Comparison of the efficacy of the immediate-release and osmotic push-pull system formulations of nifedipine for tocolysis.

AIM: To compare the immediate-release (IR) and osmotic push-pull system formulations of nifedipine used for tocolysis in prolonging pregnancy, neonatal outcomes and maternal-fetal adverse effects. METHODS: We evaluated 140 pregnant women who received the IR (n = 72) and osmotic push-pull system (n = 68) formulations of nifedipine for tocolysis due to threatened preterm labor between 240/7 and 336/7 weeks of gestation. Groups were compared in terms of efficacy of tocolysis in prolonging pregnancy for more than 48 h, 7 days and up to 37 weeks of gestation, total number of days gained for prolonging pregnancy, delivery weeks, maternal-fetal adverse effects and neonatal outcomes including ventilation support, need for intubation or surfactant, intraventricular hemorrhage, respiratory distress syndrome, necrotizing enterocolitis, admission to neonatal intensive care unit, neonatal death, Apgar scores at the 1st and 5th minutes. RESULTS: There was no significant difference between the two groups in prolonging pregnancy for more than 48 h or 7 days, total number of days gained after tocolysis initiation, delivery weeks, the number of births at 340/7 -366/7 weeks or after 37 weeks of gestation (P > 0.05). Maternal-fetal adverse effects and neonatal outcomes were similar in both groups (P > 0.05). CONCLUSION: The efficacy of IR and osmotic push-pull system formulations of nifedipine have similar effects in terms of tocolysis and neonatal outcomes, adverse effects. Osmotic push-pull system formulation of nifedipine may be an alternative medication in tocolytic therapy due to its ease of use and the absence of loading dose necessity.

Unusual facio-upper arm band of a fetus mimicking amniotic band syndrome.

Amniotic band syndrome can lead to a wide spectrum of congenital abnormalities including orofacial and visceral defects. It is associated with malformations in truncal, craniofacial regions and the limbs, whereas it sometimes may imitate some genetic disorders. Here, we present an atypical case mimicking amniotic band syndrome with a facio-upper arm band that was having multiple fetal structural abnormalities including scoliosis, bilateral cleft lip and palate, upper limb abnormality, unilateral anophthalmia with contralateral microphthalmia, left hypertrophic kidney and severe ventriculomegaly.

A conditional knockout mouse line of the oxytocin receptor.

Oxytocin plays important roles in reproductive physiology and various behaviors, including maternal behavior and social memory. Its receptor (Oxtr) is present in peripheral tissues and brain, so a conditional knockout (KO, -/-) would be useful to allow elimination of the receptor in specific sites at defined times. We created a line of mice in which loxP sites flank Oxtr coding sequence (floxed) enable Cre recombinase-mediated inactivation of the receptor. We expressed Cre recombinase in these mice either in all tissues (Oxtr(-/-)) or the forebrain (Oxtr(FB/FB)) using the Ca(2+)/calmodulin-dependent protein kinase IIalpha promoter. The latter KO has reduced Oxtr binding beginning 21-28 d postnatally, leading to prominent reductions in the lateral septum, hippocampus, and ventral pallidum. The medial amygdala is spared, and there is significant retention of binding within the olfactory bulb and nucleus and neocortex. We did not observe any deficits in the general health, sensorimotor functions, anxiety-like behaviors, or sucrose intake in either Oxtr(-/-) or Oxtr(FB/FB) mice. Females of both KO types deliver pups, but only the Oxtr(FB/FB) mice are able to eject milk. Oxtr(-/-) males show impaired social memory for familiar females, whereas the Oxtr(FB/FB) males appear to recognize their species but not individuals. Our results confirm the importance of oxytocin in social recognition and demonstrate that spatial and temporal inactivation of the Oxtr will enable finer understanding of the physiological, behavioral, and developmental roles of the receptor.

Relationship between second-trimester amniotic fluid levels of Prokineticin-1 and Matrix Metalloproteinase-2 with adverse pregnancy outcome.

