Search

VII. ÖZET Çeşitli glokom olgularında göz içi basıncını kontrol etmek için kullanılan beta- bloker ilaçların burun mukozasından emilimi ile pulmoner yan etkiler de dahil olmak üzere çeşitli sistemik yan etkiler ortaya çıkabilmektedir. Bu çalışmada topikal olarak kullanılan timolol, betaxolol ve karteololün pulmoner fonksiyonlara etkileri solunum fonksiyon testleri (SFT) ile araştırıldı. Bu amaçla PAAG tanısı ile halen topikal beta-bloker kullanan 20 kişilik bir çalışma grubu oluşturuldu. Çalışma grubu oluşturulurken anamnezlerinde kronik astım ve obstrüktif akciğer hastalığı olanlar, akciğer fonksiyonlarını etkileyebilecek ilaç kullananlar ve sigara içenler çalışma kapsamına dahil edilmedi. Çalışma grubundaki hastalara 1 ay süre ile topikal % 0.5 timolol tedavisi uygulandıktan sonra SFT yapılarak kaydedildi. Daha sonra glokom biriminde göz muayenesi yapılarak ilacı değiştirildi ve topikal % 0.5 betaxolol tedavisine geçildi. Bir ay sonra spirometrik testler tekrarlanarak kaydedildi. Hasta glokom biriminde değerlendirilerek çalışma grubunda uygulanan son ilaç olan % V lik karteolol tedavisine geçildi, bir aylık karteolol tedavisini takiben spirometrik testler yinelendi. FVC, FEV1/FVC ve PEFR ölçüm değerlerinin istatistiki olarak irdelenmesinde üç ilaç arasında anlamlı bir fark bulunamadı (p>0.05). Topikal timolol uygulanan hasta grubunda FEV1 parametresi gerçek değerler ortalaması 1.84±0.23 İt. iken betaxolol grubunda 2.06+0.29 İt. ve karteolol grubunda ise 2.01 ±0.14 It.olarak bulunmuştur. FEV1 parametresinde topikal timolol uygulanımı ile betaxolol uygulanımı arasında istatistiki olarak anlamlı fark elde edildi (p0.05). FEF 25-75 parametresi gerçek değerler ortalaması timolol grubunda 2.52±0.36 İt/sn iken betaxolol grubunda 2.97±0.60 İt/sn ve karteolol grubunda ise 2.76±0.55 İt/sn olarak bulunmuştur. FEF 25-75 parametresi bakımından timolol grubu ile betaxolol grubu arasında istatistiki olarak anlamlı farklılıklar bulundu (p0.05). Topikal betaxolol kullanımı ile karteolol kullanımı arasında da FEF 25-75 parametresi bakımından istatistiki bir fark bulunamadı (p>0.05). 37 44

The effects of 6 weeks of treatment with dilevalol 100 mg once daily, or carteolol 10 mg once daily, on renal blood flow (RBF), glomerular filtration rate (GFR) and total renal vascular resistance (TRR) were studied in 10 patients with mild-to-moderate essential hypertension in a randomised cross-over experiment. Both drugs lowered the systolic and diastolic blood pressures to a similar extent without altering the heart rate. Carteolol non-significantly decreased RBF by 9.2% and GFR by 12.3% without altering. TRR, whereas dilevalol produced a significant reduction in TRR by 13.2% (p less than 0.05), a non-significant decrease in RBF by 4.6% and no change in GFR. Neither drug changed plasma osmotic pressure, serum total protein concentration, electrolytes or plasma aldosterone concentration. Plasma renin activity tended to be lower in the dilevalol phase as compared to the carteolol phase. The results suggest that dilevalol may cause a greater decrease in TRR and less reduction in GFR when compared to carteolol in patients with mild-to-moderate essential hypertension. The difference in the renal effects might be due to the difference in the potency of vasodilatory properties of both drugs at the doses applied.

The effect of systemic application of carteolol, which induces almost the same plasma carteolol level as obtained by a long-term instillation on rabbit eyes, on the tissue blood flow in the optic nerve head (ONH) was investigated in rabbits. The plasma carteolol levels in 27 rabbits which received 3-week instillation, intravenous injection (10, 20, 30 micrograms/kg), or continuous intravenous injection (2.5, 5, 20, 40, 80 micrograms/kg/hr) were measured by gas chromatography-negative-ion chemical ionization mass spectrometry. The plasma level with 3-week instillation was determined as 5.55 ng/ml and a continuous intravenous injection (5 micrograms/kg/hr) caused nearly the same plasma level. The intravenous injection of this dose significantly increased the ONH blood flow which was determined by the hydrogen clearance method, compared with controls from 30 minutes to 2 hours after the injection (n = 10). The vascular resistance in ONH was thought to be reduced because mean blood pressure and intraocular pressure (n = 6) were not significantly changed. The results suggest that the plasma carteolol level in rabbits after a long-term instillation can increase ONH blood flow due to a decreased vascular resistance.

The effect of a single instillation of topical carteolol on iridial tissue circulation of pigmented rabbits was studied. The blood flow rate and a quantitative index of tissue blood velocity (NBiris) were measured simultaneously, using the microsphere technique and the laser speckle method, before and 2 hours after the instillation of 20 microliters of 2% carteolol or the vehicle. Consecutive changes of intraocular pressure and NBiris were also studied at 30-minute intervals for 2.5 hours after a single instillation of 2% carteolol in one eye and the vehicle in the contralateral eye. To provide a control, intraocular pressure and NBiris were measured according to the same schedule after the vehicle instillation in both eyes. Two hours after carteolol instillation, iridial blood flow rate and NBiris significantly increased to 127 +/- 8% and 122 +/- 9% (mean +/- SEM, n = 8) of the baseline. Unilateral instillation of carteolol significantly reduced intraocular pressure by about 9 mm Hg in both the carteolol- and vehicle-treated eyes (P < 0.001, analysis of variance); and NBiris was significantly increased by about 20% in both eyes (P < 0.001, analysis of variance), compared with control eyes.

The microdialysis method was used to evaluate the pharmacokinetics of the beta-adrenergic antagonists carteolol and timolol and the new ophthalmic solution WP-934 in rabbit aqueous humor, following instillation. A probe with a microdialysis membrane (length, 5 mm; diameter, 0.2 mm) was implanted in the anterior chamber of the pigmented rabbit and perfused with Ringer's solution. Twenty microliters of 0.5% timolol maleate (0.5% Timoptol(R)), 2% carteolol hydrochloride (2% Mikelan(R)), or a novel preparation of 0.5% timolol maleate (WP-934) that gels after instillation were then instilled. The concentrations of these drugs in dialysates were measured using high-performance liquid chromatography and an electrochemical detection system. In vitro relative recovery of the membrane with timolol and carteolol was approximately 17.5% and 21. 6%, respectively. Timolol and carteolol levels in aqueous humor increased rapidly after instillation of Timoptol and Mikelan and reached maximal levels (Cmax) within 60 minutes. The Cmax of carteolol (4.25 microg ml-1) was lower than that of timolol (5.52 microg ml-1), suggesting that the corneal permeability of timolol is higher than that of carteolol. After instillation of WP-934, the Cmax of timolol (12.32 microg ml-1) was 2.2-fold higher than that after instillation of Timoptol. However, t1/2 values of beta-adrenergic antagonists after instillation of the three preparations were not significantly different. These data suggest that the microdialysis technique is useful for continuous monitoring of aqueous levels of beta-blockers and for analysis of their pharmacokinetic parameters while requiring much fewer animals than conventional sampling with paracentesis.

Urine specimens containing 11 common beta blockers were processed using solid-phase extraction technology to extract the drugs from the urine matrix, then converted to their cyclic methaneboronates by treatment with methaneboronic acid in ethyl acetate. The compounds tested included acebutolol, atenolol, alprenolol, bisoprolol, betaxolol, carteolol, penbutolol, propranolol, pindolol, timolol, nadolol, sotalol, labetolol, metoprolol, and oxprenolol. The extraction efficiencies were greater than 90% for all drugs tested. The cyclic methaneboronates formed by this procedure generally possessed good chromatographic properties. The mass spectral behavior of the methaneboronates was excellent, with all compounds containing several high mass fragments and every tested compound possessing a unique mass spectrum.

