Marked Increase In Plasma Concentration Research Articles

Metformin impairs bile acid homeostasis in ethinylestradiol-induced cholestasis in mice

Metformin, an oral antidiabetic drug, recently demonstrated a reducing effect on bile acids (BA) plasma concentrations in one patient with intrahepatic cholestasis of pregnancy (ICP) by unknown mechanism. Therefore, the aim of the present study was to examine the effect of metformin on BA homeostasis and related molecular pathways in the liver and intestine using a mouse model of ICP. The cholestasis was induced in female C57BL/6 mice by repeated administration of ethinylestradiol (10 mg/kg BW s.c.) and/or metformin (150 mg/kg BW orally) over 5 consecutive days with subsequent bile collection and molecular analysis of samples. We demonstrated that metformin significantly increased the rate of bile secretion in control mice. This increase was BA dependent and was produced both by increased liver BA synthesis via induced cholesterol 7α-hydroxylase (Cyp7a1) and by increased BA reabsorption in the ileum via induction of the apical sodium-dependent BA transporter (Asbt). In contrast, metformin further worsened ethinylestradiol-induced impairment of bile secretion. This reduction was also BA dependent and corresponded with significant downregulation of Bsep, and Ntcp, major excretory and uptake transporters for BA in hepatocytes, respectively. The plasma concentrations of BA were consequently significantly increased in the metformin-treated mice. Altogether, our data indicate positive stimulation of bile secretion by metformin in the intact liver, but this drug also induces serious impairment of BA biliary secretion, with a marked increase in plasma concentrations in estrogen-induced cholestasis. Our results imply that metformin should be used with caution in situations with hormone-dependent cholestasis, such as ICP.

Age‐dependent vulnerability to experimental acute pancreatitis is associated with increased systemic inflammation and thrombosis

The severity and mortality rates of acute pancreatitis (AP) are significantly elevated in the elderly population. However, due to a lack of appropriate animal models, the underlying mechanisms for this age-dependent vulnerability remain largely unknown. The purpose of this study was to characterize a murine model of AP, which displays age-associated severity, and to use this model to identify pathophysiologies that are distinctive of the aged with AP. AP was induced in young (4-5 months), middle-aged (12-13 months), and aged (23-25 months) C57BL/6 mice by repeated injection of caerulein, a homologue of the gastrointestinal hormone cholecystokinin. Approximately 10% of aged mice died during AP, while young and middle-aged mice showed no mortality. Although both young and aged mice exhibited early signs of edema and inflammation in the pancreas, kidney, and lung, young mice showed signs of recovery within 24 h, while aged mice exhibited increasingly severe tissue damage and cell death. There was a significant age-dependent increase in pancreatic neutrophil activation and systemic inflammation as assessed by pancreatic myeloperoxidase and plasma interleukin-6 (IL-6) concentration, respectively. Importantly, aged but not young mice with AP showed significantly elevated thrombosis in the lung and kidney as well as a marked increase in plasma concentration of plasminogen activator inhibitor-1 (PAI-1), a primary inhibitor of the fibrinolytic system. These results demonstrate that aging is associated with increased severity of AP characterized by augmented and prolonged pancreatic inflammation and the presence of multiple extra-pancreatic sequelae including thrombosis.

The pro-inflammatory effect of uraemia overrules the anti-atherogenic potential of immunization with oxidized LDL in apoE−/− mice

