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Biomedical subjects

J Stjernschantz

Publications and source records attributed to J Stjernschantz.

At least 37 records · Page 2Linked to original sources
PubMed1997

The incidence and time-course of latanoprost-induced iridial pigmentation as a function of eye color.

Latanoprost, a phenyl-substituted analogue of prostaglandin F2 alpha administered as eye drops, induces increased melanogenesis in the iridial melanocytes of monkeys. Similar effects were seen in 12, 23 and 11% of patients in the USA, United Kingdom (UK) and Scandinavia, respectively, during one year of treatment. The highest incidence of induced pigmentation was seen in green-brown, yellow-brown and blue/grey-brown eyes, in that order. The relatively high proportion of patients with green-brown eyes in the UK explains the larger number of affected patients in this country. Typically, a concentric increase of the iris pigmentation appeared after six months (range: 3-17) and was judged to be noticeable by the patient in about 2/3 of the cases. After cessation of latanoprost, no change of the induced pigmentation has been seen in patients followed for two years, and there have been no signs of dispersion of pigment into the anterior chamber. Irides, homogeneously blue, grey, green or brown, were seldom affected. Naevi or freckles on iris, conjunctiva, or eye lids were not affected. It is intriguing that many patients with mixed eye color, particularly the blue-brown eyes, have not developed increased pigmentation even during two years of treatment. This could be due to a relatively slow melanogenesis or to refractory melanocytes in these individuals.

Adrenergic beta-Antagonists↗
PubMed1997

Delta13-reductase dependent metabolism of prostaglandins in the mammalian brain and eye.

This paper describes the distribution of NAD+-dependent 15-hydroxy prostaglandin dehydrogenase (delta13-reductase) in the mammalian brain and eye tissues. In addition, an NADH-dependent 15-ketoprostaglandin delta13-reductase (15-PGDH) activity was determined in the brain and eye tissue of some species. The rabbit brain and eye tissues were obtained after arterial perfusion with PBS buffer while the monkey, bovine and porcine tissues were obtained without any treatment. [3H]-PGF2alpha or [3H]-15-keto-17-phenyl-18,19,20-trinor-PGF2alpha1-1-isopropy l ester was incubated with different eye tissue preparations under various conditions. No 15-PGDH activity was observed in the monkey brain while 14% of exogenous PGF2alpha was metabolized to its 15-keto-13,14-dihydro-metabolite by the porcine brain. The 15-PGDH activity in the monkey eye tissue was undetectable. Both brain and different eye tissues hydrolysed 15-keto-17-phenyl-18,19,20-trinor-PGF2alpha-1-isopropyl ester to its free acid and the free acid was further metabolized to 15-keto-13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2alpha by the reduction of 13,14-double bond indicating the presence of a delta13-reductase in these tissues. These data suggest that besides the presence of esterases the mammalian brain and eye tissues possess variable amounts of delta13-reductase in spite of their low 15-PGDH activity which may be of importance in physiology and drug metabolism of these tissues.

Animals↗
PubMed1997

Mediation of prostaglandin f2 alpha-induced ocular surface hyperemia by sensory nerves in rabbits.

PURPOSE: Prostaglandin F2 alpha (PGF2 alpha) and several other prostaglandins cause surface hyperemia of the eye when applied topically. The purpose of the present study was to investigate the role of sensory nerves in prostaglandin-induced ocular hyperemia. METHODS: The ophthalmic branch of the trigeminal nerve was unilaterally electrocoagulated in rabbits using a stereotaxic technique. Two weeks later the animals received bilaterally one drop of PGF2 alpha-isopropyl ester (PGF2 alpha-IE) at a dose of 1 microgram/ eye. The blood flow to the different parts of the eye was measured with the radioactively labeled microsphere technique before, 30 and 60 min after treatment with PGF2 alpha-IE. RESULTS: In the control eyes with intact sensory innervation, PGF2 alpha-IE caused a marked increase in blood flow to the surface structures of the eye (conjunctiva, anterior sclera, eyelids and nictitating membrane) and the iris, and a moderate increase in the blood flow to the ciliary processes, but no increase in the choroidal blood flow. In the denervated eyes the increase in blood flow to the surface structures was almost completely abolished, and there was also a tendency toward less increase in blood flow in the anterior uvea. CONCLUSIONS: These results indicate that PGF2 alpha-induced ocular surface hyperemia, at least at the early stage, is mediated to a large extent by sensory nerves.

Animals↗
PubMed1996

Latanoprost, a prostaglandin analog, for glaucoma therapy. Efficacy and safety after 1 year of treatment in 198 patients. Latanoprost Study Groups.

