Attenuation of cocaine self-administration by chronic oral phendimetrazine in rhesus monkeys.

Chronic treatment with the monoamine releaser d-amphetamine has been consistently shown to decrease cocaine self-administration in laboratory studies and clinical trials. However, the abuse potential of d-amphetamine is an obstacle to widespread clinical use. Approaches are needed that exploit the efficacy of the agonist approach but avoid the abuse potential associated with dopamine releasers. The present study assessed the effectiveness of chronic oral administration of phendimetrazine (PDM), a pro-drug for the monoamine releaser phenmetrazine (PM), to decrease cocaine self-administration in four rhesus monkeys. Each day, monkeys pressed a lever to receive food pellets under a 50-response fixed-ratio (FR) schedule of reinforcement and self-administered cocaine (0.003-0.56 mg/kg per injection, i.v.) under a progressive-ratio (PR) schedule in the evening. After completing a cocaine self-administration dose-response curve, sessions were suspended and PDM was administered (1.0-9.0 mg/kg, p.o., b.i.d.). Cocaine self-administration was assessed using the PR schedule once every 7 days while food-maintained responding was studied daily. When a persistent decrease in self-administration was observed, the cocaine dose-effect curve was re-determined. Daily PDM treatment decreased cocaine self-administration by 30-90% across monkeys for at least 4 weeks. In two monkeys, effects were completely selective for cocaine. Tolerance developed to initial decreases in food-maintained responding in the third monkey and in the fourth subject, fluctuations were observed that were lower in magnitude than effects on cocaine self-administration. Cocaine dose-effect curves were shifted down and/or rightward in three monkeys. These data provide further support for the use of agonist medications for cocaine abuse, and indicate that the promising effects of d-amphetamine extend to a more clinically viable pharmacotherapy.

Simvastatin protection against acute immune-mediated glomerulonephritis in mice.

In addition to cholesterol lowering, 3-hydroxy-3-nethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors limit inflammatory changes associated with atherosclerosis. There is also support for their use as inhibitors of progression in chronic renal disease, irrespective of cause. In this study, their capacity to limit acute renal inflammation was evaluated. For this purpose, mice were treated with Simvastatin either prior to, at the time of, or shortly after induction of nephrotoxic nephritis. The severity of disease was determined by evaluation of blood urea nitrogen (BUN), proteinuria, and renal histologic changes. The reversibility of benefit was evaluated by the administration of mevalonic acid along with nephrotoxic serum (NTS) and Simvastatin The severity of the acute nephritis, including proteinuria, elevated BUN, and histologic changes, was ameliorated in a dose-dependent manner, when Simvastatin was administered either prior to NTS injection or at the time of NTS injection. By contrast, Simvastatin did not alter the course of established nephritis. Coadministration of mevalonic acid, the immediate substrate following HMG-CoA reductase, abolished Simvastatin's renoprotective effect, indicating that the benefit is, at least in part, due to interference with HMG-CoA reductase and biosynthetic substrates downstream from the enzyme. These findings provide the rationale for the evaluation of the efficacy of HMG-CoA reductase inhibitors in patients with recurrent forms of renal inflammation, to limit the severity of acute exacerbations of disease, prevent renal scarring and slow the rate of progression.

Increased rat mammary tissue vitamin A associated with increased vitamin A intake during lactation is maintained after lactation.

Although increases in dietary vitamin A increase milk vitamin A, little is known about effects of vitamin A intake on mammary tissue vitamin A levels during and after the reproductive cycle. First, we measured vitamin A concentrations in milk, mammary tissue and liver of lactating rats fed 0, 4, or 50 micromol of vitamin A/kg diet during pregnancy and through d 12 of lactation. Liver vitamin A concentration was significantly affected by diet in lactating females and pups 12 d after parturition. Milk vitamin A concentrations were significantly higher (7.1 +/- 2.2 micromol/L, n = 8) in dams fed 50 micromol/kg than in those fed 0 or 4 micromol/kg (1.9 +/- 0.3, n = 5 and 2.9 +/- 0.7 micromol/L, n = 7; P < 0.001), as were mammary tissue vitamin A concentrations (5.1 +/- 1.1 versus 2.2 +/- 0.4 and 2.4 +/- 0.6 nmol/g; P < 0.001). Next, we maintained female rats on 50 or 10 micromol vitamin A/kg diet during pregnancy and lactation and then on 4 micromol/kg diet after pups were weaned on d 21. On d 21, mammary tissue vitamin A concentrations were 3.14 +/- 0.75 versus 1.52 +/- 0.21 nmol/g in dams fed 50 versus 10 micromol/kg (n = 4/group; P < 0.001). Mammary tissue vitamin A concentrations were not significantly affected by time from 7 to 49 d after lactation and averaged 8.5 +/- 0.4 and 4.9 +/- 0.8 nmol/g on d 49 in dams fed 50 versus 10 micromol/kg (n = 4; P < 0.001). We conclude that diet-induced differences in rat mammary tissue vitamin A developed during pregnancy and lactation are maintained for > or =7 wk after lactation.

