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1.
Eur J Pharmacol ; 432(2-3): 187-94, 2001 Dec 07.
Article in English | MEDLINE | ID: mdl-11740955

ABSTRACT

Factor Xa is a serine protease positioned at the convergence point of the intrinsic and extrinsic coagulation pathways and is therefore an attractive target in the development of novel anticoagulant drugs. The objective of this study was to evaluate the efficacy of CI-1031 (N-[2-[5-amidino-2-hydroxyphenoxy]-6-[3-(1-methyl-1H-imidazolin-2-yl)-phenoxy]-3,5-difluoropyrid), a potent and selective inhibitor of Factor Xa, in a canine electrolytic injury model of arterial and venous thrombosis. Enoxaparin (enoxaparin sodium), a low molecular weight heparin currently approved for treatment and prevention of deep vein thrombosis and unstable angina, was also tested for efficacy in this model. CI-1031 was administered intravenously to anesthetized dogs at three doses: 1.25, 2.5 and 5 microg/kg/min (n=5 for each group) as a continuous infusion for 5.5 h. The control group (n=5) received a continuous infusion of vehicle (3.69 mmol citric acid and 0.9% sodium chloride solution) at a rate of 1 ml/kg/h. Ninety minutes after administration of CI-1031 prothrombin times increased 1.2-, 1.6- and 2.0-fold over baseline values in the 1.25, 2.5 and 5 microg/kg/min groups, respectively. The time to formation of an occlusive thrombus in the femoral arteries averaged 69+/-5 min in the control group compared to 127+/-19, 192+/-33 and 219+/-15 min in the low-, mid- and high-dose CI-1031 groups. In the femoral veins, occlusion time in the controls averaged 56+/-11 min compared to 153+/-22, 137+/-30 and 214+/-26 min in the three treatment groups. Thrombus weights in the control arteries averaged 51+/-4 mg compared to 45+/-5, 28+/-10 and 15+/-3 mg in the CI-1031 treated groups. On the venous side, control thrombus weights averaged 96+/-18 mg compared to 75+/-16, 51+/-16 and 25+/-4 mg in the low-, mid- and high-dose CI-1031 groups. A plasma CI-1031 concentration of approximately 400 ng/ml was associated with a 50% reduction in thrombus weight relative to control animals. Enoxaparin was administered intravenously at a loading dose of 50, 100 or 200 IU/kg for 1 h followed by a maintenance infusion of 25, 50 or 100 IU/kg/h for 4.5 h. The most dramatic changes in coagulation parameters were observed in thrombin time with virtually no changes in prothrombin time. Enoxaparin elicited a dose-dependent increase in time to thrombotic occlusion and a dose-dependent decrease in thrombus weight similar to that observed with CI-1031. Time to occlusion in the enoxaparin-treated groups averaged 117+/-33, 188+/-32 and 217+/-22 min in the low-, mid- and high-dose groups in the femoral arteries and 84+/-22, 171+/-31 and 133+/-33 min in the femoral veins. Thrombus weights averaged 33+/-10, 12+/-5 and 10+/-4 mg in the arteries and 32+/-9, 13+/-2 and 21+/-6 mg in the veins in the low-, mid- and high-dose groups. Blood loss with CI-1031 tended to be less than enoxaparin at doses that provided comparable efficacy. These results demonstrate that CI-1031, like enoxaparin, is an effective antithrombotic agent in an established canine model of arterial and venous thrombosis. CI-1031 provided dose-dependent efficacy with minimal changes in ex vivo coagulation parameters, suggesting it may be a safe and effective antithrombotic agent for both arterial and venous indications.