To investigate the levels of Prokineticin-1 (PROK1) and matrix metalloproteinase-2 (MMP-2) in second-trimester amniotic fluid (AF). AF samples were investigated in 81 patients. AF-PROK1 and AF-MMP-2 were not significantly associated with adverse pregnancy outcomes (preeclampsia, intrauterine growth retardation, spontaneous preterm birth, gestational diabetes, gestational hypertension). AF-PROK1 levels in patients with abnormal first-trimester screening were significantly higher than those who underwent amniocentesis due to abnormal second-trimester screening tests (p = .04). AF-PROK1 or AF-MMP-2 do not have a role in the prediction of adverse pregnancy outcomes.

Effects of betamethasone on fetoplacental and maternal hemodynamics in preterm pregnancies.

OBJECTIVE: To evaluate the possible effects of prenatal steroid administration on Doppler parameters of the umbilical artery, uterine artery, middle cerebral artery, and ductus venosus, the cerebroplacental ratio, and the amniotic fluid index in preterm fetuses. METHODS: The present prospective observational study was performed at the Perinatology Department of Trakya University, Edirne, Turkey, between June 1, 2015, and September 1, 2016. It included patients with healthy singleton pregnancies who had received betamethasone at 24-34 weeks of pregnancy. Doppler parameters were measured before (0 hours) and 24, 48, and 72 hours after the administration of betamethasone (two intramuscular doses of 12 mg each, administered 24 hours apart). RESULTS: There were 68 patients included. Pairwise comparisons demonstrated that, at 72 hours after betamethasone administration, the umbilical artery resistance index (P=0.038), the middle cerebral artery systolic/diastolic velocity ratio (P=0.007), and the amniotic fluid index (P=0.017) were reduced, whereas the end-diastolic velocity of the middle cerebral artery was increased (P=0.012), compared with baseline values. CONCLUSION: Betamethasone had favorable effects on fetal cerebral circulation, with increased end-diastolic velocity in the middle cerebral artery; this could represent a positive effect on cerebral blood circulation and decreased flow resistance in the umbilical artery.

Microvascular effects of selective prostaglandin analogues in the eye with special reference to latanoprost and glaucoma treatment.

Prostaglandin F(2alpha) analogues have recently been introduced on the market for glaucoma treatment. While these drugs have a well-documented intraocular pressure reducing effect only a limited number of studies have been published regarding their effects on the microvasculature in the eye. Since many naturally occurring prostaglandins have marked effects on the cardiovascular system it is conceivable that synthetic prostaglandins used as glaucoma drugs may exert microvascular effects in the eye, even if they exhibit receptor selectivity. Latanoprost, the active principle of Xalatan((R)) eye drops, is a selective FP prostanoid receptor agonist, and much of the paper is focused on the microvascular effects of latanoprost and some closely related prostaglandin analogues. The purpose of the paper is to review the literature on the microvascular effects of prostaglandins in the eye, and to present some unpublished data on the effects of selective prostaglandin analogues. Most of the prostaglandin analogues studied exhibit selectivity for the FP prostanoid receptor. Results from studies with the following prostaglandin analogues are presented in the paper: PGF(2alpha)-isopropyl ester (PGF(2alpha)-IE), 17-phenyl-18,19,20-trinor-PGF(2alpha)-isopropyl ester (17-phenyl-PGF(2a)-IE), 15-keto-17-phenyl-18,19, 20-trinor-PGF(2alpha)-isopropyl ester (15-keto-17-phenyl-PGF(2a)-IE), 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF(2alpha)-isopropy l ester (latanoprost), 13,14-dihydro-15R,S-17-phenyl-18,19, 20-trinor-PGF(2alpha)-isopropyl ester (PhXA34), 17-phenyl-18,19, 20-trinor-PGE(2)-isopropyl ester (17-phenyl-PGE(2)-IE), and 19R-hydroxy-PGE(2) (19R-OH-PGE(2)). The regional blood flow has been determined with radioactively labelled microspheres, the blood volume with (51)Cr labelled erythrocytes and the capillary permeability to albumin with (125)I and (131)I labelled albumin. PGF(2alpha)-IE has been shown to exert marked microvascular effects in the rabbit anterior segment including vasodilatation, increased capillary permeability, and a breakdown of the blood-aqueous barrier. 17-phenyl-PGF(2alpha)-IE, 15-keto-17-phenyl-PGF(2alpha)-IE, and PhXA34/latanoprost exerted significantly less vasodilatory effect, and little effect on capillary permeability was seen with the FP receptor agonists when studied with Evans blue. Intravenous administration of PhXA34 at a dose range of 1-100 microg/kg b.w. had no consistent effect on the regional blood flow in the eye indicating that FP receptors in the ocular blood vessels are not expressed in the rabbit, or alternatively are not functionally coupled to regulation of vascular tone. In cats topical application of PGF(2alpha)-IE had no significant effect the on the regional blood flow in cannulated eyes. No blood flow experiments were performed in intact eyes with PGF(2alpha)-IE. 17-phenyl-PGF(2alpha)-IE and latanoprost caused some vasodilation in the anterior segment. None of the analogues had any significant effect on the blood volume in the ocular tissues, but an increase in capillary permeability to albumin was seen in several tissues of the eye. However, in the eyelid, nictitating membrane and conjunctiva exposed to high concentrations of the prostaglandins no or only little leakage of albumin was detected. It appears that the intraocular microvasculature in the cat exhibits some sensitivity to FP prostanoid receptor agonists. (ABSTRACT TRUNCATED)

