Cardiovascular effects of topical carteolol hydrochloride and timolol maleate in patients with ocular hypertension and primary open-angle glaucoma. Night Study Group.

PURPOSE: To compare the effects of topical timolol maleate 0.5% and carteolol hydrochloride 1% on pulse rate and blood pressure. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Postoperative manipulation of the Krupin valve.

Five patients were noted to have elevated intraocular pressure following implantation of the Krupin glaucoma tube-to-plate device. In each, conjunctiva was draped flat over the plate. A muscle hook was used to manipulate conjunctiva over the tube-plate junction at the site of the valve, producing immediate increased flow through the tube, reduction of intraocular pressure, and bleb formation. In all five cases, intraocular pressure has been controlled at longest follow-up. One cause of elevated intraocular pressure following implantation of the Krupin tube-to-plate device is excessive resistance at the valve site, which can be relieved by manipulation with a muscle hook.

Temperature-metabolism relations in the cotton-top tamarin (Saguinus oedipus) model for ulcerative colitis.

Examination of temperature-metabolism relations found no significant differences between thermoregulation of temperature housed laboratory cotton-top tamarins (Saguinus oedipus) and wild tamarins in Colombia, S.A. The results indicate that tamarins do not acclimate to a temperature environment and are metabolically stressed at Ta less than 32 degrees C. This is consistent with an hypothesis of chronic metabolic stress as a factor in the etiology of cotton-top tamarin colitis, which is restricted to captive populations and not found in wild tamarins.

Periodic alternating gaze deviation in infancy.

Periodic alternating gaze is a rarely reported phenomenon. We have observed two cases that are unique in their early onset at birth and infancy. Multiple congenital defects of the posterior cranial fossa were present on MRI in both cases. A prominent abnormality shared by both was absence of normal structures in the region of the inferior cerebellar vermis. Periodic alternating gaze appears to be associated with pathologic changes in the hindbrain in these and other reported cases.

Argon laser gonioplasty in the treatment of angle-closure glaucoma.

We used argon laser gonioplasty to treat angle-closure glaucoma unrelieved by patent iridectomy. Laser energy (mean; 30 spots, 723 mW, and 0.2 second) was applied to the peripheral iris stroma to open the anterior chamber angle. Twenty of 32 eyes were successfully treated. After a median follow-up period of 18 months, 17 of these 20 successfully treated eyes (85%) had an intraocular pressure less than or equal to 19 mm Hg, and 19 of these 20 successfully treated eyes (95%) had an intraocular pressure less than or equal to 21 mm Hg. The 20 successfully treated eyes had a median duration of angle closure of 12 days. Twelve unsuccessfully treated eyes had a median duration of angle closure of 90 days. All successfully treated eyes had more than 50% of the treated angle opened by argon laser gonioplasty and all but three successfully treated eyes had more than three clock hours opened by argon laser gonioplasty. Argon laser gonioplasty may be successful in treating angle-closure glaucoma unrelieved by iridectomy, especially in cases that are recognized and treated soon after onset.

Effects of sodium valproate and oxygen on the craniofacial skeletal pattern in the CD-1 mouse embryo.

Growth retardation is a consistent finding in animal studies on the effect of sodium valproate (NaVP) in the embryo. Apart from fetal weight, the state of ossification in the embryo may be regarded as an indication of growth. The present study was to determine what effect sodium valproate at human therapeutic drug plasma levels had on the craniofacial skeletal pattern in the CD-1 mouse embryo relative to oxygen conditions, drug treatment or the interaction of the two. Two NaVP-filled Alzet osmotic minipumps were implanted subcutaneously on day 5 of gestation for continuous delivery of a total daily dosage of 850 mg/kg for 7 days. During this same time period the dams were also exposed to either normoxic (21% oxygen), hyperoxic (50% oxygen), or hypoxic (12% oxygen) controlled environments. Dams were removed from the oxygen chambers on day 12 and killed on day 18 of gestation. The fetuses were then processed for skeletal evaluation of the craniofacial region. Ossification centers were present in all but six of the skeletal elements studied. The primary ossification delay was in the tympanic bony labyrinth. In addition, there was a decrease in maxillary and mandibular length and cranial base measurements. The greatest toxic effect on the fetus for all skeletal components studied was in the NaVP/hypoxia treated group. This finding suggests that fetal skeletal maturation may be affected by a combination of intrauterine as well as external factors.