Metabolism and disposition of bisphenol A in female rats.

Bisphenol A (BPA), which is used in the manufacture of polycarbonates, elicits weak estrogenic activity in in vitro and in vivo test systems. The objectives of this study were to compare the patterns of disposition of radioactivity in adult female F-344 and CD rats after oral administration of (14)C BPA (100 mg/kg), to isolate the glucuronide of BPA and to assess its estrogenic activity in vitro, and to evaluate the transfer of radioactivity to pups from lactating dams administered (14)C BPA. Over 6 days, F-344 rats excreted more radioactivity in urine than CD rats. The major metabolite in urine was identified as bisphenol A glucuronide (BPA gluc) by incubation with beta-glucuronidase and (1)H and (13)C NMR spectroscopy. In lactating CD rats administered (14)C BPA (100 mg/kg) by gavage, only a small fraction of the label was found in milk, with 0.95 +/- 0.66, 0.63 +/- 0.13, and 0.26 +/- 0.10 microg equiv/ml (mean +/- SD) from dams collected 1, 8, and 26 h after dosing, respectively. Radioactivity in pup carcasses indicated exposure in the range of microgram equivalents per kilogram; those values ranged from 44.3 +/- 24.4 for pups separated from their lactating dams at 2 h to 78.4 +/- 10.9 at 24 h. BPA gluc was the prominent metabolite in milk and plasma. In test systems for activation of in vitro estrogen receptors alpha and beta, BPA gluc did not show appreciable efficacy at concentrations up to 0.03 mM, indicating that metabolism via glucuronidation is a detoxication reaction.

Acular as a single agent for use as an antimiotic and anti-inflammatory in cataract surgery.

PURPOSE: To assess the safety and effectiveness of ketorolac tromethamine 0. 5% (Acular) as a cost-efficient single agent to prevent intraoperative miosis and postoperative inflammation in cataract surgery. METHODS: Both eyes of 26 patients were randomized to receive Acular preoperatively and postoperatively or flurbiprofen sodium (Ocufen) preoperatively and prednisolone acetate 1% (Pred Forte) postoperatively. Time scheduled between procedures was from 2 weeks to 1 month. Pupil dilation was measured preoperatively, intraoperatively, and at the end of surgery. Cell and flare were measured 1 day, 1 week, and 1 month postoperatively. RESULTS: A comparison of the Acular and the Ocufen/Pred Forte groups (n=22) showed no statistically significant differences in dilation (preoperative versus postpostoperative) or cell and flare postoperatively. CONCLUSIONS: Using Acular as a single agent was as effective as the combination of preoperative Ocufen and postoperative Pred Forte in preventing intraoperative miosis and postoperative inflammation in cataract surgery. The use of Acular as a single agent could save the expense of using separate anti-inflammatory and antimiotic preparations preoperatively and postoperatively, enhancing convenience for the surgeon and surgical facility.

Eye movement during laser in situ keratomileusis.

PURPOSE: To measure eye motion in patients having laser in situ keratomileusis (LASIK) using a video technique and determine centration and variance of the eye position during surgery. SETTING: Laser refractive surgery center. METHODS: The procedure was videotaped in 5 consecutive eyes having LASIK performed by a single surgeon with the VISX Star S2 excimer laser. Following surgery, video images of the eyes were digitized and stored in a computer for processing. Digitized images were obtained at a rate of 25 images per second during the laser procedure. The pupil margin and a visual landmark, such as a scleral blood vessel, were identified in the initial image of each eye. Custom software was used to track the location of the landmark and the pupil center in subsequent images. RESULTS: Three of the 5 eyes were well centered on average. The remaining 2 eyes were decentered inferiorly by approximately 0.25 mm. The standard deviation in all eyes was approximately 0.10 mm. CONCLUSIONS: With these techniques, the position of the entrance pupil center relative to the excimer laser axis could be determined. Although the system is not fast enough to be used during surgery, it does allow quantification of centration and intraoperative motion after surgery.