The effect of topical 2% carteolol on tissue circulation in the albino rabbit optic nerve head (ONH) was investigated using a laser speckle tissue circulation analyzer. In the first experiment, the normalized blur (NB) value, a quantitative index of tissue blood flow velocity in the ONH, intraocular pressure (IOP), blood pressure (BP), and pulse rate were measured under general anesthesia before as well as 30, 60, 90, and 120 minutes after a 20-microL instillation of carteolol in one eye and the vehicle in the other eye in a masked, randomized manner. In the second experiment, one eye of a rabbit received carteolol twice daily for 20 days and the fellow eye received the vehicle in a masked, randomized manner. The IOP was measured every 5 days, and the NB in the ONH and IOP were measured before treatment and 2 hours after the last instillation on the 20th day. After a single instillation of carteolol, pulse rate showed a maximum reduction of 15%, and IOP in the carteolol-treated eyes showed a maximum decrease of 22%. The NB in the ONH and BP did not show any significant change during the experiment. After 20-day treatment with carteolol, IOP showed a maximum decrease of 25% in the carteolol-treated eyes and 21% in the vehicle-treated eyes. The NB showed a significant increase of 15% (P < 0.01) in the carteolol-treated eyes and 11% (P < 0.01) in the vehicle-treated eyes. It was indicated that long-term topical carteolol increased the blood velocity in the ONH tissue both in the carteolol- and vehicle-treated contralateral eyes in albino rabbits.

To compare the efficacy and safety of a newly developed ophthalmic solution containing carteolol 2% and pilocarpine (2% (CBS341A) with a timolol 0.5% and pilocarpine 2% fixed combination. A randomized, double-masked, multicenter study was conducted in 209 patients with primary open-angle glaucoma or ocular hypertension, whose intraocular pressure (IOP) was higher than 21 mm Hg on bet-blocker twice a day alone. The test medications were administered twice daily for 4 months. IOP was measured at 9 and 11 a.m. at the beginning of the study (with beta-blocker alone) and after one and four months of treatment. Adverse effects were recorded. Both combinations caused a similar, statistically significant decrease in IOP. At four months, in the CBS341A group a 2.4 mm Hg (9%) reduction in IOP was achieved at 9 a.m. and 4.1 mm Hg (17.3%) at 11 a.m. compared with respectively 3 mm Hg (11%) and 4.5 mm Hg (19.5%) in the timolol-pilocarpine group. No statistical difference was observed between the two groups in safety and efficacy. The carteolol-pilocarpine combination appears as safe and as effective as the timolol-pilocarpine combination in the medical treatment of primary open-angle glaucoma or ocular hypertension.

32 ÖZET U.Ü. Tıp Fak. Göz Hastalıkları Anabilim Dalı Glokom biriminde Kasım 1992-Temmuz 1998 tarihleri arasında üç grupta izlenen PAAG toplam 42 hastanın 79 gözüne timolol maleate % 0.5, betaxolol % 0.5 ve carteolol % 2 tedavileri uygulanmıştır. PAAG tanısı, GİB 22mmHg ve üstünde olması, glokomatöz görme a- lanı defekti ya da optik sinir başında çukurlaşma, kriterlerinden en az ikisi temel alınarak yapılmıştır. Timolol'dan başka topikal veya sistemik beta bloker almış olanlar, trisiklik anti depresan ve monoaminoksidaz inhibitörü (MAOI) alanlar çalışma kapsamı dışında bırakıldılar, tekrarlayan solunum rahatsızlığı ve ileri derecede kalp rahatsızlığı bulunanlarla, periferik vasküler hastalığı olanlar, okular enfeksiyon ve enflamasyonu olanlar korneal travma sı ya da göz içi cerrahisi geçirenler çalışma dışı bırakıldı. Ayrıca sekonder ve dar açık glokomlu olgular, kontakt lens kullananlar, diabetik retinopatisi olanlar, `myastenia graves`i olanlar, belirgin kataraktlı hastalar çalışmaya alınmamıştı Glokom birimimizde her üç ayda düzenli kontrol muayeneleri yapılan hastalardan GA'ları stabil olanların 6 ay-1 yıl aralıklarla, instabil olanların 3 ayda bir olmak üzere Humphrey bilgisayarlı perimetreyle görme alanı mua yeneleri alınmıştır. Görme alanı muayeneleri HFA, STATPAC-1 in tam eşik değer strateji sini uygulayan santral 24-2 ve 30-2 eşik değer programlarıyla çapı III olan beyaz üzerine beyaz uyaran kullanılarak yapıldı. Görme alanı kayıpları, generalize ortalama hassasiyet kaybını ifade eden `mean deviation`(MD) ve lokalize görme alanı kaybı ifade eden `corrected standart pattern derivasyon`(CSPD) ve `Advanced Glaucoma Intervention Study` (AGIS) yöntemleriyle değerlendirilmiştir. Gruplar arasında, demografik yönden carteolol grubunda kadın/erkek oranın fazla olması dışında farklılık yoktu. GİB, timolol olan grupta tedavi öncesi dönemde 22-28 mmHg ortalama 23.52±1.97 mmHg, betaxolol alan grupta 22 -31 mmHg ortalama 24.12±2.45 mmHg, carteolol alan grupta 22 - 28 mmHg ortalama 23.14+1.45 mmHg idi. Tedavi süresince timolol alan33 grupta GİB 11-23 mmHg, betaxolol alan grupta 13 mmHg-24 mmHg, carteolol grubunda 12-24mmHg arasında değişmekteydi. Ortalama takip süresi timolol grubunda 37 (15 -55 ay), betaxolol gru bunda 40 ay (15 -62ay), carteolol % 2 grubunda 25 ay (18-33 ay) idi. Görme alanı muayeneleri arasındaki ortalama süre timolol grubun da; 10,5ay (2-22,5ay),betaxolol grubunda; 10 (4-19,5ay), carteolol grubunda; 10ay (5-16,5ay)idi. 15 Aylık izlem süresinde ilk 3 ayda timolol, carteolol grublarında daha belirgin olmak üzere, her üç grupta da ortalama GİB' larında başlangıca göre belirgin bir düşme görüldü(p0,05). 3.- 6. Aylar arasında carteolol grubundaki ortalama GİB düşüşü, betaxolol ve timolol gruplarından daha fazlaydı. Fakat gruplar arası karşılaştırma istatistiki olarak anlamlı değildi(p>0,05). 6. aydan sonra her üç grubun kendi içindeki ortalama GİB'larında belirgin düşüş gözlenmedi(p>0,05). Gruplar arasındaki karşılaştırmalarda istatistiki anlamlı lık tespit edilmedi. (p>0,05) Timolol maleate % 0.5 grubunda 8 hastanın 12 gözünde(% 52.17), % 0.5 betaxolol grubundaki 12 hastanın 19 gözünde(% 76), Carteolol % 2 grubunda ise 6 hastanın 7 gözünde (% 33.3) GİB düşürmede ve görme a- lanlarında ortalama hassasiyet kaybını engellemiştir. Gruplar içi tedavi öncesi ve tedavi sonu yapılan karşılaştırılmalarda betaxolol'un, timolol ve carteolol gruplarına göre ortalama hassasiyet kaybını azaltmada istatistiki olarak an lamlı olduğu tespit edilmiştir(p0. 05). Gruplar arası karşılaştırmada da istatistiki anlamlılık tespit edilmemiştir(p>0, 05)34 AGİS yöntemiyle her bir grubun başlangıç ve tedavi sonu yapılan karşılaş tırmalarında, timolol grubundan 10 hastanın 15 (%65.21) gözünde, betaxolol grubundaki 14 hastanın 23(%92) gözünde, carteolol grubundaki 11 hastanın 18 (%85.71) gözünde görme alanları korunmuş veya düzelme gös terildi. Gruplar içi başlangıç ve tedavi sonu AGİS dereceleri karşılaştırıldığın da betaxolol grubunda istatistiki anlamlılık mevcutken (p0,05). Gruplar arası karşılaştırmada betaxolol grubunun görme alanlarındaki düzelme ve stabilizasyon, timolol grubuna göre istatis tiksel olarak anlamlı bulunurken(p0.05). Timolol ve carteolol grubları arasındaki karşılaştırmada istatistiki anlamlılık yoktu(p>0,05). Carteolol % 2 grubunda 1 hastada ilaca bağlı uykusuzluk, bir hastada da aşın kaşıntı ve kızarıklık görüldü. Diğer gruplarda yan etki görülmedi. Çalışmamızda lokalize görme alanı kayıplarını önleyici etkisinin betaxolola göre daha az, fakat timolola göre anlamlı olduğu, lokalize ve diffüz GA kayıplarını değerlendirmede etkili yöntem olan AGİS ile de carteoloPun betaxololdan sonra GA progresyonunda üstünlüğü izlenmiştir. Bu çalışmada carteolol'un betaxolola iyi bir alternatif olabileceğini göstermektedir. 47