Effects of sodium valproate and oxygen on the CD-1 mouse fetus.

This study reports the effects of valproic acid (VA) on the CD-1 mouse fetus when the drug is administered continuously via osmotic minipumps at human therapeutic drug plasma levels. Two VA-filled Alzet osmotic minipumps were implanted subcutaneously on gestation day 5 for continuous exposure of a total daily dosage of 850 mg/kg on gestation days 5-12. Dams were then exposed continuously to either normoxic (21% oxygen), hyperoxic (50% oxygen), or hypoxic (12% oxygen) controlled environments during gestation days 5-12, in order to determine if hyperoxic maternal conditions offered a protective environment for the fetus, and conversely, if hypoxia exacerbated teratogenicity. Dams were sacrificed on gestation day 18, and litter and fetal data were collected. It was determined in separate groups under normoxic conditions that the osmotic minipump system maintained VA plasma levels corresponding to human therapeutic levels. Sodium valproate was found to induce developmental toxicity in the CD-1 mouse fetus at human therapeutic drug plasma levels. Fetal weights were reduced, and the number of resorptions, deaths, and hematomas was increased. While hypoxia exacerbated the toxic effect on the fetus, hyperoxia failed to ameliorate the outcome.

Carbon disulfide axonopathy. Another experimental model characterized by acceleration of neurofilament transport and distinct changes of axonal size.

The role of axonal transport in the development of structural changes of axons can be examined using experimental models. Two different compounds, 2,5-hexanedione (2,5-HD) and carbon disulfide (CS2), cause axonopathies characterized by the formation of neurofilaments (NF) containing enlargements in preterminal regions of central and peripheral axons. These axonopathies are excellent experimental models of the giant axonal neuropathies, a group of acquired and inherited human diseases of the central and peripheral nervous system. We previously reported that following administration of 2,5-HD, transport of NF is accelerated while number of NF and cross-sectional area are decreased in regions of the axon proximal to the enlargements. We proposed that acceleration of NF transport leads to a 'longitudinal' redistribution of NF which are decreased proximally and increased distally where they form the NF containing axonal enlargements. We have now carried out morphometric, transport and immunocytochemical studies in primary visual axons of rats exposed to CS2. NF-containing axonal enlargements were observed in optic tract and superior colliculus and they increased in number in a proximodistal direction. There was no detectable axonal degeneration and the cross-sectional area of axons proximal to the enlargements was decreased. Transport of NF was markedly accelerated. Immunostaining showed that all 3 NF subunits and phosphorylated epitopes of the 200-kDa NF subunit were present in the NF-containing axonal enlargements. All these findings were similar to those previously observed in the 2,5-HD axonopathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition and enhancement of skin tumors in mice by dimethyl sulfoxide depending on method of application.

The role of dimethyl sulfoxide [(DMSO) CAS: 67-68-5] in experimental tumorigenesis was investigated because of conflicting reports in the literature ranging from inhibition to no effect to enhancement. With the use of numbers of skin tumors produced on the back of the mouse following topical applications of carcinogenic agents as the variable and with acetone serving as the control solvent, the following results were obtained: When DMSO was the solvent for benzo[a]pyrene (CAS: 50-32-8) in the single-stage model (C3H mice), tumor numbers doubled. When DMSO was the solvent for 7,12-dimethylbenz[a]anthracene (CAS: 57-97-6) serving as initiator in the two-stage model (CD-1 mice), tumor numbers were unaffected. In the two-stage model, when DMSO was the solvent for the potent promoter phorbol-12-myristate-13-acetate [(PMA) CAS: 16561-29-8] or was applied to skin at the initiation site (the back) before PMA, tumor numbers were reduced to one-third of control. However, when DMSO was applied before PMA to the abdomen, a site remote from initiation, tumor numbers doubled. Enhancement of PMA appears to be unique. Recognition that diverse effects can occur depending on the method of application of DMSO may help to decipher the conflicting literature on its relation to tumorigenesis, could be of value in probing the mechanism of tumor promotion, and might signal further caution in its clinical use.

Inhibitory effect of toluene on tumor promotion in mouse skin.