Uraemia increases oxidative stress, plasma titres of antibodies recognizing oxidized low-density lipoprotein (oxLDL) and development of atherosclerosis. Immunization with oxLDL prevents classical, non-uraemic atherosclerosis. We have investigated whether immunization with oxLDL might also prevent uraemia-induced atherosclerosis in apolipoprotein E knockout (apoE-/-) mice. ApoE-/- mice were immunized with either native LDL (n = 25), Cu(2+)-oxidized LDL (n = 25), PBS (n = 25), the apolipoprotein B-derived peptide P45 (apoB-peptide P45) conjugated to bovine serum albumin (BSA) (n = 25) or BSA (n = 25) prior to induction of uraemia by 5/6 nephrectomy (NX). Immunization with oxLDL increased plasma titres of immunoglobulin G (IgG) recognizing Cu(2+)-oxLDL and malondialdehyde-modified LDL (MDA-LDL). However, 5/6 NX induced a marked increase in plasma concentrations of anti-oxLDL antibodies as well as pro-atherogenic cytokines [interleukin (IL)-2 (IL-2), IL-4, IL-6 and IL-12)] in native mouse LDL (nLDL)-, oxLDL- and PBS-immunized mice. Even though nLDL- and oxLDL-immunized mice displayed higher anti-MDA-LDL IgG titres than the PBS group, aortic atherosclerosis lesion size was not affected by immunization. Immunization with the apoB-peptide P45, which consistently reduces classical atherosclerosis in non-uraemic mice, also did not reduce lesion size in uraemic apoE-/- mice. The results suggest that the pro-inflammatory and pro-atherogenic effect of uraemia overrules the anti-atherogenic potential of oxLDL immunization in apoE-/- mice.

The probiotic Bifidobacteria infantis: An assessment of potential antidepressant properties in the rat

It is becoming increasingly apparent that probiotics are important to the health of the host. The absence of probiotic bacteria in the gut can have adverse effects not only locally in the gut, but has also been shown to affect central HPA and monoaminergic activity, features that have been implicated in the aetiology of depression. To evaluate the potential antidepressant properties of probiotics, we tested rats chronically treated with Bifidobacteria infantis in the forced swim test, and also assessed the effects on immune, neuroendocrine and central monoaminergic activity. Sprague-Dawley rats were treated for 14 days with B. infantis. Probiotic administration in naive rats had no effect on swim behaviours on day 3 or day 14 following the commencement of treatment. However, there was a significant attenuation of IFN-γ, TNF-α and IL-6 cytokines following mitogen stimulation ( p < 0.05) in probiotic-treated rats relative to controls. Furthermore, there was a marked increase in plasma concentrations of tryptophan ( p < 0.005) and kynurenic acid ( p < 0.05) in the bifidobacteria-treated rats when compared to controls. Bifidobacteria treatment also resulted in a reduced 5-HIAA concentration in the frontal cortex and a decrease in DOPAC in the amygdaloid cortex. The attenuation of pro-inflammatory immune responses, and the elevation of the serotonergic precursor, tryptophan by bifidobacteria treatment, provides encouraging evidence in support of the proposition that this probiotic may possess antidepressant properties. However, these findings are preliminary and further investigation into the precise mechanisms involved, is warranted.

犬急性膵炎7例におけるC-反応性蛋白およびα&lt;SUB&gt;1&lt;/SUB&gt;-酸性糖蛋白の血漿濃度の変化

Plasma concentrations of two acute phase proteins, C-reactive protein (CRP) and α1-acid glycoprotein (α1AG), were measured in seven dogs with acute pancreatitis. All dogs were positive for canine trypsin-like immunoreactivityin plasma at admission to our hospital (Day 0). High plasma concentrations of CRP (>5.0mg/dl) weredetected in four dogs, and high plasma concentrations of α1AG (>500, μg/ml) were found in two dogs. Onedog died on Day 3 with marked increases in plasma concentrations of both CRP and α1AG. Persistently higherconcentrations of both CRP and α1AG were detected in two dogs that required prolonged treatment for pancreatitis.In four dogs with a remarkable recovery, plasma concentrations of either CRP or α1AG returned tonormal ranges in the early stages of treatment. These findings suggest that serial measurements of plasmaconcentrations of both CRP and α1AG were useful markers for evaluating the effects of treatment and prognosisin dogs with acute pancreatitis.

