Factors affecting therapeutic concentration of topical aminocaproic acid in traumatic hyphema.

Epsilon-aminocaproic acid (EACA) decreases rebleeding in traumatic hyphema through antifibrinolytic activity. Therapeutic levels were achieved in aqueous humor of rabbits after topical application. Aqueous humor EACA levels were significantly higher after pretreatment with 0.5% proparacaine. Use of EACA (60%) in a carboxypolymethylene (CPM) vehicle (0.5%, 1%, 2%, 3%, and 4%) was examined. Aqueous humors levels at 4 hours ranged from 6.18-20.42 micrograms/ml. The 2% and 3% formulas achieved the highest concentrations in aqueous. Use of EACA (15%, 30%, 40%, and 60%) in 4% CPM was also studied. At 2 and 4 hours after treatment, the 30% EACA solution most effectively achieved therapeutic levels. Velcro closure devices were attached to the rabbit's eyelids, and 200 microliters of 30% EACA in 2% CPM was administered. After 3 hours the patched eyes had a mean aqueous EACA level of 60.09 micrograms/ml compared with 8.97 micrograms/ml in unpatched eyes. When dose size was studied in patched eyes, 200-microliters doses achieved aqueous levels of 60.09 micrograms/ml, and 100-microliters doses resulted in levels of 10.40 micrograms/ml. Since epithelial toxicity was observed in eyes that had been patched, the optimum topical regimen appeared to be 200 microliters of 30% EACA in 2% CPM every 6 hours in unpatched eyes.

Topically applied aminocaproic acid concentrates in the aqueous humor of the rabbit in therapeutic levels.

Systemically administered aminocaproic acid, used to reduce the incidence of secondary hemorrhage in traumatic hyphema, has been shown to accumulate in the aqueous humor of rabbits in a dose-dependent manner. Eight topical preparations of aminocaproic acid were studied to determine aqueous humor concentrations. The vehicles studied included the following: sodium chloride, 0.85 g/dL; polyvinyl alcohol, 1.4 g/dL; hydroxypropyl methylcellulose, 0.4 g/dL; benzalkonium chloride, 0.01 g/dL; ethylenediamine tetraacetic acid disodium, 0.01 g/dL; dimethyl sulfoxide, 11 and 39.6 g/dL; and carboxypolymethylene, 4 g/dL. All contained 735 g/L of aminocaproic acid except for dimethyl sulfoxide (39.6 g/dL) and carboxypolymethylene (4 g/dL), which contained 238 and 600 g/L of aminocaproic acid, respectively. Aqueous humor and plasma samples were assayed for aminocaproic acid content following topical administration. Aqueous humor concentrations of aminocaproic acid ranged from undetectable (less than 0.01 mg/dL) to 5.75 mg/dL. Plasma concentrations ranged from undetectable (less than 0.01 mg/dL) to 9.85 mg/dL. Polyvinyl alcohol (1.4 g/dL) and carboxy polymethylene (4 g/dL) provided the highest aqueous humor aminocaproic acid concentrations. The aqueous humor levels with topical aminocaproic acid administration were comparable with those achieved by systemic administration. Plasma drug levels with topical aminocaproic acid were between 5% and 33% of levels achieved by systemic aminocaproic acid. This study demonstrates that aminocaproic acid can be effectively delivered into the anterior chamber of rabbits by topical application.

Systemic aminocaproic acid reduces fibrinolysis in aqueous humor.

Systemically administered aminocaproic acid has been demonstrated to reduce the incidence of secondary hemorrhage in traumatic hyphema. To directly determine the concentration of aminocaproic acid in the aqueous humor, four groups of rabbits were studied following administration of four different regimens of intravenously administered aminocaproic acid. Plasma and aqueous humor samples were assayed for drug content and antifibrinolytic activity. Peak aqueous humor concentrations of aminocaproic acid ranged from 2.5 to 33 mg/dL and varied according to the systemic dose administered. The antifibrinolytic activity paralleled the aminocaproic acid content, with a peak range from 310 to 683 s. These findings indicate a direct relationship between antifibrinolytic activity and the concentration of aminocaproic acid in aqueous humor.

Topical aminocaproic acid in the treatment of traumatic hyphema.