Corneal ablation patterns to correct for spherical aberration in photorefractive keratectomy.

PURPOSE: To determine the spherical aberration introduced by photorefractive keratectomy (PRK) and customize ablation patterns to compensate for this aberration and improve post-PRK visual performance. SETTING: Department of Ophthalmology, University of Arizona, Tucson, Arizona, USA. METHODS: Presurgical and postsurgical corneal topography of 16 patients who had PRK with the Summit OmniMed laser were obtained. The data were applied to a schematic eye model, and exact ray tracing was used to determine the introduction of spherical aberration from the procedure. Optimization routines were used to determine the ideal ablation pattern. RESULTS: The magnitude of the spherical aberration introduced into the eyes after PRK increased with the level of attempted correction. The theoretical ideal ablation pattern requires additional flattening of the ablation periphery to avoid the introduction of spherical aberration. CONCLUSIONS: Current PRK ablations introduce spherical aberration into the eye. Modifying the existing ablation algorithms to compensate for spherical aberration may boost postoperative visual performance.

Evaluation of an aqueous drainage glaucoma device constructed of ePTFE.

Aqueous drainage devices for the treatment of glaucoma are subject to the same limitations as most polymeric implants, namely a healing response comprised of chronic inflammation and fibrosis. The most widely used devices are currently made of silicone or polypropylene, materials that exhibit biocompatibility difficulties when they are implanted on the sclera underneath the conjunctiva of the eye. Decreased outflow of aqueous fluid to the conjunctival space caused by the development of a fibrous capsule around the device accounts for at least 20% of aqueous shunts failures. Clearly, the need exists to improve the healing response to aqueous drainage devices, and one approach is to develop new polymers or polymer modifications. Improved devices would elicit a limited fibrotic response while increasing neovascularization around the implant. Previous studies have indicated that denucleation markedly improves the healing characteristics and biocompatibility of expanded polytetrafluoroethylene (ePTFE). We reasoned that altering the design of drainage devices to allow the use of denucleated ePTFE in vivo might minimize fibrosis, thereby improving shunt function. We found that after 8 weeks in vivo, experimental shunt function was equivalent to the Baerveldt shunt, while there was less scarring with increased neovascularizatin. These findings suggest that ePTFE has potential as an improved, long-term alternative material for use in constructing glaucoma shunts.

Practical ophthalmic microbiology.

Infection is commonly encountered in everyday ophthalmic practice. It is of great importance that all ophthalmic personnel are familiar with the basic etiologies of these infections, and the basic techniques which are used in diagnosis. When evaluating a patient with possible infection, it is often of great help to be familiar with the normal microbial flora of the human body. This normal flora has been detailed in the article. The assumption is that knowledge of a patient's flora can help guide decisions about the possible etiologies of an infection. When presented with an obvious ocular infection, health care personnel should review the "usual suspects"--that is, the common etiologies for each type of infection. The key to combating ocular infections lies in accurate treatment of the presumed infectious agent. Therefore, the techniques and steps used in the identification of the etiology of an infection should be known to all ophthalmic personnel. The proper sterile techniques of obtaining a specimen from a suspected corneal ulcer or conjunctivitis and the plating of the specimen on specific agar for identification are essential to everyday practice (Figure 8). Patients who will undergo surgery, regardless of the type, are being placed at a special risk for infection. These post-operative infections can destroy the work of the most careful and exact surgical technique. It is an essential part of the procedure that the patient be protected as best they can from subsequent infection. The techniques to reduce the risk of post-operative infection have been detailed above. Proper preparation of a sterile field, sterile draping, and perioperative antibiotics can reduce the chance of a subsequent infection. It is important that these basic steps of care be properly provided to help insure successful surgical outcomes and excellence in health care.

Purulent pericarditis with tamponade in a postpartum patient due to group F streptococcus.