Subject(s)
Amidines/pharmacology , Anticoagulants/pharmacology , Enoxaparin/pharmacology , Pyridines/pharmacology , Thrombosis/prevention & control , Venous Thrombosis/prevention & control , Amidines/blood , Animals , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Electrolysis/adverse effects , Factor Xa Inhibitors , Partial Thromboplastin Time , Prothrombin Time , Pyridines/blood , Thrombin Time , Thrombosis/etiology , Time Factors , Venous Thrombosis/etiology
2.
J Thromb Thrombolysis ; 10(3): 277-84, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11122549

ABSTRACT

Direct thrombin inhibitors represent a new class of drug that may offer a therapeutic alternative for the treatment and prevention of thrombembolic conditions, especially on the venous side of the systemic circulation. CI-1028 (PD 172524/LB30057) is a potent, highly selective inhibitor of thrombin that is orally bioavailable. The efficacy of this compound has been demonstrated in animal models in which intra-venous administration was used. The objective of this study was to evaluate the efficacy of CI-1028 after oral administration in a canine electrolytic injury model of venous and arterial thrombosis. CI-1028 was administered via oral gavage, and animals received either saline or 10, 15, 20, or 30 mg/kg of drug. Fifteen minutes later, the dogs were anesthetized and a femoral artery and vein were exposed and instrumented to induce electrolytic injury and thrombosis while continuously monitoring blood flow in the vessels. Maximum blood CI-1028 concentrations of 0.88+/-0.27, 1.8+/-0.3, 2.2+/-0.5, and 3.2+/-0.5 microg/mL were generally achieved 15 to 30 minutes after administering the compound in the 10-, 15-, 20-, and 30-mg/kg groups, respectively. Administration of CI-1028 increased the time to occlusion (TTO), the principal efficacy end point, in a dose-dependent manner in both arteries and veins. The TTO in the control group (n=8) averaged 66+/-11 minutes in the arteries and 69+/-6 minutes in the veins. In dogs treated with 10 mg/kg (n=8), the TTO was not significantly different from that of the control group. In the 15-mg/kg group (n=9) TTO averaged 140+/-27 minutes in the arteries (p=not significant) and 125+/-15 minutes (p<0.05) in the veins. In the 20-mg/kg group (n=8), TTO was significantly longer than controls in both types of vessels, averaging 168+/-30 minutes in the arteries (p=0.05) and 155+/-21 minutes (p<0.05) in the veins. Likewise, at 30 mg/kg (n=8) both the arterial (179+/-17 minutes) and venous (188+/-15 minutes) TTO was significantly prolonged compared with controls. Surgical blood loss and template bleeding times tended to increase in a dose-dependent manner but a statistically significant elevation was detected for template bleeding time only at the highest dose. Dramatic changes in thrombin time were detected, consistent with the CI-1028 mechanism of action. Virtually no changes were detected in prothrombin time. Maximum activated partial thromboplastin time (aPTT) and activated clotting time changes were detected approximately 30 minutes after dosing, and they were approximately twofold and fivefold baseline values, respectively, at the highest dose. In conclusion, these results demonstrate that CI-1028 provides dose-dependent antithrombotic efficacy after oral administration in a canine model of venous and arterial thrombosis.


Subject(s)
Benzamides/pharmacology , Thrombin/antagonists & inhibitors , Thrombosis/drug therapy , Administration, Oral , Animals , Arterial Occlusive Diseases , Benzamides/pharmacokinetics , Biological Availability , Blood Coagulation Tests , Blood Flow Velocity/drug effects , Blood Loss, Surgical , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Fibrinolytic Agents/administration & dosage , Fibrinolytic Agents/pharmacology , Hemorrhage/chemically induced , Venous Thrombosis
3.
Circ Res ; 86(1): 101-8, 2000.
Article in English | MEDLINE | ID: mdl-10625311