Therapeutic effects of coenzyme Q10 (CoQ10) and reduced CoQ10 in the MPTP model of Parkinsonism

Coenzyme Q10 (CoQ10) is a promising agent for neuroprotection in neurodegenerative diseases. We tested the effects of various doses of two formulations of CoQ10 in food and found that administration in the diet resulted in significant protection against loss of dopamine (DA), which was accompanied by a marked increase in plasma concentrations of CoQ10. We further investigated the neuroprotective effects of CoQ10, reduced CoQ10 (ubiquinol), and CoQ10 emulsions in the (MPTP) model of Parkinson's disease (PD). We found neuroprotection against MPTP induced loss of DA using both CoQ10, and reduced CoQ10, which produced the largest increases in plasma concentrations. Lastly, we administered CoQ10 in the diet to test its effects in a chronic MPTP model induced by administration of MPTP by Alzet pump for 1 month. We found neuroprotective effects against DA depletion, loss of tyrosine hydroxylase neurons and induction of alpha-synuclein inclusions in the substantia nigra pars compacta. The finding that CoQ10 is effective in a chronic dosing model of MPTP toxicity, is of particular interest, as this may be more relevant to PD. These results provide further evidence that administration of CoQ10 is a promising therapeutic strategy for the treatment of PD.

Immunoreactive Insulin-Like Growth Factor in Plasma during Pre- and Post-Partum Periods of Thoroughbred Mares from which the Newborn were Removed: its Pattern, Physiological Function and Relation to Other Hormones

Plasma concentrations of immunoreactive (ir-) insulin-like growth factor I (IGF-I) were measured in 9 pregnant mares from 30 days before foaling to Day 7 after ovulation of the first post-partum estrus (foal heat) in order to characterize its pattern and investigate its possible role in mares during that time. A marked increase in plasma concentrations of ir-IGF-I was observed during the last month of pregnancy. After foaling, ir-IGF-I sustained its high concentration for the first week after parturition and it gradually decreased thereafter. Throughout the observation period of the current study, a significant positive correlation between ir-IGF-I and FSH (r=0.58, p<0.05) was found. The significant increase in ir-IGF-I and FSH shortly prior to parturition may be responsible for the rapid resumption of ovarian activity in mares and the initiation of foal heat in thoroughbred mares. Statistically significant positive correlation between ir-IGF-I, FSH and ir-inhibin levels observed in the current study confirm the previous suggestion that ir-inhibin secreted during late pregnancy in mares may be biologically inactive.

Tetrathiomolybdate protects against cardiac damage by doxorubicin in mice

Cardiac toxicity is the limiting factor in therapy with doxorubicin, an otherwise useful cancer drug. In this article we detail our study of a mouse model of doxorubicin-induced cardiac toxicity in which, after 4 days' treatment, doxorubicin caused marked increases in plasma concentrations of creatine kinase, lactic dehydrogenase, and troponin I, indicators of cardiac injury; marked increases in the plasma concentrations of tumor necrosis factor-alpha and interleukin-1(beta), both inflammatory cytokines; and a marked increase in the plasma concentration of interleukin-2, an indicator of cytotoxic T-cell activation. Therapy with tetrathiomolybdate, designed to limit copper availability, eliminated almost all of the increases of these six parameters in plasma. The marked protection against cardiac injury by doxorubicin in tetrathiomolybdate-treated animals suggests that tetrathiomolybdate would be of use clinically in helping prevent doxorubicin toxicity in patients. In other preclinical work, it has been shown that tetrathiomolybdate potentiates the chemotherapeutic effect of doxorubicin in cancer, so a double benefit might accrue clinically from the combined use of tetrathiomolybdate and doxorubicin. The mechanism by which tetrathiomolybdate protects against doxorubicin toxicity is of considerable interest. Our working hypothesis, based on the inhibition of interleukin-2 by tetrathiomolybdate as shown here, is that tetrathiomolybdate interrupts the inflammatory cascade at the activated-T-lymphocyte stage.