PURPOSE: To determine efficacy and safety of latanoprost, a prostaglandin analog for glaucoma, during 1 year of treatment. METHODS: After baseline measurements, 0.005% latanoprost was topically applied once daily for 12 months in patients from Scandinavia, the United Kingdom, and the United States who had elevated intraocular pressure (IOP). Diagnoses included ocular hypertension, chronic open-angle glaucoma, exfoliation syndrome, and pigment dispersion syndrome. Treatment was masked for the first 6 months and open-label during the second 6 months. RESULTS: Of the 272 patients initially enrolled, withdrawals were due to inadequate IOP control (1%), increased iris pigmentation (5%), other ocular problems (3%), systemic medical problems (3%), and nonmedical reasons (14%). Latanoprost significantly (P < 0.0001) reduced diumal IOP from 25.3 +/- 3.0 mmHg (mean +/- standard deviation) at baseline to 17.4 +/- 2.7 mmHg (32% reduction) at 12 months in the 198 patients who completed 1 year of treatment. The IOP reduction was maintained at a consistent level throughout the 12 months without evidence of drift, and was not affected by sex, age, race, or eye color. Overall, latanoprost caused a possible or definite increase in iris pigmentation in 12% of the 272 patients, all of whom had multicolored irides at baseline. One half of these patients with increased pigmentation withdrew before completing 1 year of therapy. Visual field, optic disc cupping, visual acuity, refractive error, conjunctival hyperemia, aqueous flare, anterior chamber cellular response, lens examination, blood pressure, heart rate, blood tests, and urinalysis were not appreciably altered. CONCLUSION: Latanoprost safely and effectively reduces IOP for 1 year in patients of diverse nationalities, providing further evidence for its usefulness in chronic glaucoma therapy.

Administration, Topical↗
PubMed1996

A six-month, randomized, double-masked study comparing latanoprost with timolol in open-angle glaucoma and ocular hypertension. The Latanoprost Study Group.

PURPOSE: To compare the intraocular pressure (IOP)-reducing effect and side effects of 0.005% latanoprost administered once daily with 0.5% timolol administered twice daily in patients with open-angle glaucoma or ocular hypertension. METHODS: This was a randomized, double-masked study with two parallel groups and a treatment period of 6 months. The primary objective of the study is to compare the IOP-reducing effect of lantanoprost with that of timolol at the end of the 6-month treatment period. A total of 294 patients were included: 149 were in the latanoprost group and 145 were in timolol group. Latanoprost was administered in the evening. RESULTS: Diurnal IOP (9:00 am, 1:00 pm, 5:00 pm) was reduced from 25.2 to 16.7 mmHg (33.7%) with lantanoprost and from 25.4 to 17.1 mmHg (32.7%) with timolol as determined at the end of the 6-month treatment period. No upward drift in IOP occurred with either drug during the treatment period. Latanoprost caused a somewhat more conjunctival hyperemia than timolol and more corneal punctuate epithelial erosions. However, both drugs were generally well tolerated. The most significant side effect of latanoprost was increased pigmentation of the iris which was observed in 15 patients (10.1%). Timolol caused more systemic side effects than latanoprost. CONCLUSIONS: Latanoprost 0.005% administered once daily in the evening reduced IOP at least as well as timolol 0.5% administered twice daily. Latanoprost was generally well tolerated systemically and in the eye. However, the drug has an unusual side effect of increasing the pigmentation of the iris, particularly in individuals with green-brown or blue-brown eyes.

Adrenergic beta-Antagonists↗
PubMed1996

Latanoprost as a new horizon in the medical management of glaucoma.

Latanoprost is a new prostaglandin F2 alpha analogue specifically developed for the treatment of glaucoma. Latanoprost is a selective FP receptor agonist, with a primary mode of action of increased uveoscleral outflow of aqueous humor. A dose of 50 micrograms/mL (0.005%) once daily has been found optimal in clinical trials. Latanoprost reduces the nocturnal intraocular pressure in addition to the diurnal, and has been shown to be additive to other glaucoma medication. In long-term phase III clinical trials, latanoprost 0.005% once daily has been proven to be at least as effective as timolol 0.5% twice a day. The main side effect of latanoprost is increased iridial pigmentation, which is relatively frequent in patients with mixed color of the iris. This unique side effect is based on the ability of prostaglandins to stimulate melanin formation in melanocytes. The advantages of latanoprost compared with other glaucoma medication comprise different mode of action, good intraocular pressure-reducing effect, once-daily dosing, and absence of systemic side effects. The long-term consequences of increased iridial pigmentation need to be further studied.