ABSTRACT

Hypercholesterolemia may render atherosclerotic plaques prone to rupture. To test this hypothesis, catheters with matrix-covered balloons were implanted into the aorta of rabbits fed standard or 0. 5% cholesterol chow (n=70). In 1 month, fibrous plaques developed around the balloon. Time-dependent accumulation of cholesteryl esters and free cholesterol was detected in the plaques of the cholesterol-fed group only. The pressure needed to rupture the plaque by balloon inflation was used as an index of plaque strength. Three months after the catheter implantation, the breaking pressure was 2.1 times lower (P<0.05) in cholesterol-fed rabbits. It was accompanied by collagen loss, as measured by plaque hydroxyproline content, but not with deficiency of collagen cross-linking. Sirius red staining showed preservation of collagen originally covering the balloon and accumulation of nascent collagen in the lesions of standard chow-fed rabbits. In the cholesterol-fed group, both mature and new collagen underwent degradation predominantly in the plaque shoulders. Collagen breakdown was associated with local accumulation of foamy macrophages. Gel zymography demonstrated relative enhancement of gelatinolytic activity at 92 and 72 kDa, as well as caseinolytic activity at 57, 45, and 19 kDa in the lipid-laden plaques. Lipid accumulation in the plaque was also associated with a loss of smooth muscle cells, the cellular source of the collagen fibers. The remaining smooth muscle cells showed increased collagen synthesis, although it was insufficient to counterbalance collagen degradation and cell loss. Thus, we have obtained direct evidence that hypercholesterolemia is accompanied by enhanced local collagen degradation, which is potentially responsible for plaque weakening.


Subject(s)
Arteriosclerosis/pathology , Arteriosclerosis/physiopathology , Collagen/metabolism , Hypercholesterolemia/physiopathology , Animals , Arteriosclerosis/metabolism , Cholesterol/blood , Collagen/physiology , Hypercholesterolemia/blood , Hypercholesterolemia/metabolism , Lipids/blood , Matrix Metalloproteinases/metabolism , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Pressure , Rabbits , Tissue Distribution
4.
Circ Res ; 83(7): 705-13, 1998 Oct 05.
Article in English | MEDLINE | ID: mdl-9758640

ABSTRACT

Atherosclerotic plaque rupture is the main cause of coronary thrombosis and myocardial infarcts. Currently, there is no animal model of plaque disruption. We have developed a rabbit model in which an atherosclerotic plaque can be ruptured at will after an inflatable balloon becomes embedded into the plaque. Furthermore, the pressure needed to inflate the plaque-covered balloon may be an index of overall plaque mechanical strength. The thoracic aorta of hypercholesterolemic rabbits underwent mechanical removal of endothelial cells, and then a specially designed balloon catheter was introduced into the lumen of the thoracic aorta. As early as 1 month after catheter placement, atherosclerotic plaque formed around the indwelling balloon. The plaques were reminiscent of human atherosclerotic lesions, in terms of cellular composition, patterns of lipid accumulation, and growth characteristics. Intraplaque balloons were inflated both ex vivo and in vivo, leading to plaque fissuring. The ex vivo strategy is designed to measure the mechanical strength of the surrounding plaque, while the in vivo scenario permits an analysis of the plaque rupture consequences, eg, thrombosis. In addition, our model allows local delivery of various substances into the plaque. The model can be used to study the pathogenesis of plaque instability and to design plaque stabilization therapy.


Subject(s)
Arteriosclerosis/pathology , Catheterization/adverse effects , Animals , Aorta, Thoracic/injuries , Arteriosclerosis/complications , Disease Models, Animal , Humans , Rabbits , Rupture , Stress, Mechanical , Thrombosis/etiology
5.
Atherosclerosis ; 139(1): 137-45, 1998 Jul.
Article in English | MEDLINE | ID: mdl-9699901