Bacterial pericarditis with cardiac tamponade is a life-threatening disorder that has been associated with a variety of organisms. There is usually an associated underlying condition or a seeding of the pericardium from an infection elsewhere. We report the development of cardiac tamponade and a subsequent pericardial constriction due to group F streptococcus purulent pericarditis. We believe this to be the first report of a postpartum patient with purulent pericarditis.

Customized and low spherical aberration corneal ablation design.

PURPOSE: The purpose of this study was to use the Arizona Eye Model to help guide customization of corneal excimer ablation and reduce spherical aberration. METHODS: Myopic eyes were treated with the Nidek EC-5000 excimer laser with a 5.5-mm diameter optic ablation zone and a 7.0-mm diameter transition ablation zone. We analyzed preoperative and postoperative corneal topographies using height mapping. From this data, refractive error profiles and maps were constructed using the Arizona Eye Model. The first group of patients had refractions between -2.00 and -5.00 D. Data was obtained by subtracting postoperative topography from preoperative topography. We then plotted the ideal ablation pattern if no additional spherical aberration was introduced when compared to preoperative topographies. RESULTS: We found that in the central 4 mm, the ablation pattern was highly acceptable, with negligible spherical aberration. As the ablation moved out toward 6 mm, there was increasing spherical aberration. Newer ablation designs require more flattening in the midperiphery of the cornea. These flatter peripheral designs require more blending in the periphery and larger transition zones. CONCLUSION: The use of computerized corneal topography in eye modeling is helpful in designing new ablation patterns to reduce optical and spherical aberration. Ablation zone design is critical to maximizing optical and biologic tolerance.

Custom photorefractive keratectomy ablations for the correction of spherical and cylindrical refractive error and higher-order aberration.

Photorefractive keratectomy is an evolving refractive procedure for correcting myopia, hyperopia, and astigmatism. Earlier descriptions of the patterns required for this surgery are based on paraxial optics. In this investigation the required pattern is generalized to account for spherical refractive error (defocus), axial astigmatism of arbitrary orientation, and fourth-order aberrations of the eye. The patterns described in this study can be used to customize photorefractive keratectomy and to provide corrections that account for aberration content as well as paraxial values. Furthermore, a description of the pattern along the boundary of the optical zone is given, which may prove useful in designing blending zones. An example of the use of these techniques is given for a schematic eye model.

Bilateral partial bronchial obstruction due to broncholithiasis treated with laser therapy.

The previously recognized modes of therapy for symptomatic broncholithiasis are broncholithectomy via surgery or bronchoscopy. A 46-year-old woman with bilateral partial bronchial obstruction was treated with Nd-YAG laser with complete resolution of symptoms and of airway obstruction.

Topical nonsteroidal anti-inflammatory agents in ophthalmology.

Nonsteroidal anti-inflammatory agents or NSAIDs are potent inhibitors of prostaglandin synthesis. As such, they have found many useful roles in ophthalmology. NSAIDs are approved by the FDA to prevent intraoperative miosis during cataract surgery, reduce postoperative inflammation following cataract surgery, and control symptoms of allergic conjunctivitis and pain following refractive surgery. In addition, they have been shown to be effective in preventing cystoid macular edema following cataract surgery or treating cystoid macular edema once it occurs.

Intracorneal, aqueous humor, and vitreous humor penetration of topical and oral ofloxacin.

OBJECTIVES: To investigate the intracorneal, aqueous, and vitreous penetration of ofloxacin, and to assess the concentration of the drug after topical administration alone and after combined topical and oral administration. METHODS: Twenty consecutive patients undergoing penetrating keratoplasty with vitrectomy for bullous keratopathy received 2 drops of 0.3% ofloxacin every 30 minutes starting 4 hours before surgery. Group A (10 patients) received topical therapy alone. Group B (10 patients) received an additional 3 doses of oral ofloxacin, 400 mg, every 12 hours starting 26 hours before surgery. Aqueous humor, vitreous humor, and corneal specimens were analyzed for ofloxacin levels. RESULTS: For group A, the mean intracorneal ofloxacin level was 4.51 micrograms/mL (range, 0.58-8.77 micrograms/mL; 10 specimens), the mean aqueous humor level was 1.34 micrograms/mL (range, 0.07-4.98 micrograms/mL; 8 specimens), and the mean vitreous humor level was 0.37 micrograms/mL (range, 0.05-0.90 micrograms/mL; 8 specimens). For group B, the mean intracorneal ofloxacin level was 8.59 micrograms/mL (range, 1.18-23.24 micrograms/mL; 10 specimens), the mean aqueous humor level was 2.77 micrograms/mL (range, 0.25-5.80 micrograms/mL; 10 specimens), and the mean vitreous humor level was 2.55 micrograms/mL (range, 0.28-4.97 micrograms/mL; 9 specimens). CONCLUSIONS: Topically applied ofloxacin achieves therapeutic levels in the cornea and aqueous. Mean levels achievable are well above the 90% minimal inhibitory concentration (MIC90) for the majority of bacteria responsible for endophthalmitis and corneal ulceration. The addition of oral ofloxacin to topical therapy increased vitreous penetration 7-fold in this assay trial.