AIM—A crossover, randomised double blind study was undertaken in 30 healthy volunteers, in order to compare the tolerance of 2% carteolol with and without preservative in short term use. METHODS—Complete ophthalmic examinations were performed before and 30, 60, and 180 minutes after instillation of one drop of the solution, and after 3 days of preservative treatment. After a 5 day washout, the same examinations were done with the second drug. RESULTS—Results showed good general tolerance for both formulations. No significant difference in subjective tolerance, corneal aesthesiometry, punctuate keratitis, Schirmer's test, intraocular pressure (IOP) decrease (about 25% in the two groups at 3 hours, 10% after 3 days of treatment), resting cardiac frequency, or blood pressure was observed. However, break up time was significantly reduced from baseline by preserved carteolol both at 3 hours (10.40 (5.9) seconds to 6.15 (3.9) seconds, p=0.001) and after 3 days (7.72 (5.5) seconds, p=0.04). Preservative free carteolol did not significantly change the break up time (baseline 9.08 (5.7) seconds; 3 hours = 7.88 (5.5) seconds, not significant; day 3 = 8.35 (5.8), non-significant). CONCLUSIONS—These results confirm that carteolol is well tolerated, either with or without preservative. The preservative free group showed better stability of the tear film, without loss of effect on IOP. This difference, although mild in the healthy young subjects in the present study could be much more relevant in those patients treated long term, older patients, and/or those suffering from ocular surface disorders. In such instances, preservative free drugs could be of potential benefit to protect the lacrimal fluid integrity and corneoconjunctival surface. Keywords: glaucoma; carteolol; benzalkonium; preservatives; β blockers

48 ÖZET Günümüze kadar glokom tedavisinde bir çok ilaç kullanılmıştır. Son 20 yıldır gündemde olan topikal beta blokerler ise günümüzde, OH ve PAAG'un tıbbi tedavisinde ilk tercih edilen ajanlar olmuşlardır. Oftalmologlara selektif olmayan beta bloker tercihlerinde yardımcı olabilmek amacıyla halen ülkemizde bulunan % 0.5 timolol maleat, % 2 carteolol ve % 0.3 metipranololu ele alarak bu üç ilacın GİB ve görme alam üzerine etkileri ile oküler ve sistemik yan etkilerinin karşılaştırıldığı kapsamlı bir klinik çalışma planladık. Çalışmamızda ilk olarak % 0.5 timolol maleat, % 2 carteolol ve % 0.3 metipranolol göz damlaları her bir hasta grubuna ayrı ayrı uygulanarak, GİB düşürücü etkileri 15.,30.,60. ve 90. günlerin 2.,6. ve 12. saatlerinde ölçülerek tedavi öncesi değerler ile karşılaştırıldı. Her üç ilacın da GİB'nı istatistiksel olarak anlamlı derecede49 düşürdüğü, en fazla düşüşün 2. saat, en az düşüşün ise 12. saatte olduğu fakat etkinin yeterli derecede devam ettiği saptandı. 3 aylık takip süresince hiçbir hastaya ek glokom ilacı başlanılmadı. İlaçlar birbirleriyle karşılaştırıldığında, 15. günün 2. ve 6. saatlerinde metipranolol, 15. gün 12. saat ve diğer bütün muayene gün ve saatlerinde ise timolol maleatda GİB düşüşünün daha belirgin olduğu saptandı. Bu ilaçların GİB düşürücü etkileri 15.,30.,60. ve 90. günlerin 2.,6. ve 12. saatlerinde karşılaştırıldığında ise, 15. gün 12. saatinde timolol maleatın carteolola göre anlamlı derecede daha etkili olduğu, timolol maleat ve metipranolol ile carteolol ve metipranolol arasında ise anlamlı farklılığın olmadığı bulundu. Diğer bütün muayene gün ve saatlerinde beta blokerlerin aralarında anlamlı farklılık göstermediği saptandı. Selektif olmayan beta bloker ilaçların, tedavinin 1. haftasında ve 3. ayında görme alam üzerindeki etkileri karşılaştınldığmda anlamlı değişikliğin olmadığı saptandı. Görme alam farklılığı açısından ilaçlar kendi aralarında karşılaştırıldığında da anlamlı farklılık bulunamadı. Selektif olmayan beta bloker ilaçların oküler sübjektif yan etki gelişme açısından birbirleriyle karşılaştırıldığında anlamlı farklılığın görülmediği saptandı. Ayrıca bu ilaçların objektif yan etkilerine de rastlanılmadı. Selektif olmayan beta bloker ilaçların kardiyovasküler, gastrointestinal ve santral sinir sistemine ait yan etkileri de gözlenmedi. Bu ilaçların her birinin kullanımına bağlı olarak HDL, total kolesterol düzeylerinde anlamlı bir azalmanın, trigliserid düzeylerinde ise anlamlı bir artışın olduğu, kan lipidleri üzerindeki değişiklik açısından birbirleriyle karşılaştırıldığında ise anlamlı bir farklılığın olmadığı saptandı. Ayrıca bu ilaçlatın uygulanmasına bağlı olarak SFT'nde anlamlı olmayan bir azalmanın ortaya çıktığı, birbirleriyle karşılaştırıldığında ise yine anlamlı bir farklılığın olmadığı görüldü.50 Sonuç olarak yaptığımız bu klinik çalışmada kullanılan üç ilacın GİB ve görme alam üzerine olan etkilerinin birbirlerinden anlamlı farklılık göstermediği ancak daha uzun süreli yapılacak çalışmalarda görme alam üzerindeki etkilerin daha iyi değerlendirilebileceği, tedaviye devam etme konusunda oküler sübjektif ve objektif yan etkilerin önemli rol oynayabileceği, bununla birlikte serum HDL ve total kolesterolü düşürürken trigliserid seviyesini yükseltmeleri nedeniyle özellikle aterosklerotik hastalarda bu parametrelerin takibinin uygun olacağı kanaatindeyiz. 51 SUMMARY Until now, a lot of drugs have been used in the treatment of glaucoma. Topical beta blockers, used for last 20 years, have become the first choice in the medical treatment of OH (Ocular hypertension) and POAG (Primary open angle glaucoma). In order to help ophtalmologists in their preference, we have planned an extensive clinical study to compare the effects of % 0.5 timolol maleate, % 2 carteolol and % 0.3 metipranolol, which are currently available non-selective beta blockers in our country, on IOP and visual field and also the systemic and ocular side effects. Each group of patients received topical % 0.5 timolol maleate, % 2 carteolol and % 0.3 metipranolol, separately, and IOP (Intraocular pressure) lowering effects with the measurements taken at the 2, 6 and 12 hours were compared between the pre- treatment and the 15th, 30th, 60* and 90& days of treatment periods. All the drugs lowered the IOP significantly with the most profound decrease at the 2 n hour and the52 least at the 12 hour having sufficient continuity of effects. No other additional drag for glaucoma has been started during the follow-up of three months. In the comparison of drags, metipranolol at the 2a and 6* hours of the 15 day and timolol maleate at the 12 hour of the 15* day and at all the hours of all the other days were found to create the most profound decrease in IOP. When the IOP lowering effects of these drugs were compared at the 2nd, 6* and 12th hours of the 15* 30*, 60* and 90* days, timolol maleate was found to be significantly more effective than carteolol at the 12 hour of 15 day and there was no significant difference between metbypranolol and the other drags. There was no significant difference between the beta blockers in the other measurement hours of other days. There was no significant change when the effects of drugs on the visual field were compared in the first week and 3r month of the treatment. When the drugs were compared for the effects on the visual field, there was no significant difference between the drugs. There was no difference between the non-selective beta blockers in the development of subjective ocular side effects. There was no objective ocular side effects of the drags, either. There was no cardiovascular, gastrointestinal or central nervous system side effects of the non-selective beta blockers. The use of each drag caused significant decreases in the levels of HDL and total cholesterol and significant increase of triglyceride levels; however, the comparison between the drags for the effects on plasma lipids revealed no significant difference. In addition, FEV-1 (l.sec.forced expretory volume) decreased insignificantly with the use of all the drags, again without any significant difference between the drags.53 As a result, the drugs used in the this study were not different from each other for their effects on visual field and IOP. However, the effects on visual field will be better evaluated with long term studies. The subjective and objective ocular side effects may play a role in the decision to continue the treatment. In addition, serum HDL, total cholesterol and triglyceride levels must be closely followed in atherosclerotic patients due to the effects of drugs to decrease HDL and total cholesterol and to increase triglyceride levels. 57