ABSTRACT

Lipoprotein(a) [Lp(a)] has been proposed as a risk factor for both restenosis and coronary heart disease. Recently, we identified Lp(a) in the arterial wall during the initial rapid neointimal growth phase that occurs after balloon injury in cynomolgus monkeys. The purpose of this study was to determine the relationship between circulating Lp(a) levels and the extent of early neointimal formation. Initially, 348 cynomolgus monkeys were screened to identify 15 monkeys that had either high or low circulating Lp(a) levels. In the 15 monkeys, circulating Lp(a) levels were confirmed by two separate measurements over 6 weeks using an immunoturbidimetric assay. Cohorts were identified with plasma Lp(a) levels that differed by four fold. Lp(a) levels expressed as total mass averaged 32 +/- 4 (N = 8) and 136 +/- 12 (N = 7) mg/dl in the low and high groups, respectively. Between the two assays absolute Lp(a) levels differed by less than 6%. Iliac arteries were harvested 14 days after injury induced by expansion of the internal vessel diameter 1.4 times its initial size with an angioplasty balloon. The neointimal area in the high Lp(a) monkeys was 16% greater (0.49 +/- 0.12 mm2, N = 8 versus 0.57 +/- 0.10 mm2, N = 7) than in the low animals; however, this difference was not statistically significant (P = 0.63). Medial areas averaged 1.27 +/- 0.11 and 1.44 +/- 0.20 mm2 (P = 0.48) in these groups, respectively. Tissue Lp(a) quantification, using a mouse monoclonal anti-Lp(a) antibody, indicated that the percent total area staining positive for Lp(a) was 1.7-fold higher in the high versus the low Lp(a) group (2.7 +/- 0.4% versus 1.6 +/- 0.4%, N = 6-8); this difference was not statistical significant (P = 0.28). In summary, a four-fold increase in circulating plasma Lp(a) levels did not result in a statistically significant enhanced neointimal formation at 14 days after balloon injury. This finding suggests that studies of longer duration may be needed to amplify the trend toward increased neointimal growth observed in this study.


Subject(s)
Coronary Disease/etiology , Lipoprotein(a)/blood , Tunica Intima/pathology , Animals , Antibodies, Monoclonal/metabolism , Cholesterol/blood , Cholesterol, HDL/blood , Coronary Disease/pathology , Macaca fascicularis , Male , Mice , Triglycerides/blood
6.
Biopharm Drug Dispos ; 19(3): 185-91, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9570002

ABSTRACT

The purpose of this study was to characterize CI-992 pharmacokinetics and pharmacokinetics/pharmacodynamics (PK/PD) in sodium deplete monkeys. Panels of monkeys were administered CI-992 as a 1 h intravenous infusions (0.1 and 1 mg kg-1) or as single oral doses (0, 10, 50, and 100 mg kg-1). Mean arterial blood pressure (MABP) was monitored and serial blood samples were collected up to 24 h postdose. Plasma CI-992 concentrations were quantitated by radioimmunoassay. Pharmacokinetic parameters were calculated by noncompartmental methods. PK/PD relationships were assessed by standard methods. Oral bioavailability of CI-992 in the monkeys was < 2%; steady-state volume of distribution was 0.67 L kg-1; clearance was 10.4 mL min-1 kg-1. Following oral administration, tmax generally occurred 6-9 h postadministration; plasma CI-992 concentrations increased with increasing dose between 10 and 50 mg kg-1, but did not change appreciably from 50 to 100 mg kg-1. After intravenous administration, change in MABP was correlated with plasma CI-992 concentration through an effect compartment model in which the maximum achievable effect was a 22 mm Hg decrease in MABP; the steady-state concentration which produced half the maximum effect was 11 ng mL-1. Following the 10 mg kg-1 oral dose the maximum decrease in MABP was 19.1 mm Hg; higher doses did not produce greater maximum response but increased the duration of action. In contrast to observations following intravenous administration, a trend for decreasing MABP with increasing plasma CI-992 was not apparent following oral CI-992 administration.


Subject(s)
Antihypertensive Agents/pharmacology , Antihypertensive Agents/pharmacokinetics , Dipeptides/pharmacology , Dipeptides/pharmacokinetics , Protease Inhibitors/pharmacology , Protease Inhibitors/pharmacokinetics , Administration, Oral , Animals , Antihypertensive Agents/blood , Biological Availability , Blood Pressure/drug effects , Dipeptides/blood , Infusions, Intravenous , Macaca fascicularis , Male , Protease Inhibitors/blood , Renin/antagonists & inhibitors , Sodium/deficiency
7.
Arterioscler Thromb Vasc Biol ; 17(1): 181-7, 1997 Jan.
Article in English | MEDLINE | ID: mdl-9012654