Effects of intranasal cocaine on sympathetic nerve discharge in humans.

Cocaine-induced cardiovascular emergencies are mediated by excessive adrenergic stimulation. Animal studies suggest that cocaine not only blocks norepinephrine reuptake peripherally but also inhibits the baroreceptors, thereby reflexively increasing sympathetic nerve discharge. However, the effect of cocaine on sympathetic nerve discharge in humans is unknown. In 12 healthy volunteers, we recorded blood pressure and sympathetic nerve discharge to the skeletal muscle vasculature using intraneural microelectrodes (peroneal nerve) during intranasal cocaine (2 mg/kg, n = 8) or lidocaine (2%, n = 4), an internal local anesthetic control, or intravenous phenylephrine (0.5-2.0 microg/kg, n = 4), an internal sympathomimetic control. Experiments were repeated while minimizing the cocaine-induced rise in blood pressure with intravenous nitroprusside to negate sinoaortic baroreceptor stimulation. After lidocaine, blood pressure and sympathetic nerve discharge were unchanged. After cocaine, blood pressure increased abruptly and remained elevated for 60 min while sympathetic nerve discharge initially was unchanged and then decreased progressively over 60 min to a nadir that was only 2+/-1% of baseline (P < 0.05); however, plasma venous norepinephrine concentrations (n = 5) were unchanged up to 60 min after cocaine. Sympathetic nerve discharge fell more rapidly but to the same nadir when blood pressure was increased similarly with phenylephrine. When the cocaine-induced increase in blood pressure was minimized (nitroprusside), sympathetic nerve discharge did not decrease but rather increased by 2.9 times over baseline (P < 0.05). Baroreflex gain was comparable before and after cocaine. We conclude that in conscious humans the primary effect of intranasal cocaine is to increase sympathetic nerve discharge to the skeletal muscle bed. Furthermore, sinoaortic baroreflexes play a pivotal role in modulating the cocaine-induced sympathetic excitation. The interplay between these excitatory and inhibitory neural influences determines the net effect of cocaine on sympathetic discharge targeted to the human skeletal muscle circulation.

Characterization of the transmembrane orientation of aquaporin-1 using antibodies to recombinant fusion proteins.

Aquaporin-1 (AQP1) is a member of a family of integral membrane proteins, the aquaporins, which function as molecular channels for the movement of water across the plasma membrane. While the primary structure of AQP1 has been obtained from the cloning of its cDNA, its secondary structure is less certain. In this study, antibodies have been generated to defined regions of AQP1 in order to characterize its secondary structure. The antibodies were produced in chickens against glutathione S-transferase fusion proteins which represented loops C and E, and the carboxyl terminus of AQP1 as defined in the six-transmembrane model of Preston and Agre [(1991) Proc. Natl. Acad. Sci. U.S.A. 88, 11110]. Characterization of the antibodies showed that they recognized their corresponding fusion proteins as well as native AQP1 in erythrocytes and recombinant AQP1 expressed in COS7 cells. They differed, however, with respect to the specific conditions required for recognition. Thus, the anti-C-terminal antibodies recognized COS7 cells transfected with AQP1 that were fixed and permeabilized but did not recognize live cells (unpermeabilized). Conversely, antibodies to loop C labeled both live and fixed cells, while antibodies to loop E labeled live cells but not fixed. The data indicate that the carboxyl terminus of aquaporin-1 is intracellular and that loops C and E are extracellular. Furthermore, antibody recognition of loop E is very sensitive to the labeling conditions which may reflect an active role in the functional protein.