OBJECTIVES: To determine whether topically applied aminocaproic acid, like systemic aminocaproic acid, effectively reduces secondary hemorrhage after hyphemas and to compare the safety and effectiveness of topical application with those of systemic use and a control group. DESIGN: A prospective, randomized, double-masked, multicenter study. PATIENTS: Sixty-four patients with traumatic hyphema treated with topical or systemic aminocaproic acid and compared with 54 control patients with hyphema. Daily slitlamp examinations for hyphema grading and corneal clarity, initial and final visual acuity, applanation tonometry, and fundus indirect ophthalmoscopy were studied. Follow-up was 6 months to 5 1/2 years (mean, 2.96 years). RESULTS: Compared with the control group, topical and systemic aminocaproic acid was statistically significant in preventing secondary hemorrhage. Only 3% (2/64) of the patients who received topical or systemic aminocaproic acid had secondary hemorrhage compared with 22% (12/54) of the control group (P = .002). Final visual acuity was 20/40 or better in 30 patients (86%) in the topical group compared with 23 patients (43%) in the control group (P < .001). Final visual acuity was 20/40 or better in 20 patients (69%) in the systemic aminocaproic acid group compared with 23 patients (43%) in the control group (P = .04). The topical aminocaproic acid group had a final visual acuity of 20/40 or better in 86% of patients, compared with 69% of patients in the systemic group. CONCLUSIONS: Topical aminocaproic acid appears to be a safe, effective treatment to prevent secondary hemorrhage in traumatic hyphema. It is as effective as systemic aminocaproic acid in reducing secondary hemorrhage. No systemic side effects were observed with topical use. Topical aminocaproic acid provides an effective out-patient treatment for traumatic hyphemas.

Topical aminocaproic acid significantly reduces the incidence of secondary hemorrhage in traumatic hyphema in the rabbit model.

Systemically administered aminocaproic acid has been shown to reduce the incidence of secondary hemorrhage after traumatic hyphema. To date, no topical treatment has been shown to be effective in reducing the incidence of rebleeding in a double-masked study. Experimentally induced traumatic hyphemas in the rabbit model were treated with topical placebo gel (4% carboxypolymethylene gel only) or carboxypolymethylene gel with amino-caproic acid (treated group) in a double-masked fashion and were compared with untreated controls (control group). In both the control and placebo groups, there was a 33% rebleed rate. The treated eyes had a 10% rebleed rate that is statistically significant. The topically applied aminocaproic acid gel appears to be well tolerated locally without evidence of systemic toxicity. This study indicates that topical aminocaproic acid may be an effective alternative to systemic treatment to reduce the incidence of secondary hemorrhage in traumatic hyphema.

Incorporation of clinical pharmacology into the fourth year of the medical curriculum: teaching clinical pharmacology without a clinical pharmacologist.

In congruence with the educational goals of the institution, the pharmacology department has developed courses for senior students. By using the students' recently acquired clinical knowledge, these courses amplify material from the core course in pharmacology. Engaging students in this type of course requires significant commitment from the faculty involved and also from the dean and department chairman. This course has outlasted many curricular changes and has remained in the mainstream of medical education. Goals of this course remain consistent with current proposals to develop new directions in medical education.

Evaluation of student achievement and educational outcomes.

Development of problem-solving skills is vital to professional education as is factual recall. Student mastery must be measured to document student achievement requiredfor completion of educational requirements and professional certification. These measurements also help determine if the educational process is meeting its goal of helping students develop critical cognitive skills for therapeutic problem solving. Testing student growth in the ability to solve problems is less understood. Stressing integration of information across disciplines to derive answers is also important. Test items should resemble the real-world task that students are expected to master. Thatisreallythe essence of content validity, which means faculty should be biased toward presenting information that way. This article is based on a symposium presented at the annual meeting of the American College of Clinical Pharmacology in September 1996. Symposium goals were to define purposes and uses of student evaluations by type and format, including application of techniques that improve evaluation, precision, and validity. Technical applications of computer-based learning and evaluation of problem-solving skills are described. Actual experience with evaluation of problem solving in the curriculum is discussed. The process by which a medical school developed and implemented an evaluation system for a new problem-based curriculum is presented, followed by a critique of the successes and problems encountered during the first year of implementation. Criteria that a well-constructed evaluation program must meet are explored. The approach and philosophy of national standardized testing centers are explained.