ABSTRACT

Lipoprotein(a) [Lp(a)] has been proposed as a restenosis risk factor, but it is not known if Lp(a) is present in the injured arterial wall during the initial neointimal growth. The purpose of this study was to determine if Lp(a) is incorporated into the vessel wall during rapid neointimal formation after arterial injury in primates. In this model, distention of the iliac artery with an angioplasty catheter caused focal breaks in the internal elastic lamina (IEL) in 80% of the vessels and extensive IEL fragmentation with medial disruption in 20% of the vessels. Neointimal growth was noted in all injured arteries; thrombus formation was noted in 40% of the vessels. Based on morphometric measurements, injured arteries had neointimal areas of 0.41 +/- 0.05 (n = 4) and 0.83 +/- 0.23 (n = 6) mm2 at 14 and 28 days after injury, respectively. Control arteries had an intact IEL and a monolayer of intimal cells. Lp(a) localization was examined histologically by using a mouse monoclonal anti-Lp(a) antibody. Lp(a), found in all injured arteries, was localized primarily in the neointima in 50% of the vessels. In the subset of vessels with evidence of thrombus formation, intense Lp(a) immunostaining was associated with the thrombus. Lp(a) was specific to injured arteries as uninjured vessels did not stain. In addition, staining was not seen with a negative control, a nonspecific mouse IgG1 antibody. The presence of Lp(a) at the site of rapid neointimal growth supports a role for this lipoprotein in the response to vascular injury after balloon angioplasty.


Subject(s)
Iliac Artery/pathology , Lipoprotein(a)/analysis , Tunica Intima/pathology , Animals , Catheterization , Hyperplasia , Iliac Artery/metabolism , Macaca fascicularis , Male , Mice , Tunica Intima/metabolism
8.
J Lipid Res ; 36(6): 1294-304, 1995 Jun.
Article in English | MEDLINE | ID: mdl-7666007

ABSTRACT

Eight male cynomolgus monkeys (Macaca fascicularis) on a normal chow diet were orally administered gemfibrozil daily using a weekly rising dose protocol for 3 weeks (50, 125, and 200 mg/kg per day). At these drug doses, Lp[a] levels were reduced: 83.7% +/- 3.2 (SEM), (P < 0.024); 63.7% +/- 4.1 (P < 0.013); and 36.2% +/- 1.1 (P < 0.002), respectively, of pretreatment values. Lp[a] reduction was directly related to blood gemfibrozil concentration (range 36-428 microM, r = 0.969) and occurred without concomitant changes in apolipoprotein B. Three weeks posttreatment Lp[a] levels returned to pretreatment values. A specific ribonuclease protection assay demonstrated that liver apolipoprotein[a] (apo[a]) mRNA expression was decreased in all animals to an average of 19.1% +/- 3.0 (P < 0.0026), of pretreatment values after the 200 mg/kg treatment, whereas, albumin, apolipoprotein A-I, apolipoprotein E, and glyceraldehyde-3-phosphate dehydrogenase mRNAs were unchanged. Lp[a] levels were unaffected by gemfibrozil in HepG2 cells permanently transfected with an apo[a] 10-kringle cDNA construct containing partial 5'- and 3'-untranslated sequences and under control of a constitutive CMV promoter. However, both Lp[a] and apo[a] mRNA in primary cynomolgus monkey hepatocytes were coordinately lowered in a dose-dependent fashion by gemfibrozil. Thus, Lp[a] can be regulated by gemfibrozil at the level of apo[a] mRNA expression.


Subject(s)
Apolipoproteins A/genetics , Gemfibrozil/pharmacology , Lipoprotein(a)/blood , Liver/metabolism , RNA, Messenger/metabolism , Animals , Apolipoproteins B/blood , Base Sequence , Cell Line , DNA, Complementary/chemistry , Humans , Liver/drug effects , Macaca fascicularis , Male , Molecular Sequence Data , Ribonucleases , Transfection
9.
J Pharmacol Exp Ther ; 268(1): 372-9, 1994 Jan.
Article in English | MEDLINE | ID: mdl-8301578