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.

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.

Intraocular PMMA lenses modified with surface-immobilized heparin: evaluation of biocompatibility in vitro and in vivo.

Intraocular lenses (IOL) were surface modified with covalently linked heparin. The surface-bound heparin could not be removed by incubation in solutions known to be effective in breaking non-covalent bonds, nor by incubation in a solution of proteinase K and only to a limited extent by incubation with heparinase. In vitro studies demonstrated improved biocompatibility by the heparin surface-modified lens with respect to outgrowth of fibroblasts and macrophages, activation of granulocytes and adhesion of platelets. These results were subsequently verified in vivo in terms of less inflammatory cells on the lens surface and fewer incidences of synechiae after 3 and 6 wk IOL implantation in the rabbit eye.

Effect of latanoprost on regional blood flow and capillary permeability in the monkey eye.

OBJECTIVE: To evaluate the effects of latanoprost on regional blood flow and capillary permeability in the monkey eye. METHODS: Anesthetized cynomolgus monkeys were unilaterally treated with a single dose containing 6 pg of latanoprost; or 10 microg of PhXA34 (13,14-dihydro-15R, S-17-phenyl-18,19,20-trinor-prostaglandin F2alpha [PGF2alpha]-isopropyl ester), which contains about 50% latanoprost. Regional blood flow in the eye was measured with radioactively labeled microspheres; capillary permeability was measured by determining the extravascular plasma-equivalent albumin space using 125I-albumin, 131I-albumin, and 51Cr-labeled erythrocytes. RESULTS: Latanoprost or PhXA34 had no or only a slight effect on the regional blood flow when measured 1, 2 1/2, 3, 4 1/2, and 6 hours after dose administration, with the exception of the anterior sclera, in which a moderate increase in blood flow was detected. No effect on capillary permeability to albumin was detected when studied 30 minutes to 2 1/2 hours and 5 to 6 hours after dose administration. CONCLUSION: Latanoprost, a selective prostaglandin F receptor agonist, exerted no or only slight vascular effects for up to 6 hours after dose administration in the monkey eye, with the exception of the anterior sclera, in which a moderate increase in blood flow was detected. CLINICAL RELEVANCE: Naturally occurring prostaglandins may cause marked microcirculatory changes in the eye that could be of clinical concern. Latanoprost, a selective prostaglandin F receptor agonist, seems to be devoid of such effects.

Prostaglandin-induced iridial pigmentation in primates.

Latanoprost, a new ocular hypotensive prostaglandin F2 alpha analogue prodrug, was found to induce increased pigmentation of monkey irides in chronic toxicity studies. This prompted us to investigate the effect of naturally occurring prostaglandins on the monkey iris to determine whether this pigmentary effect is unique for latanoprost or whether it is a class effect of prostaglandins. PGF2 alpha-isopropyl ester (IE), PGE2-IE and latanoprost were applied topically to cynomolgus monkey eyes for 18-44 weeks. One eye of each animal was treated, while the other served as control. In addition, latanoprost was applied to sympathectomized monkey eyes. PGF2 alpha-IE, PGE2-IE, as well as latanoprost, induced increased pigmentation in the monkey eye. The first signs of this effect were seen after about two months of treatment. Latanoprost also induced increased pigmentation in sympathectomized eyes. It is concluded that both naturally occurring prostaglandins and their synthetic analogues can induce increased iridial pigmentation in cynomolgus monkeys, and that the effect does not require the presence of sympathetic nerves.

