Slow-release Preparation Research Articles

Suppression of Airway Inflammation by Theophylline in Adult Bronchial Asthma

Background: Chronic continuous airway inflammation caused by eosinophils has been noted to play critical roles in the pathophysiology of bronchial asthma, in addition to reversible obstruction and hypersensitivity of the respiratory tract. Therefore, suppression of chronic airway inflammation has become more important in asthma treatment. Although theophylline has been a conventionally used bronchodilator, it has been recently reported to have concurrent anti-inflammatory effects. Objective: Accordingly, we studied the effects of a slow-release theophylline preparation, Theolong^®, on airway inflammation. Methods: Administration of Theolong 400 mg/day to 24 patients with mild or moderate asthma and measuring eosinophil cationic protein (ECP), a marker of airway inflammation, and eosinophils in sputum and peripheral blood at 4 and 8 weeks. Results: As a result, sputum ECP, serum ECP and sputum eosinophil count (%) were significantly lowered after 4 and 8 weeks. Conclusion: Thus, in the theophylline-administered group, slow-release theophylline, Theolong^®, was effective in treating asthma, with anti-inflammatory effects on inflammatory cells besides its bronchodilator action.

Complicaciones motoras del tratamiento con levodopa en la enfermedad de Parkinson

Motor complications of treatment with levodopa affect more than 50% of patients after several years' treatment. This has a marked effect on patients with Parkinson's disease since these side effects are undesirable, affect the natural course of the disorder and complicate treatment. In this review we describe the main epidemiological, physiopathological and therapeutic aspects of the motor complications of levodopa. According to most epidemiological studies, starting treatment at an early age and more severe degree of the disorder are the main risk factors. The physiopathology of motor complications is varied. It has been thought to be due to loss of the buffer effect of the brain on plasma levels of levodopa, alterations in the functional state of the postsynaptic receptors and chronic intermittent use of levodopa. Management includes division and/or reduction of the dose of levodopa, use of slow-release preparations and association of dopaminergic agonists with COMT inhibitors which are the latest drugs to be tried. Various surgical possibilities in specialist centres may also be considered for serious cases of motor complications which do not respond to medical treatment. Recent advances in understanding the physiopathology and in the medical and surgical treatment permit improved control of the motor complications of chronic treatment with levodopa.

Tissue-specific effects of estrogen on monoamine oxidase A and B in the rat

Estrogen replacement therapy is widely used in postmenopausal women. The current study examines the effect of varying concentrations of estrogen on the levels of activity of monoamine oxidase A and -B in brain and in other tissues. Adult female rats were ovariectomized and randomized to receive a subcutaneous, slow-release preparation of either placebo or one of three doses of 17-β-estradiol (0.05, 0.5, or 5.0 mg pellet , estimated serum levels of 20–25 pg ml , 100–600 pg ml , and 1–2 ng ml , respectively). Animals were sacrificed at 3 weeks and MAO-A and -B activity was assessed in homogenates of heart, liver, lung, uterus, kidney, adrenal and small intestine using 5-hydroxytryptamine and phenylethylamine as substrates. Cortex, amygdala and hypothalamus were microdissected from frozen sections of the brain and were also assayed for MAO-A and -B activity. High dose estrogen (5 mg pellet ) significantly decreased MAO-B activity and resulted in lesser or insignificant changes in MAO-A activity, respectively in liver (−30%, +1%), kidney (−22%, −11%), and uterus (−57%, −35%)(p < 0.05). No significant changes in enzyme activity were observed in heart, adrenal, lung and small intestine. In brain, estrogen ( 5mg pellet ) decreased MAO-A activity in the hypothalamus (-−2.8%) and amygdala (−21%), with no significant change seen in MAO-B. Our results suggest that estrogen exerts a tissue-specific, differential regulation of MAO-A and -B activity.