Alpha-melanocyte stimulating hormone release in response to thyrotropin releasing hormone in healthy horses, horses with pituitary pars intermedia dysfunction and equine pars intermedia explants

Thyrotropin releasing hormone (TRH) stimulates an increase in plasma cortisol in horses with pars intermedia dysfunction (PPID, Cushing's disease). A similar phenomenon is observed in humans with Cushing's disease or Nelson's syndrome. The mechanism of the response in humans is not known, but an alteration in receptor expression, selectivity or responsiveness in abnormal corticotropes has been proposed. Horses with PPID, unlike humans, almost exclusively have adenomas of pars intermedia (PI) rather than pars distalis (PD) origin. Therefore, the mechanism responsible for the TRH response observed in horses likely differs. We proposed that TRH directly stimulates the PI in normal and PPID-affected horses to release proopiomelanocortin (POMC) derived peptides. Using α-melanocyte stimulating hormone (α-MSH) as a marker of a PI response and ACTH as a marker of a PD response, we were able to demonstrate a marked increase in plasma concentration of α-MSH and a modest, but significant increase in ACTH after TRH treatment in normal horses. The ability of TRH to directly stimulate release of POMC peptides was confirmed using PI and PD tissue explants. The presence of TRH receptor mRNA in PI tissue from both normal and PPID horses was confirmed using reverse transcriptase polymerase chain reaction. We conclude that TRH triggers the release of POMC-derived peptides from the PI through the direct stimulation of TRH receptors normally expressed on melanotropes. The increase in plasma cortisol following TRH in horses with PPID is likely attributable to the release of ACTH from the hyperplastic PI.

Accentuation of ANP secretion to endothelin-1 in hypertrophied atria

To investigate modulation of ANP secretion by atrial hypertrophy, the secretion of ANP in response to stretch and endothelin-1 was studied using isolated perfused quiescent atria from rats treated with monocrotaline (MCT). Male Sprague-Dawley rats were given a single subcutaneous injection of 50 mg/kg MCT or saline and were sacrificed at 6 weeks. Rats with right heart hypertrophy showed an increase in ANP mRNA and decrease in tissue concentration of ANP in hypertrophied atria and a marked increase in plasma concentration of ANP. In isolated perfused hypertrophied right atria from MCT rats, changes in atrial volume induced by increased atrial pressure caused proportional increases in mechanically stimulated extracellular fluid (ECF) translocation and stretch-activated ANP secretion. Changes in atrial volume and mechanically stimulated ECF translocation in hypertrophied right atria were not different from those in control right atria. The stretch-activated ANP secretion was suppressed without significant difference in basal ANP secretion, as compared to control right atria. Therefore, the stretch-activated ANP secretion from hypertrophied right atria into the atrial lumen in relation to the ECF translocation (ANP concentration in the interstitium) was lower than that from control atria. A positive correlation between the stretch-activated ANP secretion in relation to the ECF translocation and tissue ANP content was found in control atria but not in hypertrophied atria. Endothelin-1 caused increases in stretch-activated ANP secretion in a dose-dependent manner, which were accentuated in hypertrophied right atria. Therefore, we suggest that atrial hypertrophy causes an attenuated response to stretch and accentuated response to endothelin-1 of ANP secretion.

Dynamic changes in plasma concentrations of gonadotropins, inhibin, estradiol-17beta and progesterone in cows with ultrasound-guided follicular aspiration.

To elucidate the effects of ultrasound-guided transvaginal follicular aspiration, plasma concentrations of FSH, LH, inhibin, estradiol-17beta and progesterone, and folliculogenesis were examined in Holstein cows. Four clinically healthy cows with regular estrous cycles were scanned by ultrasound per rectum once a week for 9 weeks before the commencement of follicular aspiration. All visible follicles were divided into 3 categories based on their sizes (2 < or = small < 5 mm; 5 < or = medium < 10 mm, large > or = 10 mm). The follicular aspiration was started at random during the estrous cycle and conducted under epidural anesthesia induced with 5 ml of 2% lidocaine once a week for 6 weeks. The average number of total visible follicles > or = 2 mm in diameter at 7 days after aspiration (21.7 +/- 7.4, n = 24) was similar to that before starting aspiration (26.7 +/- 10.5, n = 36). Plasma inhibin and estradiol-17beta declined and fell to a trough on 1.5 days and returned to pre-aspiration values by 5 days after aspiration. Plasma concentrations of FSH increased and reached peak levels between 1 and 1.5 days after aspirations. Plasma concentrations of LH also increased and reached peak levels between 0.5 and 1.5 days after aspirations. Both plasma FSH and LH had returned to pre-aspiration levels by 5 days after aspirations. Plasma concentrations of progesterone did not change with the follicular aspiration. These results demonstrate that follicular aspiration decreases plasma concentrations of inhibin and estradiol-17beta, which in turn leads to a rise in plasma concentrations of FSH and LH. It is suggested that marked increases in plasma concentrations of FSH and LH after the aspiration stimulate the development and maturation of a new cohort of follicles within one week in cows.