ABSTRACT

Cl-992, a novel potent inhibitor of primate renin, was tested for blood pressure-lowering efficacy in sodium-restricted, furosemide-treated conscious normotensive cynomolgus monkeys and conscious renal hypertensive monkeys. The hypertensive monkey model provided an opportunity to determine the response to a renin inhibitor in a pathological nonhuman primate model of hypertension without concurrent diuretic treatment or dietary sodium restriction and on repeated oral administration. Cl-992 has IC50 values of 0.58 +/- 0.06 (n = 4) and 0.36 +/- 0.03 nM (n = 8) against human and monkey renin, respectively. In normotensive monkeys, oral Cl-992 at doses of 3, 10 and 30 mg/kg reduced mean arterial blood pressure (MABP) by 8 +/- 2, 15 +/- 7 and 29 +/- 7 mm Hg (n = 5 animals per dose level, P < .05), respectively (base line, 103 +/- 3 mm Hg). Intravenous Cl-992 (0.0001 to 0.1 mg/kg) also caused dose-dependent decreases in MABP and a maximum reduction of 23 +/- 4 mm Hg. The decrease in MABP after Cl-992 was paralleled by an inhibition of plasma renin activity (PRA) and a reduction in immunoreactive angiotensin II. In renal hypertensive monkeys, oral Cl-992 at doses of 3, 10 and 30 mg/kg reduced MABP by 6 +/- 2, 18 +/- 6 and 37 +/- 8 mm Hg (n = 3 or 4, P < .05), respectively (base line, 134 +/- 4 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Antihypertensive Agents/pharmacology , Dipeptides/pharmacology , Renin/antagonists & inhibitors , Administration, Oral , Animals , Antihypertensive Agents/administration & dosage , Blood Pressure/drug effects , Dipeptides/administration & dosage , Dogs , Humans , Hypertension, Renal/drug therapy , Macaca fascicularis , Male , Rats , Renin/blood
10.
Indiana Med ; 84(8): 540-4, 1991 Aug.
Article in English | MEDLINE | ID: mdl-1918916

ABSTRACT

Of the 25 million people who are hearing impaired, 85% suffer from sensorineural hearing loss (SNL). In the past decade, the identification and treatment of SNL have evolved from futile efforts to active intervention. This paper identifies nine forms of inner ear disorders causing SNL for which medical/surgical treatment is available. Physicians must realize that, with appropriate diagnosis and treatment, hearing nerve loss can have a satisfactory outcome.


Subject(s)
Deafness/therapy , Hearing Loss, Sensorineural/therapy , Autoimmune Diseases/therapy , Deafness/etiology , Hearing Loss, Sensorineural/etiology , Hearing Loss, Sudden/etiology , Hearing Loss, Sudden/therapy , Humans
11.
Laryngoscope ; 98(8 Pt 1): 840-5, 1988 Aug.
Article in English | MEDLINE | ID: mdl-3398659

ABSTRACT

Delayed endolymphatic hydrops is a disease entity that can be differentiated from Meniere's disease. This condition was first reported simultaneously by Nadol, et al. and Wolfson and Leiberman, with further clarification by Schuknecht. The disease is characterized by a profound sensorineural hearing loss in one ear, with the onset of episodic vertigo from that ear after a prolonged period of time (ipsilateral delayed endolymphatic hydrops) or the development of fluctuating hearing loss and/or episodic vertigo in the opposite ear after a prolonged period of time (contralateral delayed endolymphatic hydrops). This paper is a review of 15 cases of delayed endolymphatic hydrops, eight ipsilateral and seven contralateral. The results of this study indicate that surgical treatment for the ipsilateral form of the disease gave the best results. For the contralateral variant, it appears that medical measures should be the therapy of choice resorting, in the event of their failure, to conservative surgical intervention on what may be the only hearing ear to preserve hearing and control vertigo.


Subject(s)
Meniere Disease/etiology , Adolescent , Adult , Deafness/complications , Diagnosis, Differential , Female , Follow-Up Studies , Humans , Labyrinth Diseases/diagnosis , Meniere Disease/diagnosis , Middle Aged , Time Factors
12.
Laryngoscope ; 98(2): 150-3, 1988 Feb.
Article in English | MEDLINE | ID: mdl-3339923

ABSTRACT

In this review of 925 cases of total and anterior perforations of the tympanic membrane reconstructed through the use of formaldehyde-formed-fascia (3-F) grafts, the postoperative nonperforation rate is 97.6%; blunting and/or lateralization of the graft was avoided in 93.5% of cases. Closure of the postoperative air-bone gap within 20 dB was achieved in 70% of cases. This update of a previously reported paper reinforces our opinion that the 3-F graft is an effective tool for the closure of tympanic membrane perforation with or without ossicular chain reconstruction.