To investigate the effects of carteolol, which is a nonselective beta-adrenergic agent with intrinsic sympathomimetic activity, on silent myocardial ischemia, exercise-induced myocardial ischemia, indexes of heart rate variability, and pain-modulating system, 20 patients (mean 60 +/- 9 years) with chronic stable angina underwent exercise treadmill testing and 24-hour ambulatory electrocardiographic monitoring during 2 weeks of carteolol administration (15 mg/day) in a double-blind, placebo-controlled design. Plasma levels of beta-endorphin and bradykinin and electrical pain stimulation to the skin were measured at rest and peak exercise. Indexes of heart rate variability of both time-domain and frequency-domain analysis were derived from 24-hour ambulatory electrocardiographic monitoring. Carteolol decreased maximal heart rate responses to daily activities during ambulatory monitoring and significantly reduced the median frequency and duration of silent myocardial ischemic episodes (from 1.0 to 0.0 events/24 hr and from 16 to 0 min/24 hr, respectively). Carteolol significantly decreased the rate-pressure product at rest and during exercise with improving maximal ST segment depression, suggesting amelioration of exercise-induced myocardial ischemia. Carteolol did not significantly affect plasma levels of beta-endorphin and bradykinin or pain threshold. It significantly decreased some indexes (standard deviation of all normal sinus R-R intervals in the entire 24-hour recording and standard deviation of the mean of all 5-minute segments of normal R-R intervals of a 24-hour recording) of heart rate variability. These results suggest that carteolol may reduce total myocardial ischemic burden by the reduction of cardiac oxygen demand during daily activities and exercise stress, while not affecting plasma levels of beta-endorphin, bradykinin, and pain threshold. Because carteolol tended to decrease indexes of heart rate variability, significant caution might be necessary in prescribing the beta-blocking agents with intrinsic sympathomimetic activity like carteolol to patients with potential serious arrhythmia.

To study the effect of topical 0.5% timolol and 2% carteolol on tissue blood flow in the human optic nerve head (ONH).Using a laser speckle tissue blood flow analyzer, normalized blur (NB), a quantitative index of tissue blood velocity, was measured every 0.125 s in the temporal site of the ONH free of visible surface vessels and averaged over 3 cardiac pulses (NBONH). To serve as a baseline, NBONH and intraocular pressure (IOP) in both eyes, blood pressure (BP) and pulse rate (PR) were recorded in healthy volunteers before, 1.5, 3 and 4.5 hrs after a 30L instillation of the vehicle of timolol or carteolol. From the following day and twice daily for 3 weeks, 30L of either 0.5% timolol or 2% carteolol was instilled into one eye and the respective vehicle into the fellow eye in a masked manner. NBONH, IOP, BP and PR were again recorded on the 21st and last experiment day. IOP was also recorded on the 7th and 14th days. Carteolol concentration in the plasma was also recorded after instillation of carteolol on the 21st day.During the baseline experiments, all the parameters recorded showed no significant change. After topical timolol, IOP was significantly reduced bilaterally with more reduction in the timolol-treated eye. Bilateral NBONH, BP and PR showed little change on the 21st day. After topical carteolol, IOP was significantly reduced bilaterally with more reduction in the carteolol-treated eyes on the 21st day. NBONH in the carteolol- and vehicle-treated eyes was significantly higher on the 21st day than recorded in the same eye in the baseline experiment (P = 0.013 and 0.047), while BP and PR showed little change. The maximum carteolol concentration in plasma at 3 hrs on the 21st day averaged 1294 pg/ml.Results indicated that 3-week twice daily topical timolol treatment had no deleterious effect on the ONH tissue blood flow in the human eye, and that 3-week twice daily topical carteolol treatment may increase the tissue blood flow in the human ONH.

The effects of nicotinic and beta-adrenergic receptor antagonists on tail-tremor induced by repeated nicotine administration were investigated in rats. The daily administration of nicotine (0.5 mg/kg/day, s.c.) for 8 days resulted in an augmentation of tail-tremor. However, repeated administration of dimethyl phenyl piperazinium iodide (1 mg/kg/day, s.c.) for 8 days did not cause tail-tremor. Mecamylamine (0.5 mg/kg, i.p), administered before the nicotine injection on each day, abolished the tail-tremor. After discontinuation of the mecamylamine treatment, nicotine injections caused tail-tremor augmentation. Propranolol (20 mg/kg, i.p.), administered before the nicotine on each day, suppressed the appearance of tail-tremor. After the discontinuation of propranolol treatment, the degree of tail-tremor induced by a single injection of nicotine on day 9 was much greater in the propranolol-treated group than in the saline-treated control group. Neither carteolol (20 mg/kg, i.p.) nor metoprolol (20 mg/kg, i.p.) treatment showed such effects. Intraspinal injection of 6-hydroxydopamine markedly enhanced the tail-tremor induced on the first day of nicotine injection. This effect became more intense on subsequent administration of nicotine. The enhanced tail-tremor following 6-hydroxydopamine treatment was abolished by mecamylamine (0.5 and 1 mg/kg, i.p.), and was suppressed by propranolol (5-20 mg/kg, s.c.) in a dose-dependent manner. These results suggest that central nicotinic receptors are essential for the onset and for the further development of tail-tremor induced by the repeated administration of nicotine, and that beta 2-adrenoceptors are associated with the tremor mechanism. Moreover, spinal noradrenergic mechanisms may be involved in the manifestation of this phenomenon.

It is known that beta-adrenoceptor antagonists are effective in the treatment of akathisia, one of the extrapyramidal side effects that occur during neuroleptic treatment. Neuroleptic-induced catalepsy, a model of neuroleptic-induced extrapyramidal side effects, was considered suitable as a model for predicting neuroleptic-induced akathisia in humans, although neuroleptic-induced catalepsy was not considered a specific test for neuroleptic-induced akathisia. Therefore, the effects of carteolol, a beta-adrenoceptor antagonist, on haloperidol-induced catalepsy in rats were behaviorally studied and compared with those of propranolol and biperiden, a muscarinic receptor antagonist. Carteolol, as well as propranolol and biperiden, inhibited the haloperidol-induced catalepsy. The inhibitory effect of carteolol was almost comparable to that of propranolol, but was weaker than that of biperiden. Carteolol did not evoke postsynaptic dopamine receptor-stimulating behavioral signs such as stereotypy and hyperlocomotion in rats. Carteolol did not antagonize the inhibitory effects of haloperidol on apomorphine-induced stereotypy and locomotor activity in rats. In addition, carteolol did not evoke 5-HT1A receptor-stimulating behavioral signs such as flat body posture and forepaw treading and did not inhibit 5-hydroxytryptophan-induced head twitch in rats. Finally, carteolol did not inhibit physostigmine-induced lethality in rats. These results strongly suggest that carteolol improves haloperidol-induced catalepsy via its beta-adrenoceptor antagonistic activity and is expected to be effective in the treatment of akathisia without attenuating neuroleptic-induced antipsychotic effects due to its postsynaptic dopamine receptor antagonistic activity.

1. Carteolol, a non-selective beta-blocker with intrinsic sympathomimetic activity, admixed in a pellet diet was administered to Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of spontaneous non-insulin-dependent diabetes mellitus with mild obesity. A high dose of carteolol (0.02%) suppressed bodyweight gain without affecting food and water consumption until the appearance of glycosuria. Carteolol tended to reduce the cumulative incidence of glycosuria at 26 weeks after the beginning of administration (55, 17 and 25% in control rats, and in rats fed a low (0.002%) and high dose of carteolol, respectively). 2. At the 26th week of administration, the high dose of carteolol decreased visceral fat weight, such as that of retroperitoneal and epididymal adipose tissue, whereas the liver and the kidney were not affected. 3. Although plasma glucose and triglyceride levels in non-fasted rats were elevated with age, carteolol tended to delay the increases in those parameters. Carteolol suppressed the increase in plasma glucose levels, which indicate the diabetic pattern, in a 25th week oral glucose tolerance test. 4. These findings indicate that carteolol induces improvements in bodyweight and carbohydrate and lipid metabolism in an obese condition. Consequently, carteolol may be useful for the treatment of hypertension with obesity in order to prevent cardiovascular events.