Characterization of a Fibrin Glue–GDNF Slow-Release Preparation

One novel method to deliver trophic factor locally in the CNS is to mix it into fibrin glue. In the present studies, [ 125I]-labeled GDNF-containing fibrin glue balls were used to determine binding and spread of the trophic factor. First, the binding of different concentrations of [ 125I]-labeled GDNF in fibrin glue was determined in vitro. Within the six concentrations used (from 200 nM to 0.004 nM, 0 M as control), there was a strong linear correlation between the [ 125I]-GDNF concentration and the recovered radioactivity ( r = 0.992). The mean bound radioactivity in 16 samples with 4 nM [ 125I]-GDNF was 71262 ± 2710 CPM, and accounted for 89.8% of the mean initial count of free [ 125I]-GDNF (79369 ± 3499 CPM). Second, [ 125I]-GDNF–containing glue balls were implanted into the anterior chamber of adult rats. The implanted fibrin glue balls decreased in size with time, but could still be identified on the irises 2 wk after implantation. Radioactivity was concentrated at the implantation sites in the early stages with a distribution in the surrounding iris tissue, which became separated into focal radioactive spots at the third week. Counts of radioactivity were significantly higher in the [ 125I]-GDNF glue ball-implanted irises than controls until 14 days after implantation. A study of the [ 125I] decay over time using least-squares linear regression demonstrated first-order kinetics ( r = −0.98, p <0.02) with k = 0.0091 and T 1/2 = 76 h. Finally, [ 125I]-GDNF–containing glue balls were implanted in the spinal cord of adult rats. Radioactivity was concentrated at the implantation sites in the early stages and was later distributed more widely in the surrounding thoracic cord. The [ 125I]-GDNF–containing glue degraded over time and became a porous meshwork with decreasing radioactivity at the later time points. Radioactivity in the spinal cords subjected to implantation of [ 125I]-GDNF–containing glue balls was higher than in controls for 14 days. Study of the [ 125I] decay by time with least-squares linear regression demonstrated first-order kinetics ( r = −0.97, p = 0.001) with T 1/2 = 75.6 h. We conclude that the trophic factor GDNF becomes bound in the fibrin glue matrix from which it is gradually released. Our results suggest that fibrin glue is an effective substrate for keeping a trophic factor localized in situ for a finite period, protected from the circulation, surrounding aqueous humor or CSF.

Characterization of a fibrin glue-GDNF slow-release preparation.

One novel method to deliver trophic factor locally in the CNS is to mix it into fibrin glue. In the present studies, [125I]-labeled GDNF-containing fibrin glue balls were used to determine binding and spread of the trophic factor. First, the binding of different concentrations of [125I]-labeled GDNF in fibrin glue was determined in vitro. Within the six concentrations used (from 200 nM to 0.004 nM, 0 M as control), there was a strong linear correlation between the [125I]-GDNF concentration and the recovered radioactivity (r = 0.992). The mean bound radioactivity in 16 samples with 4 nM [125I]-GDNF was 71262 +/- 2710 CPM, and accounted for 89.8% of the mean initial count of free [125I]-GDNF (79369 +/- 3499 CPM). Second, [125I]-GDNF-containing glue balls were implanted into the anterior chamber of adult rats. The implanted fibrin glue balls decreased in size with time, but could still be identified on the irises 2 wk after implantation. Radioactivity was concentrated at the implantation sites in the early stages with a distribution in the surrounding iris tissue, which became separated into focal radioactive spots at the third week. Counts of radioactivity were significantly higher in the [125I]-GDNF glue ball-implanted irises than controls until 14 days after implantation. A study of the [125I] decay over time using least-squares linear regression demonstrated first-order kinetics (r = -0.98, p <0.02) with k = 0.0091 and T 1/2 = 76 h. Finally, [125I]-GDNF-containing glue balls were implanted in the spinal cord of adult rats. Radioactivity was concentrated at the implantation sites in the early stages and was later distributed more widely in the surrounding thoracic cord. The [125I]-GDNF-containing glue degraded over time and became a porous meshwork with decreasing radioactivity at the later time points. Radioactivity in the spinal cords subjected to implantation of [125I]-GDNF-containing glue balls was higher than in controls for 14 days. Study of the [125I] decay by time with least-squares linear regression demonstrated first-order kinetics (r = -0.97, p = 0.001) with T 1/2 = 75.6 h. We conclude that the trophic factor GDNF becomes bound in the fibrin glue matrix from which it is gradually released. Our results suggest that fibrin glue is an effective substrate for keeping a trophic factor localized in situ for a finite period, protected from the circulation, surrounding aqueous humor or CSF.