Structure-activity relationships and receptor profiles of some ocular hypotensive prostanoids.

A novel series of prostaglandin F (PGF) analogues have been prepared and evaluated in vivo and in vitro. Their intraocular pressure (IOP) lowering effects and potential side-effects, as prodrug eye drops, have been tested in cats, monkeys and rabbits. Furthermore, the PGF-analogues were tested as free acids for FP-receptor agonistic activity on cat iris sphincter. The results were compared to that of PGF2 alpha (C#1). Based on the structure-activity relationship investigations, inversion of the configuration, at carbon-9 (C#3) or carbon-11 (C#4), changes the potency and the receptor profile of PGF2 alpha. Replacement part of the omega-chain of PGF2 alpha with a benzene ring changes the potency and receptor profile of PGF2 alpha. The optimal position of the benzene ring is on carbon-17, 17-phenyl-18,19,20-trinor PGF2 alpha-isopropyl ester (C#8), and exhibited a much higher therapeutic index in the eye than PGF2 alpha or its ester. The biological activity of different substituents on the C#8 benzene ring have also been studied. Interestingly, introduction of a methyl group at positions 2 or 3 of the benzene ring (C#16 or C#17) affords compounds which are biologically more active than the methyl group at the 4-position (C#18). Furthermore, one of the analogues 13,14-dihydro-17-phenyl-18,19,20-trinor PGF2 alpha-isopropyl ester (latanoprost), has been found in clinical studies to be a highly potent and efficacious IOP-reducing agent for the treatment of glaucoma.

Fibrinous reaction on implanted intraocular lenses. A comparison of conventional PMMA and heparin surface modified lenses.

We studied the fibrinous reaction after intraocular lens (IOL) implantation in the posterior chamber of cynomolgus monkeys. In 50% of the eyes, we implanted an IOL made of conventional poly-(methyl methacrylate) (PMMA); in the remaining eyes we implanted a PMMA IOL with a heparin modified surface. Two, 4, 8, and 18 weeks after surgery the eyes were examined by slitlamp for fibrinous reactions on and around the IOL surface. At weeks 4, 8, and 18 there was a marked decrease in fibrinous reaction in the eyes with a heparin surface modified IOL. The results of this study accord with earlier findings that heparin surface modification improves the biocompatibility of the IOL.

Long-term stability of heparin-surface-modified intraocular lenses in vivo.

In vivo long-term stability of intraocular lens surfaces, modified by immobilized heparin, was studied. Lenses were implanted in the anterior chamber of rabbits and analyzed for surface concentration of heparin after varying periods of time up to two years. A new method using adsorption of 125iodine-labeled protamine was developed for quantitative measurements of immobilized heparin. Another assay, based on a monoclonal antibody against heparin, was also included. The study showed that surface-immobilized heparin did not degrade or desorb to any measurable degree during a two-year follow-up.

Heparin surface modified intraocular lenses implanted in the monkey eye.

The biocompatibility of heparin surface modified poly(methyl methacrylate) intraocular lenses (IOLs) was evaluated in two experiments following implantation in the anterior and posterior eye chambers of adult cynomolgus monkeys. Throughout the study, large inflammatory cells and prominent pigment deposits were seen on the unmodified lenses, whereas the heparin surface modified IOLs remained almost free of precipitates. Similarly, fewer posterior synechias were observed in eyes implanted with surface modified IOLs in the posterior chamber than in eyes implanted with control lenses. Histopathological examination of enucleated eyes confirmed the clinical findings. These experiments strongly support the idea that surface modification with heparin is a useful way to reduce clinical complications following cataract surgery with IOL implantation.

Using data preprocessing and single layer perceptron to analyze laboratory data.