To compare the effects of topical timolol maleate 0.5% and carteolol hydrochloride 1% on pulse rate and blood pressure.In a randomized, double-masked, parallel-design, multicenter clinical trial, we compared the effects of timolol and carteolol on pulse rate and blood pressure measured by 24-hour ambulatory blood pressure monitoring in 169 adult patients with either ocular hypertension or primary open-angle glaucoma.From noon to 8 PM, baseline mean pulse rate of 82 to 83 beats per minute (bpm) had decreased by 4 to 6 bpm in both groups after 4 weeks of therapy with timolol or carteolol. From midnight to 4 AM, the pulse rate in the carteolol group was significantly above baseline (P = .005), while the timolol group was significantly below baseline (P.001). Four times as many patients became bradycardic (heart rate,60 bpm) on timolol (18.4%) as did patients on carteolol (4.5%) from midnight to 4 AM. More than twice as many patients exhibited a resolution of their bradycardia with carteolol (46.7%) as did patients treated with timolol (18.2%) from midnight to 4 AM. Overall cardiovascular adverse effects were reported significantly more frequently in the timolol than the carteolol group (P = .002).Timolol causes significantly lower mean heart rate during the nighttime and more nocturnal bradycardia than carteolol does in patients with ocular hypertension and primary open-angle glaucoma. These differences may be because of the intrinsic sympathomimetic activity of carteolol.

Although topical beta-blockers are generally tolerated, they can produce significant systemic side effects. The systemic side effects of nonselective beta-blockers (eg, timolol, carteolol) are primarily related to the cardiovascular (beta 1-adrenergic) and respiratory (beta 2-adrenergic) systems. Carteolol has intrinsic sympathomimetic activity, which theoretically reduces the risk of adverse effects through beta blockade. It has been reported that topical timolol and carteolol unfavorably alter the lipid profile and that the effects of carteolol are less pronounced than those of timolol. Topical beta-blockers are associated with systemic events, not only acting by themselves, but also interacting with other drugs (eg, quinidine) administered orally or intravenously. To reduce systemic absorption and adverse effects, new preparations of beta-blockers, such as timolol gellan, have been developed. We should always bear in mind the potential systemic effects of topically applied beta-blockers in glaucoma therapy.

The effects of carteolol hydrochloride on visual function in normal-tension glaucoma (NTG) were investigated. 22eyes of NTG patients were divided into two groups, i.e., (1) a group receiving topical application of 2% carteolol hydrochloride b.i.d. and 2 an unmedicated group. During a 18 month period, intraocular pressure and visual field (measured by Humphrey automated perimetry) were measured every 3 months, and the measurements obtained in the two groups were compared. Analysis of the results revealed a considerable reduction in intraocular pressure in the carteolol group as compared with the control group. The progression of mean deviation tended to be less in the carteolol group, but the intergroup difference in this respect was not statistically significant. However, increase in corrected pattern standard deviation was clearly less pronounced in the carteolol group than in the control group. These results supported the conclusion that carteolol is effective in inhibiting deterioration of the local visual field. This is attributed to increased ocular perfusion due to diminished intraocular pressure, as well as an inhibitory effect upon vasoconstriction in the optic nerve head due to intrinsic sympathomimetic activity, preventing decrease in papillary blood flow and adverse effects upon ocular circulation.

It has been found that long-term therapy with topical antiglaucoma drugs may decrease the success of glaucoma filtering surgery. In this study, various antiglaucoma drugs, including carteolol, betaxolol, levobunolol, pilocarpine, and timolol, were investigated for their proliferative effect on cultured human Tenon's fibroblast cells. It was found that the 3H-thymidine uptake of cultured fibroblast cells was inhibited by commercial antiglaucoma drugs, including carteolol of 0.1% concentration (13%), 0.01% (50%) and 0.001% (53%), betaxolol of 0.05% concentration (14%), 0.005% (42%) and 0.0005% (62%), levobunolol of 0.05% concentration (2%), 0.005% (32%) and 0.0005% (55%), and timolol of 0.025% concentration (4%), 0.0025% (47%) and 0.00025% (55%), whereas the 3H-thymidine uptake was increased by commercial pilocarpine eyedrop from 103% (0.2% of concentration), 170% (0.02% of concentration) to 171% (0.002% of concentration), when cells were treated with commercial drugs for 100 min. Meanwhile, the proliferations of cultured fibroblast cells were stimulated by simultaneously combining 0.2%, 0.02% and 0.002% concentrations of pilocarpine eyedrops with other antiglaucoma drugs, such as carteolol of 0.1% concentration (50%), 0.01% (113%) and 0.001% (138%), betaxolol of 0.05% concentration (24%), 0.005% (128%) and 0.0005% (142%), levobunolol of 0.05% concentration (32%), 0.005% (87%) and 0.0005% (119%), and timolol of 0.025% concentration (15%), 0.0025% (94%) and 0.00025% (118%). Following incubation with pure pilocarpine, the proliferation of Tenon's fibroblast cells was inhibited for 84% (0.2% concentration), 84% (0.02% concentration) and 90% (0.002% concentration). When fibroblast cells were treated with commercial pilocarpine eyedrops for 24 hours, the 3H-thymidine uptake was increased to 160% (0.02% concentration) and 172% (0.002% concentration). This result shows that the commercial pilocarpine may play a crucial role for the proliferation of cultured human Tenon's fibroblast cells.

Ocular membranes have been characterized by in-situ absorption of the ophthalmic β-blockers carteolol (hydrophilic) and timolol and befunolol (lipophilic) using a cylindrical cell. After introduction of drug solution into the cell on the cornea, sclera (bulbar conjunctival and scleral layer) or palpebral conjunctiva, the disappearance of the drug from the cell was determined as in-situ absorption. The ophthalmic drugs disappeared from the conjunctival and scleral membranes although disappearance from the cornea was hardly observed. The conjunctival membrane showed the highest permeability. Lipophilic drugs were more permeable than hydrophilic. In-situ apparent permeability coefficients of the ophthalmic drugs through the conjunctiva and sclera correlated with the lipophilicity of drugs. A high drug concentration in the aqueous humor was observed after corneal application. There is a relationship between concentrations of drugs in the aqueous humor and previously reported in-vitro apparent permeability coefficients of the drugs in the cornea. This in-situ method using a cylindrical cell is a useful method of investigating the ocular absorption of ophthalmic drugs.

We investigated the effects of the topical ocular hypotensives with or without half circumference argon laser trabeculoplasty (ALT) on intraocular pressure (IOP) of normal-tension glaucoma (NTG) eyes. Seventy-two NTG patients whose pretreatment mean IOP wasor = 15 mmHg at least in one eye were included and one randomly chosen eye from one patient were used for analysis. They were followed for at least 15 months after commencement of the therapy. The mean pretreatment IOP averaged 17.2 +/- 1.6 mmHg (mean +/- standard deviation, n = 72). All eyes were first treated with topical 2% carteolol. In eyes where IOP reduction was considered unsatisfactory, topical 1% pilocarpine or 0.04% dipivefrine was added. In eyes where IOP reduction was still unsatisfactory even with the two medications, half circumference ALT was performed. Mean IOP reduction was 1.5 mmHg in the eyes treated with topical medications alone and 2.5 mmHg in those treated by topical medications plus ALT. The mean outflow pressure reduction was 16 and 26%, respectively. In 40% of the all eyes, satisfactory IOP reduction was obtained by topical medications with or without additional ALT.

Beta-blockers in eye-drops are widely used for the treatment of glaucoma. The potential allergic effect was only recently recognized.A 65-year-old man had been treated with eye-drops containing beta-blockers for bilateral chronic glaucoma for 14 years. During the last two years, he developed eczema localized on the upper and lower eyelids. Allergy screening confirmed the implication of timolol and befunolol which had been used successively. Later prescription of eye-drops containing carteolol led to recurrence of the eczema.This case of contact allergy with three different beta-blockers in the same patient is similar to others reported in the literature. All beta-blockers have a similar chemical structure, but it cannot act as a haptene. The proposed hypothesis is a cross-sensitivity which develops after primary metabolism to a common aldehyde. The risk of recurrence is high if another beta-blocker eye-drop compound is prescribed in a sensitized patient. The risk of side effects in such sensitized patients when taking oral beta-blockers is unknown.

Topical therapy with beta-antagonists, such as timolol, may cause unrecognized impairment of respiratory and cardiovascular function in elderly people. Beta-antagonists with intrinsic sympathomimetic or cardioselective properties, such as carteolol or betaxolol, may cause less impairment. In a randomized, double-masked study of glaucoma patients, over 60 years of age, without history of bronchospasm and who were using timolol (0.5%), 60 patients were allocated to betaxolol (0.5%) or carteolol (2%) or continued timolol (0.5%) treatment. Spirometry, pulse and blood pressure were measured on enrollment and after 4 weeks. In the timolol and carteolol groups there were no significant changes in mean spirometric values. Changing to betaxolol improved mean peak flow (PF) by 9.1%, from 310 to 3411/min (p < 0.05) and forced expiratory volume in 1 second (FEV1) by 9.4%, from 1.74 to 1.861 (p < 0.05). Differences in the changes in PF and FEV1 between betaxolol and timolol as well as betaxolol and carteolol groups were statistically significant (p < 0.05). Twenty-one per cent of those allocated to betaxolol showed clinically significant improvement in FEV1. There was no change in pulse or blood pressure when carteolol was substituted for timolol but an increase of 10 beats per minute (p < 0.05) in mean resting pulse in the betaxolol group. Therapy with cardioselective beta-blockade may offer significant advantages in respiratory function for elderly people with glaucoma over non-selective drugs, even if they have sympathomimetic activity.

