrahydropyrrolo[1, 2-c]quinazolin-5-one 54, obtained via this new methodology, was used as an intermediate in the synthesis of the tricyclic ring system (65) of the martinellines.

The search for orally active medications through combinatorial chemistry.

The literature of combinatorial chemistry is reviewed with particular attention paid to considerations of absorption, distribution, metabolism and excretion in the design and evaluation of libraries containing drug-like molecules. Published libraries are evaluated in particular for the likelihood that the products would possess oral bioavailability.

A simple, inexpensive apparatus for performance of preparative scale solution phase multiple parallel synthesis of drug analogs. I. Preparation of a retrospective library of quinolone antiinfective agents.

A simple inexpensive apparatus is described consisting of conveniently commercially available components which is suitable for the solution phase multiple parallel synthesis of 24-72 analogs of drug-like molecules. The use of the apparatus is illustrated by preparation of a retrospective library of over 100 analogs of antimicrobial fluoroquinolones prepared in 0% to quantitative yields. Each analog was prepared in up to 150 mg quantity and each was analyzed by NMR and mass spectrometric techniques to verify its purity and identity.

A simple, inexpensive apparatus for performance of preparative scale solution phase multiple parallel synthesis of drug analogs. II. Biological evaluation of a retrospective library of quinolone antiinfective agents.

A series of pure fluoroquinolone antiinfective agents was prepared by multiple parallel synthesis using a simple new apparatus. These compounds were evaluated biologically against Gram-positive and Gram-negative microorganisms and against a BCG strain transfected with luciferase in a fluorescence-based antitubercular assay. Activity against relatively fast growing, acid-fast Mycobacterium smegmatis was determined in part by agar-dilution streak assays. Data obtained against Escherichia coli-derived DNA gyrase does not correlate well with whole cell assays against E. coli. These compounds were assayed by a convenient glass-fiber filter binding method modified for high throughput screening. In these analogs, the results with a N-1 cyclopropyl substituent were often inferior to those obtained with a N-1 2',4'-difluorophenyl substituent. None of the new compounds prepared was superior in its antimycobacterial potency to ciprofloxacin or temafloxacin.

Hemoglobin spherulosis in the vitreous cavity.

A 50-year-old woman was evaluated for a subretinal hemorrhage that extended into the vitreous of the right eye. Examination showed multiple refractile brown spherules in the vitreous. A vitrectomy was performed, and pathologic examination of the spherules showed them to be composed of free hemoglobin. Free-hemoglobin spherulosis in the vitreous, like cholesterosis bulbi, is a manifestation of vitreous hemorrhage.

Bilateral retinal detachments in thrombotic thrombocytopenic purpura.

Bilateral serous retinal detachments are rare complications of thrombotic thrombocytopenic purpura (TTP). We report the case of a 28-year-old woman with chronic relapsing TTP with bilateral serous retinal detachments, which resolved after prompt aggressive medical therapy. Unlike several previous reports, the retinal detachments in our patient were unrelated to systemic hypertension.

Chorioretinal lesions in chronic granulomatous disease of childhood. Clinicopathologic correlations.

The authors examined an eye obtained post-mortem from a patient with chronic granulomatous disease of childhood and clinically apparent chorioretinal scars. Histologic examination disclosed numerous chorioretinal scars with associated retinal pigment epithelial changes and glial proliferation. Special stains for bacteria and fungi were negative. Additional findings were scattered pigment-containing macrophages found in the patient's spleen, liver, lymph nodes, bone marrow, lungs, kidney, thymus, choroid, and retina. The significance of the pigmented macrophages is unknown, however they may represent an abortive macrophage response to infectious agents.

Subretinal neovascularization in a pseudophakic eye treated with krypton laser photocoagulation. A clinicopathologic case report.

A 76-year-old myopic woman who had undergone bilateral extracapsular cataract extractions and received posterior intraocular lens implants underwent two sessions of krypton laser photocoagulation for subretinal neovascularization secondary to age-related macular degeneration in her right eye. The patient expired and histopathologic examination of her treated eye showed a posterior chamber intraocular lens with both haptics in the ciliary sulcus, areas of macular degeneration, evidence of krypton laser photocoagulation including a full-thickness retinal scar, and an area of clinically unsuspected subretinal neovascularization.

Indirect choroidal rupture secondary to blunt ocular trauma. A review of eight eyes.