The birth of ocular pharmacology in the 20th century.

Nineteenth century ophthalmology, characterized by significant gains in diagnostic techniques, provided the basis for great advancements in treatment during the 20th century. Drug therapy at the turn of the century was empiric, palliative, and often toxic. The development of ocular pharmacology during the 20th century provided the basis for a rational therapeutic approach to ocular disease. Foremost among the therapeutic developments were antibiotics, due to their potential to cure conditions that frequently resulted in blindness. Second, other therapeutic classes provided palliative therapy for chronic diseases, and thus decreased morbidity. For example, drugs specifically targeting many different aspects of glaucoma have had remarkable success controlling intraocular pressure and forestalling development of blindness. In addition, other new approaches provided palliative therapy for nonblinding conditions and effective adjuncts to surgical procedures. Antiallergy and anti-inflammatory drugs greatly increased patient comfort and facilitated treatment of allergic and inflammatory reactions. Local anesthetics and analgesia reduced patient discomfort during surgery. Other adjunct drugs improved surgical outcomes by reducing inflammation and infectious complications. The 21st century will undoubtedly provide novel approaches to address many of today's therapeutic dilemmas. Photodynamic therapy, growth factors, antisense technology, and genetic-based therapies all show great promise. Many of the conditions that are only treated palliatively today will be curable in the next century using many of these pharmacological advances.

Ultrasound diagnosis of filarial funiculoepididymitis.

Genital presentation of filarial disease is not uncommon in endemic areas of the world. Acute, febrile illness involving the epididymis and spermatic cord (funiculoepididymitis) is one of many such presentations. With an internationally mobile society, physicians today, even in nonendemic areas, may encounter patients with filarial infestations. We report the first case of presumptive diagnosis of this disease using scrotal ultrasound.

Development and evaluation of patient-oriented problem-solving materials in pharmacology.

Faculty from six eastern health science schools, from Florida to Nova Scotia, developed a new series of group-learning units during 1983 and 1984 using a recently developed patient-oriented problem-solving approach. The purpose of the units was to teach problem solving by applying the concepts and principles of pharmacology to therapeutic problems, and to find ways to engage students actively in their learning of this material. The development team envisioned that these goals would be met by means of well-crafted teaching units that could be evaluated and, if acceptable, used by academic pharmacologists in their teaching. The units were developed, edited, reviewed by experts, and field-tested with students at the authors' schools; editing and publication were done by the study's sponsor, the Upjohn Company. The results of the field trials (which indicated no need for revisions of the units) showed that the units were well crafted and that the students had higher scores on tests of their knowledge of pharmacology after they had used the units.

Long-term pretreatment with pentoxifylline increases random skin flap survival.

Optimizing survival of random skin flaps is essential to ensure successful rehabilitation of patients in whom flap reconstruction is necessary. This study tested the hypothesis that pentoxifylline improves random skin flap survival in porcine dorsal flank flaps when administered for at least 2 weeks preoperatively. Specific aims included establishing the mechanisms by which pentoxifylline enhanced survival. Treatment with pentoxifylline (25 mg/kg per day) for 14 days before surgery and for 7 days thereafter significantly increased mean flap survival to 73.2% +/- 4.5% compared with mean flap survival of 49.6% +/- 2.2% in untreated pigs. Increased flap survival was associated with a parallel increase in red blood cell flexibility. Plasma concentration of pentoxifylline ranged from 92.9 to 122.7 ng/mL but did not correlate directly with the improved flap survival. Likewise, pentoxifylline decreased platelet aggregation; there was a trend toward increased flap survival in those pigs with the least amount of aggregation. Thus, pentoxifylline improves random flap survival but only after a sufficient pretreatment period of at least 14 days.

Pharmacologic enhancement of random skin flap survival by prostaglandin E2.