Effect of d-ribose on purine synthesis and neurological symptoms in a patient with adenylosuccinase deficiency

Oral supplementation of 10 mmol/kg/day of d-ribose to a patient with an inherited deficit of adenylosuccinase, severe psychomotor retardation, and epilepsy caused a marked increase in plasma concentration and urinary excretion of urate, while minor changes in succinylpurine levels were observed. d-Ribose administration was accompanied by a slight improvement of behaviour and a progressive reduction of seizure frequency, which increased dramatically upon two attempts to withdraw the drug. Substitution of d-ribose with an equivalent amount of d-glucose did not result in an increase of seizure frequency.

Chronic ingestion of lycopene-rich tomato juice or lycopene supplements significantly increases plasma concentrations of lycopene and related tomato carotenoids in humans

The bioavailability of lycopene from tomato juice and 2 dietary supplements, each containing 70–75 mg lycopene, was studied in 15 healthy volunteers in a randomized, crossover design. Subjects ingested lycopene-rich tomato juice, tomato oleoresin, lycopene beadlets, and a placebo for 4 wk each while consuming self-selected diets. Treatment periods were separated by 6-wk washout periods. Plasma lycopene concentrations, assessed at baseline and weekly throughout the treatment periods, were significantly higher during tomato juice, oleoresin, and lycopene beadlet ingestion than during placebo ingestion. Mean (±SEM) increases in plasma lycopene at week 4 of tomato juice, oleoresin, and lycopene beadlet ingestion were not significantly different: 0.24 ± 0.07, 0.23 ± 0.05, and 0.24 ± 0.06 mmol/L, respectively. Plasma concentrations of phytofluene and phytoene, which were present in small amounts in tomato juice, oleoresin, and lycopene beadlets, increased significantly with ingestion of these 3 products. b-Carotene, z-carotene, and 2,6- cyclolycopene-1,5-diol (a metabolite of lycopene)—also present in tomato juice and supplements—were significantly increased with consumption of the tomato juice and lycopene beadlets, but not with oleoresin consumption. A marked increase in plasma concentrations of an unknown compound was observed; it was detected in trace amounts in tomato juice, oleoresin, and lycopene beadlets, and had a maximum absorbance at 448 nm and a molecular weight of 556. Concentrations of plasma lycopene and other carotenoids with potential for enhancing human health can be increased by ingestion of realistic amounts of tomato juice. Lycopene appears to be equally bioavailable from tomato juice and the supplements used in this study. Am J Clin Nutr 1998;68:1187–95.

Induction of superovulation by immunoneutralization of endogenous inhibin through the increase in the secretion of follicle-stimulating hormone in the cyclic golden hamster.

The present study was conducted to study the effect of immunoneutralization against endogenous inhibin on FSH, LH, oestradiol-17 beta and progesterone secretion and to investigate the effect of removal of endogenous inhibin on subsequent follicular development in the hamster. After treatment with anti-inhibin serum (inhibin-AS) at 1100 h on day 2 of the oestrous cycle (day 1 = day of ovulation), a marked increase in plasma levels of FSH and a slight increase in plasma levels of LH were noted and pituitary contents of FSH, but not LH, were also increased. In the group treated with inhibin-AS, superovulation occurred on day 1 of the following cycle. Plasma levels of oestradiol-17 beta markedly increased with the increase in the number of ovulations induced by human chorionic gonadotrophin (hCG) as compared with those in control animals. In the second cycle, plasma concentrations and pituitary contents of FSH in the animals given 200 microliters inhibin-AS still showed high values as compared with those in the animals treated with control serum, although superovulation did not occur on day 1 of the third cycle. Plasma concentrations and pituitary contents of LH in the hamster given 200 microliters inhibin-AS tended to decrease as compared with those in control animals during the second cycle. Plasma concentrations of oestradiol-17 beta in the animals treated with 200 microliters inhibin-AS changed in a similar way to controls. A marked increase in plasma concentrations of progesterone was noted on days 1 and 2 of the second cycle in the group receiving inhibin-AS. The twice daily injection of 1 IU hCG during the second cycle to the animals given 200 microliters inhibin-AS induced superovulation on day 1 of the third cycle. These results indicate that circulating inhibin may be an important indicator of the number of developing follicles and may maintain the species-specific number of developing follicles through suppression of FSH secretion in the cyclic hamster. They also suggest that high levels of inhibin slightly suppress plasma levels of LH, indicating that plasma LH may also regulate follicular development in the cyclic hamster.