Differentiation of binding sites of CGP12177 and carteolol to the beta-adrenoceptors in the guinea-pig taenia caecum was investigated. Carteolol and CGP12177 competitively antagonized the relaxation responses to isoprenaline, and the pA2 values were 9.87 and 9.33, respectively. Butoxamine, a beta 2-selective antagonist, caused competitive antagonism of the relaxant responses to carteolol, and the pA2 value for butoxamine was 6.22. However, butoxamine (10(-4) M) did not significantly affect the relaxant responses to CGP12177. CGP12177 caused competitive antagonism of the relaxant responses to carteolol, and the pA2 value for CGP12177 was 9.32. However, carteolol (10(-6) M) did not significantly affect the relaxant responses to CGP12177. The competitive inhibition curve for specific binding of 50 nM [3H]befunolol by carteolol showed a biphasic shape, although the curve by CGP12177 was monophasic. Moreover, the competitive inhibition curve for specific binding of 100 nM [3H]CGP12177 by CGP12177 showed a biphasic shape, although the curve by carteolol indicated partial inhibition. These results suggest that the low affinity site of beta-adrenoceptor and beta 3-adrenoceptors are different from each other.

To determine whether two topical beta-blockers, timolol and carteolol, differently affect plasma lipids and lipoproteins in normolipidemic Japanese patients with glaucoma.Thirty-three normolipidemic patients with primary open-angle glaucoma or ocular hypertension were randomly allocated to and completed 16 weeks of bilateral treatment with 0.5% timolol, 1.0% carteolol, or 2.0% carteolol twice daily in a three-center, prospective study. Patients using any drugs affecting plasma lipids or with a history of beta-blocker use of hyperlipoproteinemia were excluded. Fasting blood lipids and lipoproteins, including total cholesterol, high-density lipoprotein cholesterol, triglyceride, and apoproteins, were measured three times before therapy was initiated. These measurements were repeated every 4 weeks during the treatment period.The level of high-density lipoprotein cholesterol significantly decreased in the timolol treatment group but did not change in the carteolol treatment groups. The ratio of total cholesterol minus high-density lipoprotein cholesterol to high-density lipoprotein cholesterol increased in the timolol treatment group.Topical beta-blockers do affect plasma lipids in Japanese patients with glaucoma. The effects of timolol are greater than those of carteolol.

OBJECTIVES: Head-up tilt test (HUT) has been reported to be useful in the evaluation of syncope of unknown origin (SUO). However, the sensitivity of HUT with no pharmacologic provocation was relatively low and variable, ranging 32 approximately 70%. Therefore, several protocols of HUT with different degrees and durations of the tilt and modes of provocation were proposed. The purpose of this study was to determine the value of the multi-stage head-up tilt test with isoproterenol provocation (HUT-isp) in the evaluation of SUO and drug efficacy. METHODS: Sixty-seven patients presenting with SUO and 30 control subjects with no history of syncope underwent the HUT-isp. Blood pressure (BP) was measured every 2 min and whenever the patient complained of any symptom, and cardiac rhythm was continuously monitored. The HUT-isp consisted of 3 stages: first for 20 min with no provocation, second and third stages with infusion of isoproterenol for 10 min each at a rate of 2 micrograms/min and 5 micrograms/min, respectively. A positive HUT-isp was defined when syncope or presyncope was reproduced, accompanied by hypotension (< 80 mmHg) or bradycardia (< 40/min) or both, and positive responses were classified into vasodepressive, cardioinhibitory and mixed type. RESULTS: The HUT-isp was positive in 56 (83.6%) of 67 patients with SUO and 10 (33.3%) of 30 control subjects. The type of positive responses was vasodepressive in 41 (73.2%), cardioinhibitory in 4 (7.1%) and mixed in 11 (19.6%). The sensitivity of the HUT-isp in diagnosing vasovagal syncope was 83.6%, specificity 66.7% and positive predictive value 84.8%. Positive responses were developed most frequently in the 3rd stage: 76.8% in patients, 70% in controls. The effect of 3 drugs (carteolol, aminophylline and disopyramide) was evaluated in 27 patients with a repeat HUT-isp. Carteolol was effective in 12 (85.7%) of 14 patients, disopyramide in 7 (58. 3%) of 12 and aminophylline in 1 (14.3%) of 7. During the follow-up period of 175 +/- 212 days (26 approximately 623 days), none of the 20 patients with a negative repeat HUT-isp developed a recurrent syncope. CONCLUSION: The HUT-isp is thought safe and useful to evaluate syncope of unknown origin and to guide effective drug therapy.

This study examined the role played by neurohumoral factors in mediating the effects of beta-blocker therapy for congestive heart failure. Fifteen patients with congestive heart failure underwent beta-blocker therapy. Plasma norepinephrine and alpha-atrial natriuretic peptide concentrations decreased 2 weeks after initiation of beta-blocker therapy. Decrease in plasma norepinephrine level persisted for 6 months. Lymphocyte beta-adrenoceptor density increased 2 weeks after therapy but was not increased 6 months later. Left ventricular ejection fraction was unchanged 2 weeks after therapy, but it increased 6 months after introduction of beta-blockers. Plasma norepinephrine level decreased 2 weeks after the therapy in the responders (increase in ejection fraction0.10) but not in the nonresponders. Thus early reduction of neurohumoral factor levels preceded the late improvement of left ventricular contractile function and may therefore be partly responsible for the efficacy of beta-blocker therapy for congestive heart failure.

The effects of a single instillation of 2% carteolol or 0.1% dipivefrine on the tissue circulation in the human optic nerve head (ONH) was studied using a laser speckle tissue circulation analyser in 12 healthy volunteers. In the first experiment, normalized blur (NB), a quantitative index of peripheral blood velocity, was measured every 0.125 sec in an area located in the temporal site of ONH free of visible surface vessels and averaged over 5 pulses (mean NB) in both eyes before, 1.5, 3, and 4.5 hours after a 30 microliters instillation of placebo to serve as a control. Intraocular pressure (IOP), blood pressure (BP), and pulse rate (PR) were also measured. In the second experiment, a 30 microliters drop of 2% carteolol (n = 6) or 0.1% dipivefrine (n = 7) was instilled in one randomly chosen eye and the placebo for each drug in the other eye, and the above parameters were measured according to the same time schedule as in the first experiment in a double masked manner. After topical carteolol, carteolol concentration in the plasma (CC) was also measured. In the control experiments, none of the parameters showed any significant change. After topical carteolol, the IOP was significantly lower between 1.5 and 4.5 hrs in the carteolol-treated eyes and at 1.5 and 4.5 hrs in the fellow eyes as compared with that obtained in the control experiment. The mean NB was significantly higher at 3 hrs (23.1%) in carteolol-treated eyes, and at 3 hrs (17.2%) in the fellow eyes, as compared with that obtained in the control experiment (p0.05). BP and PR showed little change. The maximum CC at 3 hrs averaged 522 pg/ml. Thus a single instillation of carteolol may increase the tissue blood velocity in ONH in the human eye. After topical dipivefrine, the IOP was significantly lower at 4.5 hr in the dipivefrine-treated eyes than that obtained in the control experiment (p0.05). Mean NB, BP and PR showed no significant change.

OBJECTIVE: To compare the similarities and differences among the ocular beta-blockers. Important considerations when comparing these agents are the differences in systemic adverse effects, local tolerability, and cost. DATA SOURCE: Information was retrieved from a MEDLINE search of the English-language literature and bibliographic reviews of review articles. Index terms included beta-blockers, glaucoma, timolol, levobunolol, betaxolol, metipranolol, and Carteolol. STUDY SELECTION: Emphasis was placed on eyedrop studies, as well as properly designed and executed clinical trials that assessed dosage, dosing interval, therapeutic response, adverse effects, and cost. DATA EXTRACTION: Data from several studies were evaluated according to the study design, therapeutic response, and adverse effects. DATA SYNTHESIS: Timolol maleate, levobunolol, metipranolol, and Carteolol have similar effectiveness in lowering intraocular pressure; however, levobunolol and timolol gel forming solution may have an advantage of once-daily dosing. Studies have not been published comparing the clinical efficacy of timolol hemihydrate with that of other ocular beta-blockers. Metipranolol is cost effective in treating primary open-angle glaucoma; however, it has been associated with more ocular burning, stinging, and granulomatous anterior uveitis than other agents. The intrinsic sympathomimetic activity of Carteolol has not yet displayed a definite advantage over the other agents in terms of optic disk perfusion and systemic adverse effects. The control of intraocular pressure with betaxolol has not always been as good as with timolol; however, betaxolol has some advantages over timolol and the other topical beta-blockers in terms of systemic adverse effects. CONCLUSIONS: Considering cost, efficacy, and safety, timolol maleate is the recommended formulary agent because the other agents cannot consistently show an outstanding advantage.