This study evaluated the effect of prostaglandin E2 on skin flap survival in the porcine model. Dorsal random skin flaps on hypopigmented 15- to 25-kg pigs were used. Prostaglandin E2 (10 ng/kg per minute) was infused for 2 days prior to surgery and continued during the 7-day postoperative period. Mean flap survival was 52.58% +/- 3.62% for the control group and 68.51% +/- 3.34% for the experimental group (P < .05). A moderate correlation existed between prostaglandin E2 serum levels and flap viability. A strong correlation was noted between red blood cell flexibility and the amount of flap survival (r = .86). As red blood cell flexibility increased, the survival percentage also increased. Although prostaglandin E2 reduced adenosine diphosphate-induced platelet aggregation from a baseline of 86.08% +/- 8.33% to 54.61% +/- 17.21%, no correlation was noted between the amount of platelet aggregation and percent flap survival (r = .52).

Topical aminocaproic acid facilitates reepithelialization of persistent epithelial defects.

PURPOSE: After corneal injury, persistent epithelial defects (PED's) may occur due to the chronic failure of the regenerating epithelium to adhere to the underlying stroma. The aim of this study was to examine the potential of epsilonaminocaproic acid (EACA) as a topical treatment for PED's. EACA inhibits the activation of plasmin, which metabolizes fibronectin. Fibronectin, a glycoprotein, anchors corneal epithelium to the basement membrane and the underlying stroma. METHODS: In anesthetized rabbits, PED's were induced with sodium hydroxide (1 N). Seven days later, during the late healing phase, treatment began with administration of EACA (30%) to the right eye and administration of vehicle alone to the left eye three times daily. A control group received neither EACA nor vehicle. Rabbits were treated for 19 days. PED's were visualized by fluorescein staining. Their size was mapped using digital planimetry. RESULTS: After 11 days of treatment with EACA, treated PED's were 50% smaller than in corneas treated with vehicle alone. Following treatment for 15 days, corneas treated with EACA had significantly greater re-epithelialization than vehicle-treated or control corneas. Frozen sections stained immunofluorescently for fibronectin appeared to qualitatively contain more adherent fibronectin in treated corneas. Transmission and scanning electron microscopy indicated that the epithelium was more polymorphic, thinner and vacuolated in untreated controls compared to EACA treated eyes. Light microscopy demonstrated more continuous adherent epithelium after EACA treatment. CONCLUSIONS: Topically administered EACA decreases both the severity and incidence of persistent epithelial defects produced by alkali bums to the cornea. EACA appears to promote adherence of the regenerating epithelium to the underlying stroma. Thus, topically administered EACA may be an effective treatment for this chronic condition.

Pre-eclampsia: a hypothesis for its etiology.

A hypothesis is presented according to which the etiology of pregnancy-induced hypertension can be attributed to increased number of active uterine and arteriolar alpha-adrenergic myometrial receptors from pre-eclamptic patients in comparison with the alpha-adrenergic myometrial and arteriolar receptors from non-pre-eclamptic patients. This condition could result in the increased uterine wall irritability and the decreased uteroplacental blood flow in pre-eclampsia. It is suggested that progesterone fails to induce a reduction in alpha 1-adrenergic receptors in the pre-eclamptic patient. This will require pre-eclamptic patients and matched controls to test the hypothesis.

Correlation of neutrophil activation and skin flap survival in pharmacologically altered pigs.

In inflamed tissue, neutrophils produce tissue necrosis factors such as free oxygen radicals. We investigated the role of neutrophils in random flap survival using the tissue neutrophil marker myeloperoxidase (MPO), an in whole blood using flow cytometry with the neutrophil activation marker 2'7'dichlorofluorescein diacetate. Hypopigmented pigs were treated with the experimental 21-aminosteroid lipid antioxidant U-74389G (oxygen free radical scavenger) before dorsal random skin flaps were elevated. Extent of flap survival was measured by surface planimetry 7 days after surgery. Mean flap survival was 64.1% +/- 3.4% in the 3-mg/kg-treated group, and 68.0% +/- 3.4% in the 1-mg/kg-treated group-both significantly greater than the survival in vehicle-treated controls (48.6% +/- 2.3%). We measured MPO in tissue extracts using an enzyme-linked immunoassay, which showed less MPO in treated animals than in controls. Flow cytometry results were nonspecific. These data suggest that U-74389G improves random skin flap viability by inhibiting neutrophil infiltration into the flap.