We retrospectively studied eight eyes of seven patients sustaining indirect choroidal rupture secondary to blunt trauma. Clinical and fluorescein angiographic findings were reviewed. The ruptures were single in five eyes and multiple in three eyes. Four eyes contained macular ruptures, and three eyes contained extramacular ruptures. Peripapillary ruptures were noted in three eyes. Three eyes developed subretinal neovascularization as a complication. Location of the rupture but not visual acuity at presentation was predictive of visual outcome. All ruptures were concentric with the optic nerve and vertically oriented, consistent with a break in Bruch's membrane and an associated tethering effect by the optic nerve.

Cytomegalovirus retinitis and optic neuritis in acquired immune deficiency syndrome. Report of a case.

A 33-year-old man with acquired immune deficiency syndrome (AIDS) was found to have bilateral cytomegalovirus (CMV) retinitis with concomitant unilateral optic neuritis. The patient died and postmortem examination of both eyes disclosed CMV inclusions in all layers of the involved retinas including the retinal pigment epithelium (RPE). Also found were CMV inclusions in the optic nerve of his left eye. Immunohistochemical stains for glial fibrillary acid protein demonstrated that glial cells were infected in the optic nerve.

Age-related normalization of the browning rate of collagen in diabetic subjects without retinopathy.

The age-related changes in collagen-linked fluorescence (browning) were investigated in skin from subjects with long-standing type I diabetes. Overall browning rates were 2.4 times higher in diabetics than in controls (P less than 0.02) and slope intercept accurately reflected the mean age of onset of diabetes (11.6 vs. 11.2 yr), suggesting that the browning process has the attributes of a biological clock. Browning rates were not different in controls and diabetics without retinopathy (P greater than 0.05) but were 2.4 (P less than 0.05) and 2.7 (P less than 0.01) times increased in the presence of background and proliferative retinopathy, respectively. Compared with subjects with retinopathy, individual browning rates since onset of diabetes decreased with advancing age in subjects free of retinopathy (P less than 0.001). Extrapolation revealed that they would become identical to that of nondiabetic subjects by the age of 66.4 yr. These results suggest the presence of a mechanism that controls the browning rate of collagen in diabetics who do not develop retinopathy.

Glycation of skin collagen in type I diabetes mellitus. Correlation with long-term complications.

Nonenzymatic glycosylation (glycation) of collagen was measured by boronate affinity chromatography in skin biopsies from 41 type I diabetics with mean duration of diabetes of 25 yr (range 20-40 yr) and from 25 age-matched controls. Mean level of Amadori products was significantly increased in diabetic [7.85 +/- 1.78 (SD) nmol/mg collagen] versus control subjects [3.34 +/- 1.06 (SD) nmol/mg collagen, P less than .001] but did not correlate with age, diabetes duration, or severity of retinopathy, nephropathy, arterial stiffness, and joint stiffness. Similarly, mean collagen content per biopsies was 42% increased in diabetic versus control subjects (P less than .001) but did not correlate with age, diabetes duration, or severity of complications. A weak but positive correlation between glycohemoglobin level and glycation of skin collagen was observed. These results indicate that Amadori products cannot explain by themselves the pathogenesis of diabetic complications unless individual tissue response to glycation is different in subjects with and without complication. They do not exclude a role for the late stages of the Maillard reaction, nonenzymatic browning, in the formation of some of these complications.

Relation between complications of type I diabetes mellitus and collagen-linked fluorescence.

Nonenzymatically glycosylated proteins gradually form fluorescent cross-linked protein adducts--a process termed "browning." The rate of this reaction increases with the glucose concentration. Assaying for the presence of browning products in long-lived proteins should therefore provide information on long-term metabolic control. We measured collagen-linked fluorescence typical for nonenzymatic browning in skin-biopsy specimens from 41 subjects with longstanding Type I diabetes and from 25 controls. Fluorescence correlated with age and (weakly) with the duration of diabetes. Mean age-adjusted fluorescence values were twice as high in diabetic subjects as in control subjects (P less than 0.0001) and increased with the severity of retinopathy, nephropathy, and arterial and joint stiffness. The correlation was significant for retinopathy (r = 0.42; P less than 0.01), arterial stiffness (r = 0.41; P less than 0.01), joint stiffness (r = 0.34; P less than 0.05), and the sum of all complications (r = 0.47; P less than 0.01). Fluorescence also correlated with systolic (r = 0.42; P less than 0.01) and diastolic (r = 0.36; P less than 0.05) blood pressures. If one can assume that the fluorescence results from a browning product of glucose, our data suggest that there is an overall correlation between the severity of diabetic complications and cumulative glycemia over many years.