Decrease of tolerance to, and physical dependence on morphine by glutamate receptor antagonists

The effects of the non-competitive antagonists of the glutamate complex receptor, dizocilpine (MK 801) and ketamine and of the competitive antagonist CGP 39551 were examined on the induction of tolerance to morphine, the development of physical dependence and the expression of the abstinence syndrome to the opiate in mice. Morphine was administered in a single dose (300 mg/kg) of a slow release preparation. Dizocilpine (0.005 or 0.01 mg/kg given at 3, 12 and 24 h after the priming dose of morphine), ketamine (2, 4 or 8 mg/kg, 30 min before and 3, 6, 9 and 24 h after the priming dose) and dl-( E)-2-amino-4-methyl-5-phosphonopentanoate carboxy-ethylester (CGP 39551) (1.5 or 3 mg/kg, but not 6 or 12 mg/kg 30 min before and 12 and 24 h after the priming dose) reduced the intensity of tolerance to, and physical dependence on morphine. The drugs also reduced the intensity of the abstinence behaviour when given in a single dose, 30 min before (s.c.) naloxone (4 mg/kg)-precipitated withdrawal syndrome in mice chronically treated with morphine. Thus, the results of this study indicate that competitive and non-competitive NMDA receptor antagonists prevent morphine tolerance and decrease the development of physical dependence on the opiate in mice.

Activated Charcoal for Slow-Release Verapamil

Verapamil, a widely used calcium channel blocker, is usually absorbed rapidly after ingestion. Because of verapamil's relatively short half-life and need for frequent dosing, slow-release preparations have gained popularity. The potentially delayed absorption of these preparations may have implications for activated charcoal therapy in …

Molecular mechanisms of coronary collateral vessel growth.

Growth of coronary collaterals can change markedly the natural history of coronary artery disease: Stenoses and occlusions of the coronary arteries, even of the left main coronary artery, can be survived without infarction provided that the stenosing process has not progressed too fast, since the process of collateral development by growth needs time (a few weeks).1 2 3 However, in most cases, thrombus formation proceeds faster than vascular growth and infarcts develop. In many cases, collaterals, although they cannot prevent infarction in the majority of cases, may limit the damage and infarcts are smaller than expected from the size of the region at risk.4 Understanding collateral growth may mean to be potentially and eventually able to stimulate it by the injection of drugs, by the injection of growth factors, or by somatic gene therapy in patients at risk of infarction. In the past we have shown that collaterals grow by DNA synthesis and mitosis of endothelial and smooth muscle cells.3 These cells are quiescent in normal adult arteries, with their population kinetics close to zero. Under abnormal conditions a rapid conversion to G1 can occur and the cell cycle can be completed in ≈22 hours.3 With rapidly progressing stenosis in dogs (3 days from the onset of stenosis to complete occlusion), the labeling index of the endothelium of the midzone segment reached 7.5% and was followed by a wave of smooth muscle cell mitosis of only slightly lesser magnitude. Since controlled and regulated growth does not proceed without the presence and action of growth factor peptides and their receptors, several groups have investigated that aspect.5 6 7 8 The growth factors that are potentially involved in the process of cardiac collateralization are aFGF, bFGF, VEGF, IGF-1, and PDGF.7 9 10 11 12 13 …

Age and severe adverse drug reactions caused by nifedipine and verapamil

The association of age with risk for severe adverse drug reactions (SADRs) was studied in 2371 and 862 hospitalized patients taking nifedipine and verapamil, respectively. Nifedipine caused hypotension ( n = 22), tachycardia ( n = 3), and acute renal failure ( n = 1) (total SADR rate, 1.1%, 26 2371 ). Verapamil caused hypotension ( n = 3), bradycardia ( n = 9), and atrioventricular blocks ( n = 2) (total SADR rate 1.6% 14 862 ). The mean age of patients with and without SADRsr nifedipine 77.1 ± 1.7 71.8 ± 0.8 years, respectively ( p < 0.05), and for verapamil 73.4 ± 2.9 and 73.1 ± 0.4 years, respectively. and Sex, length of stay, comorbidity, polypharmacy, intake of slow-release preparations, daily dosage, and new intake of calcium antagonists were examined as potential confounders of the age-SADR association. After adjusting for potential confounders, age was signficantly and independently associated with SADRs caused by nifedipine, but not with SADRs caused by verapamil (OR = 1.69, 95% CI = 1.05–2.72 and OR = 1.06, 95% 1.063–1.68 for 10-year increase, respectively). Although nifedipine and verapamil did not have significantly different rates of SADRs, an age-related gradient was found only for nifedipine.