High concentrations of immunoreactive inhibin in the plasma of mares and fetal gonads during the second half of pregnancy.

Plasma concentrations of immunoreactive (ir)-inhibin were measured in seven pregnant mares from around Day 140 of gestation to Day 2 after parturition using a heterologous bovine-based radioimmunoassay (RIA). Concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), oestradiol-17 beta, progesterone and relaxin were also measured in the same samples. A marked increase in plasma concentrations of ir-inhibin, FSH and LH occurred between Day 220 and Day 300 of gestation but the concentrations of all three hormones returned to baseline by about Day 320 (three weeks before parturition). In contrast, circulating concentrations of the three placental hormones, oestradiol-17 beta, progesterone and relaxin, increased during the final weeks of pregnancy and then decreased markedly to basal values within two days of parturition. There was a positive correlation between circulating concentrations of ir-inhibin and FSH (r = 0.75, P < 0.01) rather than the expected negative correlation. ir-inhibin was not detected in homogenates obtained at Day 190 of pregnancy and form term placenta, but high concentrations of ir-inhibin were present in homogenates of fetal and newborn gonads. Despite the high concentrations of ir-inhibin in these homogenates, they failed to exert any suppressive bioactivity on FSH secretion by rat pituitary cells cultured in vitro. Furthermore, immunohistochemical staining revealed the presence of inhibin in the interstitial cells of equine fetal gonads at Day 190 of gestation. These findings demonstrate for the first time that high concentrations of ir-inhibin, LH and FSH are secreted into the peripheral circulation of the mare during the second half of pregnancy. However, ir-inhibin present in the plasma of pregnant mares appears to be biologically inactive. This hormone is not presumed to be of placental origin but it is proposed that either the enlarged fetal gonads or the maternal ovaries, or both of these organs, may be a source of inhibin in response to the coincident increase in circulating concentrations of LH and FSH.

The effect of physiological manoeuvres on the absorption of inhaled nedocromil sodium.

In a previous study we showed, in both asthmatic patients and in healthy subjects, a marked increase in plasma concentration of nedocromil immediately following an exercise challenge with associated FEV1 measurements. To identify which component of the exercise challenge is responsible, we have now studied the effect of various manoeuvres on plasma nedocromil concentration in eight healthy subjects after inhalation of 1 ml nedocromil solution (1% w/v) via a Wright nebuliser. Each patient was dosed on six occasions, separated by at least 3 days. Between 15 and 23 min after dosing one of the following manoeuvres was performed: control (no manoeuvre); steady exercise for 8 min, a series of FEV1 measurements, exercise plus FEV1 measurements, three Valsalva manoeuvres and hyperventilation for 3 min. Mean plasma drug concentrations under control conditions were similar at 15 and 23 min after dosing. However, there were significant increases in plasma drug concentration following exercise, FEV1 manoeuvres and exercise plus FEV1 manoeuvre. There were no significant changes in plasma drug concentration following Valsalva manoeuvres and hyperventilation. The results suggest that certain manoeuvres increase the absorption of nedocromil sodium, probably as a consequence of an increase in lung volume.

The Use and Abuse of Toxicokinetics: What Does Actual Data Tell Researchers?