Subject(s)
Tympanoplasty/methods , Adolescent , Adult , Aged , Child , Child, Preschool , Follow-Up Studies , Graft Survival , Humans , Middle Aged , Reoperation
14.
Am J Otol ; 8(4): 307-12, 1987 Jul.
Article in English | MEDLINE | ID: mdl-3631237

ABSTRACT

This study demonstrates the superiority of a valved implant (Denver-Arenberg valve) over simple sac decompression surgery for Meniere's disease. The valved implant has the advantage of better hearing results. Effectiveness in the relief of vertigo is equal for the two types of procedures. The phenomenon of enhanced high-frequency hearing gain has been observed only with valved implants. Rather spectacular hearing gains in a minority of patients have occurred primarily with the valved implant. Although the numbers are too small to draw any firm conclusions, it would seem that the valved implant is also useful in treating cochlear hydrops. Whether other therapeutic modalities will prove to be more beneficial than either of these procedures is not addressed in this article.


Subject(s)
Ear, Inner/surgery , Endolymphatic Sac/surgery , Prostheses and Implants , Adult , Aged , Audiometry/methods , Evaluation Studies as Topic , Female , Follow-Up Studies , Humans , Male , Meniere Disease/surgery , Middle Aged
16.
Laryngoscope ; 93(3): 326-40, 1983 Mar.
Article in English | MEDLINE | ID: mdl-6300574

ABSTRACT

Neoplasms in the external auditory canal (EAC) of ceruminous gland origin have been generally classified under the title of ceruminoma, which is inaccurate and misleading. There have emerged four distinct types of ceruminous gland tumors of the EAC. They are 1. ceruminous adenoma, 2. adenoid-cystic carcinoma, 3. ceruminous adenocarcinoma, and 4. pleomorphic adenoma (mixed tumor). The natural course and clinical approach to these tumors can be determined by accurate histopathologic evaluation. This paper presents 10 cases of tumors of glandular origin in the EAC, 4 cases being ceruminous adenomas, 3 cases being adenoid-cystic carcinomas, 2 cases being ceruminous adenocarcinoma, and 1 case of pleomorphic adenoma (mixed tumor). In reviewing these cases as well as those in the literature, a number of recommendations are suggested: 1. Identifying a tumor of the glandular structures of the EAC solely as a ceruminoma is no longer acceptable without accompanying histologic specificity. 2. Early wide excisional biopsy is imperative for diagnosis. 3. The signs and symptoms of the tumor do not always correlate with the histopathologic diagnosis and subsequent clinical behavior of these tumors. 4. Ceruminous adenoma and pleomorphic adenoma are benign tumors and are best treated only by wide local excision. 5. Adenoid-cystic carcinoma and ceruminous gland adenocarcinoma are pernicious, malignant tumors which are best treated, in general, by an initial aggressive wide en bloc surgical resection or, if there is extension to the middle ear and temporal bone, by resection of the temporal bone and contiguous structures. 6. Postoperative irradiation has an essential role in managing these malignant tumors. 7. Five year survival rates for the malignant tumors do not reflect the biological behavior pattern of "late" local and distant recurrence and metastasis.


Subject(s)
Ear Canal , Ear Neoplasms/diagnosis , Ear Neoplasms/surgery , Adenocarcinoma/diagnosis , Adenocarcinoma/surgery , Adolescent , Adult , Aged , Carcinoma, Adenoid Cystic/diagnosis , Carcinoma, Adenoid Cystic/surgery , Child , Ear Neoplasms/pathology , Female , Humans , Male , Middle Aged , Neoplasms, Germ Cell and Embryonal/surgery
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