In the two-stage mouse model for skin tumorigenesis with phorbol-12-myristate-13-acetate (PMA) as promoter, topical application of 40 microliters of toluene 2X/week at the initiation/promotion site (the back) reduced the average number of tumors/mouse (ANT/M) to approximately one-fourth that of controls. Control procedure involved initiation of C3H mice with benzo[a]pyrene (BaP) and CD-1 mice with 7,12-dimethylbenz[a]anthracene (DMBA) followed by promotion with from 1 to 5 micrograms PMA in 40 microliters acetone 2X/week. Forty microliters of toluene 2X/week per se was a weak promoter (6-13% of control ANT/M), and produced mild skin irritation at the application site but behavior and body weights were normal. The toluene inhibition of tumorigenesis was not a direct chemical action on PMA since similar effects occurred whether toluene was the vehicle for PMA or whether it was applied up to 1 day before PMA (i.e., prepromotion). Prepromotion with acetone had no effect on tumorigenesis, substantiating its use as control vehicle and suggesting that the toluene inhibition was a specific tissue reaction. The inhibitory effect appeared to be on PMA promotion rather than on initiation since toluene and acetone produced similar numbers of tumors when used as the vehicle for BaP or DMBA in two-stage or BaP in single-stage trials. The inhibition was not permanent since tumorigenesis returned to control rates 2-3 weeks after prepromotion with toluene ceased but promotion with PMA in acetone continued. Toluene may be unique among reported promotion inhibitors in that it is a widely used commercial chemical which sometimes serves as a vehicle in cancer-screening trials. Since its metabolism is reasonably well defined, it may be of value in exploring further the process of tumor promotion.

Acceleration of skin tumorigenesis in mice by submandibular and sublingual gland excision.

Sialoadenectomized CD-1 male mice reached 50% incidence earlier and developed new tumors faster than either sham operated or control mice. Surgically treated mice regained normal body weight within two weeks, at which time skin tumors were induced by benzo[a]pyrene initiation and 12-O-tetradecanoylphorbol-13-acetate promotion.

The interaction of topically applied toluene and ambient temperature on O2 uptake of tissue homogenates.

These studies examined the role of toluene in temperature-cancer experiments where it was used as a solvent for benzo(a)pyrene (BaP). Toluene (0.08 ml/wk topically) and ambient temperature (cool Ta = 16 degrees C, normal Ta = 23 degrees C and warm Ta = 32 degrees C) interacted to affect O2 uptake of tissue homogenates. After 3.5 weeks of acclimation and 2 weeks of toluene (0.16 ml total), O2 uptake of muscle homogenates was elevated 32% for all Ta's; O2 uptake of skin homogenates was elevated 139% for all Ta's; however, O2 uptake of liver homogenates was elevated 665% in cool Ta, elevated 36% in normal Ta but depressed 50% in warm Ta. The pattern of liver homogenate O2 uptake of C greater than N greater than W is similar to that for tumorigenesis when BaP is dissolved in the toluene, although toluene alone is nontumorigenic. Common cellular mechanisms may be involved in the metabolism of toluene, the activation of BaP and in thermogenic acclimation.

Effect of temperature on benzo[a]pyrene-induced hyperplastic and neoplastic skin lesions in mice.

The time required for tumor development and death in inbred C3H/HeJ mice treated with 1.0 or 0.1 mg benzo(a)pyrene (BP) twice weekly was shortest in mice kept in a cool environment (CE), intermediate in mice kept in a normal temperature environment (NE), and longest in mice kept in a warm environment (WE). Incidence of tumors (predominantly squamous carcinomas) and mortality was 100% by 36 weeks in all environments in the high-dose group. In the low-dose group, by 36 weeks tumor incidence was least in the WE compared with that in the NE and CE. Squamous carcinomas predominated in the NE and CE, but the incidence of fibromas and epithelial hyperplasias exceeded that of squamous carcinomas in the WE. Cutaneous epithelial hyperplasia, considered a preneoplastic change, was evaluated by light and electron microscopy at weekly intervals for 70 days. Increased epidermal thickness was induced by the toluene (T) vehicle alone, was significantly enhanced by BP treatment, and was more severe in mice in the CE and NE than in the WE. Although epithelial hyperplasia induced by BP was interpreted as a preneoplastic lesion, no ultrastructural differences were detected between T- and BP-treated mice in any environment. Results indicated that WE diminished the preneoplastic proliferative response of skin to BP and subsequently delayed the onset of squamous carcinomas induced by high doses of BP and reduced the incidence of squamous carcinomas at low doses of BP.