Pharmacokinetic data obtained in 71 toxicity studies on 38 compounds were investigated. Twenty-four studies (33%) were of “I-type” nonlinear kinetics where the plasma concentration did not increase as much as the dose increased, while 14 studies (20%) were of “S-type” nonlinear kinetics where the plasma concentration increased super-proportionally. Some marked increase in plasma concentrations during repeated administration occurred exclusively in “S-type” nonlinear kinetics cases, while decreases were found in some “I-type” kinetics cases. Plasma concentrations at dose levels which produced toxicity were less than the human therapeutic plasma concentrations in 6% of studies and in 18% for those compounds which did not produce toxicity. The intertest compounds difference in items investigated seemed to be much greater than the interstudies (animal species) difference. It should be stressed from these results that the well-designed assessment of systemic exposure in toxicity studies should be requested onl...

THE ROLE OF HISTAMINE IN THE CARDIOVASCULAR EFFECTS OF ATRACURIUM

We have investigated the effect of a bolus injection of atracurium 0.6 mg kg-1 on the cardiovascular system in 16 patients undergoing aortocoronary bypass surgery. H1- and H2-receptor antagonists were administered to eight patients before the neuromuscular blocker. A standard anaesthetic was used comprising fentanyl, flunitrazepam, etomidate and enflurane. After administration of atracurium, haemodynamic changes and plasma histamine concentrations were measured at frequent intervals. In the first group, who received only atracurium, a brief but marked decrease in SVR and MAP occurred, accompanied by an increase in Cl, together with a marked increase in plasma concentration of histamine. In the second group, who received H1- and H2-receptor block, there was no decrease in MAP and only a small increase in plasma histamine concentration. However, there were significant changes in SVR and Cl similar to those in atracurium group.

Slow Estradiol-induced Vitellogenesis in the Tuatara, Sphenodon punctatus

The vitellogenic response to exogenous estradiol-17β in wild male and female tuatara (Sphenodon punctatus) is extremely slow to induce. Tuatara given slowrelease implants containing 4-11 μg estradiol/g body mass showed a marked elevation in plasma estradiol concentrations within 2 d (to levels of up to 2,967 pg/mL) but no marked increases in plasma concentrations of calcium, total protein, or inorganic phosphate within 11 d. A small increase in the amount of electrophoretically detectable vitellogenin in the plasma (expressed as a percentage of total plasma protein) was evident by 11 d. Plasma concentrations of progesterone in individual females and testosterone in individual males were low (<3. 7 ng/mL and <3.8 ng/mL, respectively) during the 11 d. Several individuals captured 4-9 mo after administration of implants showed very high plasma levels of vitellogenin (up to 59% of total plasma protein), calcium (up to 61 mmol/L), total protein (up to 108 g/L), and inorganic phosphate (up to 39 mmol/L); these concentrations are similar to those seen in other estrogen-treated reptiles within much shorter time periods. Estradiol-induced vitellogenesis in tuatara is slower to induce and may occur at a lower maximal rate than in other reptiles examined. These responses are probably explained by the cool body temperatures exhibited by tuatara and are consistent with the slow rate of natural vitellogenesis observed in wild female tuatara.

Effectiveness of interval nitrate therapy in angina pectoris

Because of rapid tolerance development, the use of multiple daily doses of oral nitrates or continuous application of transdermal nitrate systems can no longer be considered justified. Only with an interval treatment, which prevents nitrate accumulation in the plasma such that, from low baseline values, renewed administration of the drug results in a marked increase in plasma concentration, is it possible to utilize the antianginal and antiischaemic effects of nitrates for meaningful long-term treatment. For isosorbide dinitrate and isosorbide 5-mononitrate, as well as for transdermal nitroglycerin systems, interval treatment dosing regimens with maintained effectiveness documented in controlled studies have been delineated. To some degree, the principle of interval treatment can be achieved with continuously applied transdermal patches designed for discontinuous release of their content, which yield maintained though somewhat attenuated effects. Recent studies have shown that the tolerance to nitroglycerin, which develops within the first 12h of contact with currently available transdermal patches, can be prevented by gradually increasing the plasma concentration during this period of time. Evidence for clinically relevant rebound phenomena during interval treatment has not been observed.