Actinobacillus actinomycetemcomitans endophthalmitis with subacute endocarditis.

Endocarditis and unilateral endophthalmitis due to Actinobacillus actinomycetemcomitans heart disease. The ocular infection was notable for its localized presentation and slow evolution. Treatment with systemic, subconjunctival, and topical gentamicin sulfate and ampicillin sodium achieved 20/20 acuity with a residual chorioretinal scar in the nasal periphery. Intravitreal injection of the organism into a rabbit confirmed its minimal pathogenicity within the eye. This organism must now be considered in patients with differential diagnosis of endogenous endophthalmitis complicating endocarditis and septicemia.

Quantitative vitreous fluorophotometry in insulin-treated cystic fibrosis patients.

A series of 22 patients with cystic fibrosis (CF) of similar clinical severity (9 with normal carbohydrate tolerance and 13 with insulin-treated fasting hyperglycemia) was examined with quantitative vitreous fluorophotometry. All of the CF patients studied had normal fundi on ophthalmoscopy, fundus photographs, and fluorescein angiography. Mean vitreous fluorescein concentration in the CF patients whose hyperglycemia was treated with insulin (11.79 ng/ml) was significantly higher than in CF patients with normal carbohydrate tolerance (6.98 ng/ml, P less than 0.005). Thus, CF patients with fasting hyperglycemia demonstrate a breakdown of the blood-retinal barrier. When CF patients with fasting hyperglycemia were compared with age- and sex-matched type I diabetics, there was no significant difference in mean vitreous fluorescein accumulation. Thus, breakdown of the blood-retinal barrier, one of the earliest detectable functional abnormalities that may be associated with the microangiopathy of diabetes mellitus, also occurs with equal frequency and severity in the diabetes secondary to pancreatic fibrosis associated with CF.

Temporal and pharmacological parameters of puromycin-induced amnesia.

Mice were trained in step-down passive avoidance behavior. Bitemporal injections of puromycin (PM) were given either immediately or delayed until 24 hrs after training. PM produced a marked amnesia in both cases during retention testing 3 days later. The amnesia persisted during a second retention test 6 days after training. Of all the antibiotics, only PM is effective as an amnestic agent when injections are delayed 24 or more hours after training. cycloheximide (CXM) was also injected bitemporally immediately after training. However, CXM produced a weaker amnestic effect even though it produced a much greater inhibition of cerebral protein synthesis, more rapidly, and of longer duration. In an effort to attenuate the amnesia produced by PM, in separate experiments, the mice were injected with combined injections of PM and and CXM (bitemporally): mice were also given combined injections of PM (bitemporally) and amphetamine (subcutaneously). The amnesia produced by immediate injections of PM wa not attenuated by either CXM or amphetamine. However, the amnesia produced by delayed injections of PM was attenuated by both CXM and amphetamine. These results suggest that delayed injections of PM (25 hours after training) block the expression or retrieval of memory. This study also supports the contention that puromycin has two separate effects on memory with different temporal parameters depending on when the drug is injected relative to initial training.

Sector B-scan ultrasonographic 'hemangiomalike' pattern.

Eleven patients with unilateral exophthalmos had sector B-scan ultrasonography. The ultrasonograms were all similar and demonstrated a "hemangiomalike" pattern consisting in a rounded, well-outlined orbital mass with a sharp anterior border, moderate to strong tissue reflectivity, and fair to good sound transmission. Although the postoperative pathologic findings in six cases confirmed the presence of cavernous hemangioma of the orbit, other lesions, such as hemangiopericytoma, lymphangioma, orbital varix, meningioma, and mixed cell tumor, were found to show a similar ultrasonographic pattern.

Indomethacin as a means of preventing cystoid macular edema following intracapsular cataract extraction.

It has been theorized that prostaglandins E1 and E2 may be responsible for the vascular leakage leading to cystoid macular edema following cataract extraction. Indomethacin is a known inhibitor of prostaglandin synthesis. A prospective, double-blind study to evaluate the effect of oral indomethacin on four and eight week cases of postoperative CME following intracapsular cataract extraction as determined by fluorescein angiography was carried out on 42 patients. Twenty patients received 25 mg of indomethacin three times a day for three days preoperatively and three weeks postoperatively. Twenty-two patients received a placebo on an identical schedule. Four (20%) patients in the indomethacin group and five (22.7%) patients in the placebo group had positive angiograms for CME. No contributory factor resulting in CME was found.