Animals↗
PubMed1996

Localization of the prostaglandin F2 alpha receptor messenger RNA and protein in the cynomolgus monkey eye.

PURPOSE: To determine the distribution of the prostaglandin F2 alpha (FP) receptor within the monkey eye. METHODS: The expression and localization of the FP receptor was studied by in situ hybridization and immunohistochemistry. Cryosections of the eye were hybridized with a 35S-labeled FP receptor riboprobe, and paraffin sections were immunostained with polyclonal antibodies against an FP receptor peptide. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed on cultured cell populations from the eye. RESULTS: Results of the three methods largely correlated with each other. The highest expression of FP receptor mRNA and protein was found in the corneal, conjunctival, and iridial epithelium, the ciliary muscle, and ciliary processes. Iridial and choroidal melanocytes, the retina, and the optic nerve expressed lower levels of both FP receptor message and protein. Using immunohistochemistry, the FP receptor protein was found in connective tissue fibroblasts, the corneal endothelium, and the vasculature; however, FP receptor expression was not detected using in situ hybridization. With RT-PCR, cultured retinal pigment epithelial and ciliary muscle cells from the cynomolgus monkey eye were found to express the FP receptor. CONCLUSIONS: The FP receptor was found to be distributed widely in the ocular tissues, suggesting an array of autocrine and paracrine functions of PGF2 alpha in the eye.

Amino Acid Sequence↗
PubMed1995

Derivatives of 17-phenyl-18,19,20-trinorprostaglandin F2 alpha isopropyl ester: potential antiglaucoma agents.

The 15R and 15S epimers of a series of phenyl substituted analogs of 17-phenyl-18,19,20-trinorprostaglandin F2 alpha isopropyl ester [(15S)-3] have been synthesized. The intraocular pressure (IOP) lowering effects and potential side effects of these novel derivatives have been studied in cats and rabbits. In addition, the effects of selected analogues on IOP have been studied in monkeys. Furthermore, we have hydrolyzed some of the isopropyl esters and assessed the ability of the resulting carboxylic acids to contract the cat iris sphincter muscle in vitro. In general, the 15S-derivatives were more active than the 15R-epimers. Derivatives substituted with an acetyl group in the benzene ring appeared to have a better side effect profile as compared to (15S)-3. Furthermore, substitution with an aromatic moiety had a dramatic effect on the activity in that the resulting compounds reduced IOP in cats but had little effect on the pupil diameter. Thus, the activity profile of (15S)-3 may be changed by the introduction of substituents in the benzene ring.

Animals↗
PubMed1995

Effects on intraocular pressure and side effects of 0.005% latanoprost applied once daily, evening or morning. A comparison with timolol. Scandinavian Latanoprost Study Group.

PURPOSE: To compare the effect on intraocular pressure (IOP) and side effects of 0.005% latanoprost applied once daily, morning or evening, with 0.5% timolol applied twice daily. METHODS: A 6-month randomized, double-masked, multicenter study with three parallel groups was undertaken. Two hundred sixty-seven patients were randomized, 84 to timolol, 89 to latanoprost in the morning for 3 months and then in the evening for another 3 months, and 94 to latanoprost with the treatment schedule reversed. RESULTS: After 6 months, timolol reduced diurnal IOP from 24.6 to 17.9 mmHg (27%); latanoprost applied in the morning, from 25.5 to 17.7 mmHg (31%); and latanoprost applied in the evening, from 24.8 to 16.2 mmHg (35%). The efficacy of latanoprost applied in the evening was statistically superior to latanoprost applied in the morning and to timolol (P < 0.001). Latanoprost induced a slight increase in conjunctival hyperemia in 31.4% of treated patients, compared with 15.9% for timolol. Sporadic episodes of mild punctate corneal epithelial erosions were three times as frequent in latanoprost-treated eyes as in timolol-treated eyes. The most significant ocular side effect was increased pigmentation of the iris observed in five and suspected in seven more latanoprost-treated eyes. All these eyes had a mixed green-brown or blue/gray-brown iris color. Timolol reduced heart rate by 3 beats/minute (P < 0.005). CONCLUSIONS: The effect on diurnal IOP of latanoprost applied once daily in the evening is superior to that of timolol. The main difference in side effects is increased pigmentation of the iris induced by latanoprost, most likely due to stimulation of melanogenesis in iris stromal melanocytes.

Adrenergic beta-Antagonists↗
PubMed1994

Cloning of the rat and human prostaglandin F2 alpha receptors and the expression of the rat prostaglandin F2 alpha receptor.