Aminocaproic acid and tranexamic acid increase the rate of acute corneal reepithelialization in Sprague Dawley rats.

Antifibrinolytic agents, epsilon-aminocaproic acid (EACA) and tranexamic acid (TXA), have been reported to be efficacious in the treatment of chronic persistent epithelial defects. Within the regulatory mechanism of corneal reepithelialization, fibronectin serves as a primary adhesive component in the healing process and anchors regenerating epithelial cells to underlying stroma. EACA and TXA inhibit the activation of plasmin thereby decreasing plasmin-induced catabolism of fibronectin. In this study, acute reepithelialization following treatment with EACA and TXA was evaluated in the cultured rat cornea model. Sprague Dawley rat corneal explants with 3 mm corneal defects, induced with 1 N NaOH, were cultured with either EACA or TXA. After 12 or 24 hr incubation periods, corneal explants were stained with bromodeoxyuridine stain for measuring cellular division and migration or Trypan Blue for measuring the extent of dead cells. Both EACA and TXA increased the rate of reepithelialization in comparison to an untreated control. EACA was up to 35% more efficacious than TXA. Thus, this study demonstrated an acute effect for EACA and TXA versus the previously reported efficacy of chronic therapy required for persistent epithelial defects. Broad applications may prove beneficial in the clinical treatment of corneal abrasions, persistent corneal epithelial defects, or alkali burns.

Comparison of topical steroids for acute anterior uveitis.

This study objectively compares efficacy of dexamethasone Na phosphate 0.1%, fluorometholone 0.1% (FML), loteprednol etabonate 0.5% (Lotemax [LE]; Bausch & Lomb Pharmaceuticals, Inc., Tampa, FL), prednisolone acetate 1% (Pred Forte [PRED F]; Allergan Pharmaceuticals, Irvine, CA), and generic prednisolone acetate 1% (PRED A). These steroids were administered for 24 hours or 72 hours to New Zealand white rabbits with endotoxin-induced uveitis. Intraocular pressure (IOP), slit-lamp examination, and confocal microscopy were performed daily. Internalization of the glucocorticoid receptor (GC) was assayed in iris tissue by Western blot, and protein in aqueous humor by Bradford assay. Only LE and PRED F treatments significantly internalized GC receptor after 72 hours of treatment. Only LE and PRED A reduced protein concentration between 24 hours and 72 hours of treatment. All drugs improved clinical signs after 24 hours of treatment. None of the steroids promoted return of the inflammation-induced corneal thickness to baseline. While none returned IOP to baseline, LE was most effective. Confocal microscopy indicated that only treatment with LE reverted the abnormal endothelial-cell shape to normal. In conclusion, all steroid treatments reduced uveitis to some degree but LE was consistently effective. A longer observation period may be required to document the return of IOP and corneal thickness to baseline values.

Topical versus intravenous administration of tranexamic acid: a comparison of intraocular and serum concentrations in the rabbit.

BACKGROUND: Tranexamic acid has been shown to greatly reduce the incidence of secondary hemorrhage when administered orally or intravenously. Topical administration of the drug should result in much lower serum concentrations, with fewer adverse effects. We performed a study to determine whether topical application of tranexamic acid would yield higher intraocular concentrations and lower serum concentrations of drug than intravenous administration. METHODS: Ten New Zealand white rabbits received 25 mg/kg of tranexamic acid intravenously every 8 hours for 3 days. Another group of 10 rabbits received one drop (0.05 mL) of commercially available tranexamic acid solution (100 mg/mL) every 8 hours for 3 days to one eye. Tranexamic acid levels in the aqueous humour, vitreous humour and serum 1 hour after administration of the last dose of drug were determined. RESULTS: Analysis of variance showed that aqueous concentrations of tranexamic acid were significantly higher with topical delivery than with intravenous administration (15 vs. 9 micrograms/mL)(p < 0.05). Serum concentrations were significantly lower following topical administration (9 vs. 19 micrograms/mL)(p < 0.01). The drug was not detected in the vitreous humour in either group. INTERPRETATION: Topical delivery of tranexamic acid may prove to be valuable in yielding therapeutic intraocular concentrations of drug in patients with hyphema while minimizing systemic toxicity.