The effects of carteolol 2% and a fixed combination of carteolol 2% and pilocarpine 2% (CBS 341 A) eye-drops on intraocular pressure (I.O.P.) were compared in a multicenter double-blind, cross-over prospective trial. Twenty-eight patients were initially selected after at least three weeks of carteolol 2%, with a morning I.O.P. greater than 21-mmHg. They received 2 drops a day (b.i.d.), in a random order, alternating two weeks of carteolol 2% alone or two weeks of CBS 341 A. After each two-week period a 12-h I.O.P. curve was plotted. Compared to carteolol the combination reduced I.O.P. on average by around 20% (4 mmHg), with maximum effect 4h after instillation. The effectiveness was confirmed after twelve hours. Some side effects were reported with CBS 341 A, due to the well known pharmacological effects of pilocarpine. The new combination could be useful for second-line therapy in glaucoma.

A specific and sensitive gas chromatographic-high-resolution mass spectrometric method for the determination of 5-(3-tert.-butylamino-2-hydroxy)propoxy-3,4-dihydrocarbostyril (carteolol), which is a beta-blocker giving depression of intraocular pressure, was developed to elucidate the pharmacokinetics of its ophthalmic application. Carteolol has been determined by high-performance liquid chromatography but with less satisfactory sensitivity. Carteolol was derivatized with pentafluorobenzoyl (PFB) amide followed by dimethylethylsilyl (DMES) ether, resulting in a high negative-ion current. The PFB-DMES derivative of carteolol was determined by the gas chromatography-negative-ion chemical ionization mass spectrometry (GC-NICI-MS) using selected-ion monitoring at low and high mass spectrometric resolution. the detection limit was less than 100 fg when the fragment ion was monitored at m/z 552.2067 in the NICI mode using methane as a reagent gas. The quantification limit of carteolol in human plasma with this method was less than 30 pg/ml. The proposed GC-MS method is considered to have sufficient specificity and sensitivity to study the pharmacokinetics of carteolol used as an ophthalmic solution.

It has demonstrated that carteolol can increase the endothelium-dependent vasodilation induced by alpha-2 adrenergic agonist. In order to evaluate the effect of carteolol, and to clarify the mechanism, we examined the effects of 10 μ m carteolol on the vasodilation induced by increasing doses (10 −7−10−4 ) M) of clonidine in perfused rat mesenteric arteries preconstricted with 100 μ m phenylephrine. Clonidine elicited a dose-dependent vasodilation of the mesenteric arteries preconstricted with phenylephrine. Carteolol enhanced the vasodilation induced by higher doses (10 −5 and 10 −4 M) of clonidine, although carteolol itself exerted no direct vasodilating effect. On the other hand, 10 μ m propranolol or 10 μ m metoprolol did not augment the clonidine-induced vasodilation. In the presence of 100 μ m N G -monomethyl l -arginine (LNMMA), an analogue of l -arginine, the enhancement of the clonidineinduced vasodilation by carteolol was abolished. This inhibition by LNMMA was restored with 300 μ m l -arginine, but not with 300 μ m D -arginine. These results suggest that carteolol enhances the clonidine-induced vasodilation by an endothelial-related mechanism mediated by the release of endothelium-derived nitric oxide in resistance vessels.

Several recent publications have suggested that the long-term use of topical antiglaucoma medications may be detrimental to the outcome of trabeculectomy. In this study we investigated the effect of topical beta-blocker medications on the proliferation and viability of human Tenon's capsule fibroblasts in tissue culture to see if there was a direct mechanism of enhanced proliferation. None of the tested medications stimulated the proliferation of fibroblasts. They were shown to have an inhibitory effect on proliferation and were toxic to cells at higher concentrations. The relevance of these findings to wound healing following trabeculectomy is discussed.

The aim of the study was to compare 2 combinations of eye drops containing 2% carteolol and 2% pilocarpine: LCM 1010: ready to use eye drops CBS 341A: eye drops to be reconstituted (freeze-dried powder + solvent).Ninety-seven patients with primary open angle glaucoma or simple ocular hypertension were included in a randomized, double-blind multicentric study comparing 2 parallel groups of treatment. Intra-ocular pressure was greater than 21 mmHg with beta-blocker alone. One instillation of 2% carteolol-2% pilocarpine combination was given twice a day for one month. Before and after this treatment, intra-ocular pressure was measured at 9 am (12 hours after evening instillation) and at 11 am (2 hours after morning instillation).Both treatments reduced intra-ocular pressure by a comparable amount and there was no significant difference between groups at either measure: at 9 am: 2.11 +/- 2.39 mmHg (mean +/- SD) for LCM 1010 1.79 +/- 1.73 mmHg for CBS 341 A p = 0.25 at 11 am: 3.75 +/- 3.83 mmHg for LCM 1010 3.40 +/- 1.69 mmHg for CBS 341 A p = 0.42. Both eye drops were generally well tolerated.Efficacy and safety of ready to use eye drops 2% carteolol-2% pilocarpine combination proved to be comparable to that of eye drops to be reconstituted in the treatment of ocular hypertension poorly controlled by beta-blocker eye drops alone.

The aim of the study was to compare 2 beta-blocker eye drops at a low concentration: 0.5% carteolol and 0.1% timolol.The study was designed as a random-order, double-blinded comparison of 2 parallel treatment groups. Fifty patients with early primary open angle glaucoma or high intraocular pressure were included. The treatment lasted 4 weeks, on the basis of 1 drop twice daily. Diurnal I.O.P. curve was assessed with 4 measurements from 8.30 a.m. to 4.30 p.m. before and after treatment. The 8.30 a.m. measure of the final assessment of I.O.P. curve was established prior to morning medication. The mean values of the 4 measures were compared.Both treatments reduced IOP by a comparable amount: 4.25 +/- 1.2 mmHg (mean +/- SD) for carteolol and 4.69 +/- 1.9 mmHg for timolol. The decrease of IOP was found at every time of assessment, without any significant difference between treatments. Both eye drops were very well tolerated.The results of this study show that the new beta-blocker eye drop solution 0.5% carteolol is effective for initial management of high intraocular pressure.

A novel technique is described in which the effect of the beta-adrenoceptor antagonists timolol and carteolol, and the vasodilators sodium nitroprusside (SNP) and verapamil on intraocular pressure (IOP) and the distribution of ocular flow in the bovine arterially perfused eye is investigated using radiolabelled microspheres. At maximum IOP-reducing dose timolol was found to significantly reduce perfusion in the choroid and, at higher dose, it was found to significantly reduce perfusion in the iris. By contrast, a maximal IOP-reducing dose of carteolol markedly reduced perfusion in the iris, ciliary body and choroid. Vasoconstriction induced by carteolol was not inhibited by the alpha-antagonist phentolamine. Against a background of vascular tone induced by noradrenaline, SNP and verapamil were found to significantly increase perfusion in the iris, ciliary body and choroid. The effects of these drugs upon the vasculature of the bovine perfused eye are varied and complex and may not bear a direct relationship to their ocular hypotensive effect.

To investigate the distribution and elimination of carteolol in pigmented rabbits, 14C-carteolol eye drops were instilled singly and repeatedly. After single ocular instillation, the radioactivity in the iris and ciliary body reached maximum levels at 24 h. The elimination rate of pigmented tissues decreased at a half-life of approximately 15 days. The concentration of radioacitivy in pigmented tissues increased markedly by repeating the ocular instillation and reached a maximum after the 8oth repeated instillation. The concentration of radioactivity at 1 h after 80th instillation was 63.7 times that in the iris, 61.1 times that in the ciliary body and 17.2 times that in the retina & choroid after single instillation. No accumulation of radioactivity was found in other ocular tissues.