We have cloned the FP receptor from rat corpus luteum and human uterus cDNA libraries, respectively. The coding DNA sequence in the rat cDNA is 1101 bp and is similar to the mouse cDNA coding for a receptor protein of 366 amino acids. The human sequence shows a 5 bp deficiency in the 3' region, truncating the coding sequence to 359 amino acids. Northern blot analysis indicates highest expression in the ovary. Cell lines have been established giving stable expression of the FP receptor. Activation of the cloned FP receptor gave an increase in intracellular calcium, indicating signaling via phospholipase C-mediated phosphoinositide turnover. Using [3H]PGF2 alpha, binding of PGs showed the rank order of fluprostenol > PhXA70 > PGF2 alpha > or = PhXA85 > PGD2 > PGE2.

Amino Acid Sequence↗
PubMed1994

Role of nitric oxide in PGF2 alpha-induced ocular hyperemia.

The effect of nitric oxide synthase inhibition on prostaglandin F2 alpha (PGF2 alpha)-induced ocular hyperemia in the rabbit has been studied. PGF2 alpha was administered topically as the isopropyl ester (PGF2 alpha-IE) unilaterally, with the other eye serving as a control. The regional blood flow in the eye was determined with radioactively-labelled microspheres in conscious animals. Synthesis of nitric oxide (NO) was blocked by L-NMMA (200 mg kg-1 b.w., i.v.). PGF2 alpha-IE induced marked hyperemia of the surface structures of the eye (conjunctiva, eye lids, nictitating membrane, anterior sclera), as well as increased blood flow of the anterior uvea. L-NMMA blocked the hyperemia of the surface structures but not completely the increase in blood flow of the anterior uvea. PhXA41 (13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2 alpha-isopropyl ester), a selective prostaglandin FP-receptor agonist, had no significant effect on the ocular blood flow. These results indicate that PGF2 alpha causes surface hyperemia of the eye by activating nitric oxide synthase, but this mechanism seems to be only partly involved in the increase in blood flow of the ciliary processes and the iris. The PGF2 alpha-induced ocular hyperemia is unlikely to be mediated by FP receptors.

Amino Acid Oxidoreductases↗
PubMed1994

Corneal permeability to and ocular metabolism of phenyl substituted prostaglandin esters in vitro.

The corneal permeability to and metabolism of four phenyl substituted prostaglandin analogues have been studied in vitro. Porcine corneas were mounted in incubation chambers dividing each chamber into an epithelial and endothelial side compartment. The analogues were added to incubation medium on the epithelial side. The permeability coefficients of 17-phenyl-18,19,20-trinor-PGF2 alpha-1-isopropyl ester (PhDH100A), 15-keto-17-phenyl-18,19,20-trinor-PGF2 alpha-1-isopropyl ester (PhXA12), 13,14-dihydro-15-hydroxy (R, S)-17-phenyl-18,19,20-trinor-PGF2 alpha-1-isopropyl ester (PhXA34) and 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2 alpha-1-isopropyl ester (PhXA41) were determined to be in the range of 5.1-11.0 x 10(-6) cm x s-1. All analogues in the endothelial compartment had been hydrolysed to corresponding acids but any other metabolism of PhDH100A, PhXA34 and PhXA41 after 4 h of incubation was minimal. In contrast, PhXA12 free acid was extensively metabolised to the 13,14-dihydro metabolite. To investigate whether the porcine ocular tissues contain 15-hyroxyprostaglandin dehydrogenase (15-PGDH) activity, prostaglandin F2 alpha (PGF2 alpha) and PhDH100A were used as substrates. PGF2 alpha and the phenyl-substituted analogues were also tested for their capacity as substrate to 15-PGDH in general. The 15-PGDH activity was low in all ocular tissues. The capacity of various ocular tissues or purified 15-PGDH to metabolise PhDH100A was lower than with PGF2 alpha as substrate. PhXA34 and PhXA41 were found not to be metabolised by 15-PGDH. Thus, the phenyl substituted PG esters penetrated the cornea and in the process were hydrolysed to their corresponding acids. No appreciable further metabolism occurred except for PhXA12 which was reduced by delta 13-reductase.

Animals↗
PubMed1993

Phenyl-substituted prostaglandins: potent and selective antiglaucoma agents.