During daily work in hospitals a large amount of clinical data is produced each day. Totally computerized patient records are not yet widely used but a large part of essential information is already stored on computer files. These include laboratory test results, diagnoses, codes for operations, codes of histopathological diagnoses and maybe even the patient's medication. Accordingly, these databases include much clinical knowledge that would be useful for clinicians. Laboratories try to support clinicians by producing reference values for laboratory tests. It is, of course, necessary information but, however, it does not give very much information about the weight of evidence that an abnormal laboratory test will give in special clinical settings. We have developed a software package - DiagaiD - in order to build a smart link between patient databases and clinicians. It utilizes neural network-based machine learning techniques and can produce decision support which meets the special needs of clinicians. From example cases it can learn clinically relevant transformations from original numeric values to logical values. By using data transformation together with a single layer perceptron it is possible to build nonlinear models from a set of preclassified example cases. In this paper, we use two small datasets to show how this scheme works in the diagnosis of acute appendicitis and in the diagnosis of myocardial infarction. Results are compared with those obtained using logistic regression or backpropagation neural networks. The performance of our neuro-fuzzy tool seemed to be slightly better in these two materials but the differences did not reach statistical significance.

Hydrostatic and oncotic pressures in the interstitium of dehydrated and volume expanded rats.

The pressures in the renal interstitial space seem to have important influence on the setting of the sensitivity of the tubuloglomerular feedback that controls the glomerular filtration rate (GFR), and on the rate of proximal tubular fluid reabsorption. Measurements were made of interstitial pressure conditions, GFR, renal plasma flow (RPF), urinary excretion of sodium and potassium, and plasma renin activities in dehydrated animals and normopenic controls, before and after saline volume expansion (5% of body weight and hour). Colloid osmotic pressure, estimated from the protein concentration in renal hilar lymph, was 7.5 mmHg in the dehydrated animals (controls 2.8 mmHg) and decreased to 3.1 (controls 1.7 mmHg) after volume expansion. The lymph flow rate was increased in both groups of animals after volume expansion. Interstitial hydrostatic pressure, measured in the subcapsular space, was 2-3 mmHg in dehydrated and control animals and increased to 3-4 mmHg after volume expansion. In dehydrated rats GFR and RPF was reduced to 60% of the control values, but after volume expansion they regained control values. After volume expansion, urinary excretion of fluid and electrolytes increased more in controls than in dehydrated rats. Plasma renin activity was decreased in both groups of rats after volume expansion. Thus, in dehydrated animals there was a high colloid osmotic pressure and a low hydrostatic pressure in the renal interstitium, while after volume expansion the oncotic pressure fell and the hydrostatic pressure rose. The effect of volume expansion was found to be dependent on the preceding volume balance situation in the animal.

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.

Activation of the tubuloglomerular feedback mechanism in dehydrated rats.

To study the influence of the tubuloglomerular feedback control (TGF) on the regulation of glomerular filtration rate (GFR) during dehydration, micropuncture experiments were performed on surface nephrons of dehydrated rats. Dehydration was achieved by withdrawal of food and water for 24 h. The urine flow rate decreased to 1.5 microliters/min (controls 2.9 microliters/min) and GFR decreased in these rats to 0.80 ml/min (controls 1.22). TGF was studied by two different micropuncture procedures. With the first technique the changes in proximal stop-flow pressure in response to changes of the late proximal microperfusion rate were measured. With this technique the perfusion rate necessary to induce a half maximal stop-flow pressure response, the turning point, was also determined. An increased TGF sensitivity was found in dehydrated rats, as indicated by increased stop-flow pressure responses (35 versus 26%) and decreased turning points (16 versus 21 nl/min). With the second micropuncture technique the single nephron GFR (SNGFR) was measured at distal and proximal tubular sites, in the same nephron. Distal SNGFR was decreased during dehydration to 32.2 nl/min, versus 42.7 nl/min in controls. A significant difference between paired SNGFR measurements in the same nephron was observed during dehydration, the proximal value being 5.3 nl/min higher than the distal, whereas this difference was not seen in control rats. This finding indicates that activation of the feedback mechanism takes place to reduce SNGFR. It is concluded that the decrease in whole kidney GFR is partly caused by the observed increase in feedback activity. The present results are also in agreement with our earlier hypothesis that the hydrostatic and oncotic pressure conditions within the interstitial space surrounding the macula densa cells modulate the sensitivity of the tubuloglomerular feedback mechanism.