1. 1. The stereoselectivities of β-adrenergic partial agonists for the high affinity binding site of β-adrenoceptors in the guinea-pig ciliary body, right atria and trachea were studied. 2. 2. The inhibition curves by the S(−)-isomers of befunolol and carteolol were not significantly different from that by the R(+)-isomers in the guinea-pig ciliary body. 3. 3. The inhibition curves by the S(−)-isomers of befunolol and carteolol were about 10 times as potent as the R(+)-isomers in the guinea-pig atria and trachea. 4. 4. The p K i values of the S(−)-isomers of befunolol and carteolol were significantly larger than those of R(+)-isomers in the guinea-pig atria and trachea but not larger than those of the R(+)-isomers in the guinea-pig ciliary body. 5. 5. These results suggest that the high affinity binding site of β-adrenoceptors in ciliary body cannot discriminate stereoselectively between the R(+)- and S(−)-isomers, while in other tissues there is stereoselectivity between the two enantiomers.

The respective effects of 6 month's administration of beta-blockers (atenolol, metoprolol, carteolol and arotinolol), calcium-channel blockers (nicardipine, diltiazem) and angiotensin converting enzyme inhibitor (enalapril) on hemoglobin A1c (HbA1c) levels were evaluated in hypertensive patients with non-insulin-dependent diabetes mellitus (NIDDM), using a retrospective method. NIDDM patients with stable HbA1c and body weight were selected for this study. The following results were obtained. (1) The administration of nicardipine or beta-blockers significantly elevated HbA1c levels. (2) The administration of diltiazem or enalapril did not have any influence on HbA1c levels. These findings suggest that not only beta-blocker but nicardipine (dihydropyridine type calcium-channel blocker) may cause deterioration in glucose metabolism in NIDDM patients.

The purpose of this study was to investigate the intestinal permeability of ophthalmic beta-blockers and evaluate the utility of intestinal membrane for predicting the ocular permeability. The penetrations of beta-blockers were measured across the isolated jejunum and colon of the albino rabbit using a two-chamber glass diffusion cell. beta-Blockers tested include atenolol, carteolol, tilisolol, timolol, and befunolol. Colonic membrane showed lower permeability of hydrophilic drugs than jejunal membrane. Scraping the entire cell monolayer of jejunum increased the drug permeability. There was a significant correlation between colonic permeability coefficients and lipophilicities of beta-blockers. The permeability coefficients through jejunum and scraped jejunum were not susceptible to drug lipophilicities. Jejunum, scraped jejunum, and colon showed permeability coefficients almost equal to those of sclera, conjunctiva, and cornea, respectively. There was a significant correlation between permeability coefficients through colon and cornea. These results indicate that the steady-state permeability of ophthalmic beta-blockers through ocular membranes may be predicted by measuring the permeability through certain intestinal membranes. However, the analyses of intestinal permeability using Fick's equation showed the functional difference of intestinal permeability from ocular permeability of ophthalmic beta-blockers.

The vascular relaxing properties of three beta adrenoceptor antagonists, betaxolol, carteolol and timolol, currently used in the treatment of glaucoma, were characterized, compared and contrasted in the porcine long posterior ciliary artery. Isolated arterial ring segments precontracted with increased extracellular KCl (plus 40 mM) or the thromboxane analog, U-46619 (3 × 10 −7 M), were relaxed in a concentration-dependent fashion by betaxolol, carteolol, timolol or nitroprusside. In vessel segments depolarized with increased extracellular KCl, EC 50 values indicated that the intrinsic relaxant sensitivity to betaxolol was equal to that of nitroprusside, six-fold greater than that of carteolol, and ten-fold greater than that of timolol. Similarly, the maximum relaxation occurring at equimolar concentrations (10 −4 M) for the beta adrenoceptor antagonists was betaxolol > carteolol=timolol. Qualitatively similar results were noted in ring segments of the rabbit external iliac artery precontracted with increased extracellular KCl (plus 30 mM). Under conditions in which specific receptor-linked events are absent and voltage-gated Ca + + entry is maximized, the Ca + + concentration response relationship in porcine long posterior ciliary artery was shifted to the right in an apparent competitive manner by betaxolol, reflecting a 5.6-fold reduction in the sensitivity to Ca + + . Conversely, nitroprusside reduced the Ca + + sensitivity three-fold in a noncompetitive fashion; not only shifting the Ca + + concentration response relationship to the right, but also depressing the maximum by 57%. Porcine long posterior ciliary arterial segments precontracted to a similar degrec with U-46619, in which voltage-gated Ca + + entry is only one component of many specific cell signalling transduction mechanisms contributing to the precontraction, exhibited a sensitivity to betaxolol that was six-fold less than to nitroprusside, but two-fold greater than to timolol and 20-fold greater than to carteolol. These results are consistent with an obvious direct vascular relaxing capacity for beta adrenoceptor antagonists that primarily represents a capacity for inhibiting voltage-gated Ca + + entry in vascular smooth muscle. Additionally, the differential potencies of these three beta adrenoceptor antagonists characterized in this study suggests that this property is much more likely to contribute to any potentially beneficial effects of betaxolol than carteolol or timolol.

This study evaluated the effect of beta-adrenoceptor blocking agents (beta-blockers) with or without intrinsic sympathomimetic activity on the 24-hour blood pressure profile of 15 untreated patients with essential hypertension. After a 4-week run-in period, subjects were randomly assigned to an 8-week treatment period of once-daily carteolol (15 mg/d) or atenolol (50 mg/d). The groups were crossed over at week 8. Office blood pressure and heart rate were recorded every 2 weeks and 24-hour ambulatory blood pressure monitoring was performed immediately preceding and at the conclusion of each period. Both drugs significantly reduced (P0.01) office blood pressure and heart rate throughout the two treatment periods. The 24-hour ambulatory blood pressure monitoring at 0.5- and 1-hour intervals revealed that systolic blood pressure in 2 of 8 sleeping hours and diastolic blood pressure in 4 of 8 sleeping hours were significantly higher (P0.05) after carteolol treatment than after atenolol treatment. The average values for both daytime and nighttime blood pressures, however, were significantly lower at the end of both periods. Although atenolol lowered heart rate throughout the 24-hour period, there was a smaller reduction in heart rate with carteolol than with atenolol during daytime (-5.4 +/- 4.9 beats/min vs -12.7 +/- 6.6 beats/min, P0.005, respectively). Heart rate increased during nighttime (P0.02) and was significantly greater than with atenolol treatment (5.0 +/- 7.2 beats/min vs -5.7 +/- 8.0 beats/min, P0.001, respectively). These results suggest that the different effects of the two beta-blockers on heart rate and nighttime blood pressure may be attributed to the presence or absence of intrinsic sympathomimetic activity.

Fifty-eight healthy, normolipidemic adult men participated in a prospective, masked, randomized crossover study designed to compare the effects of two topical nonselective beta-adrenergic antagonists, carteolol and timolol, on plasma high-density lipoprotein cholesterol levels. Two eight-week treatment periods were separated by an eight-week drug-free period. Carteolol 1.0% or timolol 0.5% was used, one drop twice daily, in both eyes without nasolacrimal occlusion. Fresh plasma was assayed for levels of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and apolipoproteins A-I and B-100. With indistinguishable effects on intraocular pressure, carteolol and timolol induced different (P = .013) decrements in high-density lipoprotein cholesterol levels. Carteolol treatment decreased high-density lipoprotein cholesterol levels by 3.3% (-0.04 mmol/l) and raised the ratio of total to high-density lipoprotein cholesterol levels by 4.0% (0.15 unit); timolol treatment decreased high-density lipoprotein cholesterol levels by 8.0% (-0.10 mmol/l) and raised the ratio of total to high-density lipoprotein cholesterol levels by 10.0% (0.37 unit). There was no differential drug effect on the other lipid variables measured. Ocular nonselective beta-adrenergic antagonist therapy can produce clinically relevant decrements in high-density lipoprotein cholesterol levels in healthy men.

The effects of various β-adrenergic receptor antagonists on nicotine-induced tail-tremor were investigated in rats. Atenolol (5 and 10 mg/kg, IP), arotinolol (5 and 10 mg/kg, IP), and carteolol (5 and 10 mg/kg, IP), hydrophilic β-adrenergic receptor antagonists, did not affect the tail-tremor induced by nicotine given a a dose of 0.5 mg/kg SC. However, propranolol (5–20 mg/kg, IP) and pindolol (5–20 mg/kg, IP), nonselective and lipophilic β-adrenergic receptor antagonists, did suppress the tail-tremor dose dependently. In contrast, metoprolol (5–20 mg/kg, IP), lipophilic and β 1 -selective adrenergic receptor antagonists, did not show such an effect. These results suggest that nicotine-induced tail-tremors may be mediated through central β 2 -adrenergic receptors as an appearance and developmental mechanism.