A series of phenyl-substituted analogues of prostaglandin F2 alpha (PGF2 alpha) were prepared and evaluated for ocular hypotensive effect and side effects in different animal models. In addition, the activity of the analogues on FP receptors was studied in vitro. The results were compared with those of PGF2 alpha and its isopropyl ester. The phenyl-substituted PGF2 alpha analogues exhibited good intraocular pressure reducing effect, were more selective, and exhibited a much higher therapeutic index in the eye than PGF2 alpha or its isopropyl ester. The analogues exhibited high activity on FP receptors in a stereoselective manner for the 15 alpha-hydroxyl group.

Animals↗
PubMed1993

Intraocular pressure-reducing effect of PhXA41 in ocular hypertension. Comparison of dose regimens.

PURPOSE: To investigate the intraocular pressure (IOP)-reducing effect and side effects of PhXA41, a new prostaglandin F2 alpha (PGF2 alpha) analog, in ocular hypertension and to compare two different dose regimens of PhXA41. METHODS: This was a 2-week randomized, placebo-controlled, double-masked study. PhXA41 eye drops at a concentration of 0.006% (60 micrograms/ml) were administered either once daily (evening) or twice daily (morning and evening) to patients with bilateral ocular hypertension. Each PhXA41 group consisted of 20 patients and the placebo group consisted of 10. RESULTS: PhXA41, administered once or twice daily, reduced IOP by 8.9 and 7.1 mmHg, respectively, in the two treatment groups at the end of the 2-week treatment period. No clear-cut drift in the IOP reduction was observed during the treatment period, but the maximum response was obtained on day 2 in the group receiving PhXA41 twice daily. Both dose regimens of PhXA41 caused more conjunctival hyperemia than the placebo. At the end of the treatment period, 64% to 74% of the patients receiving PhXA41 exhibited no or barely detectable hyperemia. The corresponding figure in the placebo group was 90%. PhXA41 was well tolerated and only one patient dropped out of the study. CONCLUSIONS: PhXA41 reduced IOP by 28% to 36% in patients with ocular hypertension with only mild side effects. Dosing once daily was at least as effective as twice daily. PhXA41 has the potential of becoming a useful new drug for glaucoma treatment.

Adult↗
PubMed1993

Intraocular pressure-reducing effect of PhXA41 in patients with increased eye pressure. A one-month study.

PURPOSE: To establish the dose-response relationship for the effect on intraocular pressure (IOP) and side effects during long-term treatment of patients with ocular hypertension with the prostaglandin F2 alpha (PGF2 alpha) analog PhXA41. METHODS: A three-center, randomized, double-masked study where IOP, conjunctival hyperemia, and ocular irritation were followed during a 1-month twice-daily treatment with placebo or 35, 60, or 115 micrograms/ml PhXA41 in 60 patients with ocular hypertension, primary open-angle glaucoma, or capsular glaucoma. RESULTS: The three concentrations of PhXA41 reduced the average IOP between 31% and 38% during the second day of treatment, with only a weak dose-response relationship. The initial effect declined somewhat during the first 2 weeks of treatment but then remained at the same level for the rest of the study, with a pressure reduction of approximately 20% for all three concentrations. On the second day of treatment, mild conjunctival hyperemia could be observed in most treated patients. Nineteen of 45 PhXA41-treated patients, compared with 2 of 15 placebo-treated patients, reported to have mild to moderate ocular irritation. These side effects became less pronounced during the study, and at the end there was little difference in the degree of conjunctival hyperemia between placebo- and drug-treated eyes, and no drug-related ocular irritation was reported with the two lowest concentrations of PhXA41. CONCLUSIONS: It is confirmed that the PGF2 alpha analog PhXA41 is a major improvement with respect to the effect-side effect relationship and that it may become a valuable new agent for the treatment of glaucoma.

Adult↗
PubMed1992

Cholecystokinin contracts isolated human and monkey iris sphincters; a study with CCK receptor antagonists.

The contractile effects of cholecystokinin (CCK) on iris sphincter and ciliary muscles from monkey and human eyes were studied using an isolated smooth muscle bath. The ability of the CCKA receptor antagonists, lorglumide and loxiglumide, to inhibit CCK-8s-induced contraction was also examined. Various neuropeptides reported to be present in capsaicin-sensitive sensory neurons were also screened for contractile effect. CCK contracted isolated human and monkey iris sphincters at nM concentrations. Both antagonists caused a rightward shift of the dose-response curve for CCK-8s on the monkey iris sphincter. The ciliary muscle from both species failed to contract in response to CCK-8s. Of the eight other neuropeptides screened on the monkey iris sphincter, only [Arg8]vasopressin elicited a weak contraction when used in microM concentrations. These results indicate that the primate iridial sphincter muscle exhibits a high sensitivity to CCK, and that CCKA receptor antagonists effectively block the CCK-induced contraction.

Aged↗