Pharmacotherapy of opioids: present and future developments.

The clinically available opioids have different physicochemical properties, resulting in differences in clinical profile with regard to potency, onset, and duration of activity. However, they all have comparable side-effects after acute systemic application. Several approaches can be used to overcome these side-effects. The following approaches, with special emphasis on the perioperative use of the opioids, are discussed: (1) the use of alternative routes of administration, such as via the spine (epidurally and intrathecally); (2) optimization of opioid delivery by means of slow-release preparations, chronic infusions with indwelling catheters, and transdermal delivery systems; (3) use of additional agents to potentiate the analgesic properties of the opioids so that the dose of opioid can be reduced; and (4) searching for new analgesics on the basis of knowledge of the pain-transmission system and the different opioid receptors with their functional interactions.

New directions in the drug treatment of Parkinson's disease.

Parkinson's disease, a clinical syndrome with 4 cardinal features (bradykinesia, resting tremor, increased muscular rigidity and impaired postural balance), is mainly caused by the loss of dopaminergic neurons in the substantia nigra pars compacta. Although levodopa remains the 'gold standard' in the treatment of the disease, several emerging strategies are currently being developed. The first concerns new symptomatic drugs that either potentiate the effects of levodopa (e.g. slow-release preparations of levodopa, catechol-O-methyltransferase inhibitors and new dopamine agonists) or target clinical symptoms resistant to dopaminergic drugs (e.g. glutamate antagonists). The second strategy is to find drugs that are able to prevent or delay the neuronal death observed in Parkinson's disease. Several neuroprotective drugs are now in development in experimental research, but clinical trials in this area are still lacking. The development of these new drugs also depends on the validation of new clinical methodologies.

Poster 22: Prevention of Subglottic Stenosis: The Use of a Slow Release Preparation of 5‐Fluorouracil and Triamcinolone Acetonide in Rabbits

Otolaryngology–Head and Neck SurgeryVolume 113, Issue 2 p. P133-P133 Original Article Poster 22: Prevention of Subglottic Stenosis: The Use of a Slow Release Preparation of 5-Fluorouracil and Triamcinolone Acetonide in Rabbits Duncan R. Ingrams FRCS, presenter, Duncan R. Ingrams FRCS, presenter Boston, MassachusettsSearch for more papers by this authorSteven W. Sukin BA, Steven W. Sukin BA Boston, MassachusettsSearch for more papers by this authorPaul Ashton PhD, Paul Ashton PhD Boston, MassachusettsSearch for more papers by this authorHannu J. Valtonen MD, PhD, Hannu J. Valtonen MD, PhD Boston, MassachusettsSearch for more papers by this authorMichail M. Pankratov MS, Michail M. Pankratov MS Boston, MassachusettsSearch for more papers by this authorStanley M. Shapshay MD, Stanley M. Shapshay MD Boston, MassachusettsSearch for more papers by this author Duncan R. Ingrams FRCS, presenter, Duncan R. Ingrams FRCS, presenter Boston, MassachusettsSearch for more papers by this authorSteven W. Sukin BA, Steven W. Sukin BA Boston, MassachusettsSearch for more papers by this authorPaul Ashton PhD, Paul Ashton PhD Boston, MassachusettsSearch for more papers by this authorHannu J. Valtonen MD, PhD, Hannu J. Valtonen MD, PhD Boston, MassachusettsSearch for more papers by this authorMichail M. Pankratov MS, Michail M. Pankratov MS Boston, MassachusettsSearch for more papers by this authorStanley M. Shapshay MD, Stanley M. Shapshay MD Boston, MassachusettsSearch for more papers by this author First published: August 1995 https://doi.org/10.1016/S0194-5998(05)80798-3Read the full textAboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume113, Issue2August 1995Pages P133-P133 RelatedInformation

Dizepam induces tolerance in the isolated skin of Pleurodema thaul

The effects of the long-term administration of diazepam on the potential difference and short-circuit current of the isolated skin of the toad Pleurodema thaul (P. thaul) were investigated. Diazepam applied in a concentration range of 0.6 × 10 −6 to 5.2 × 10 −5 M decreased both electrical parameters. This response was unaffected by flumazenil indicating that the action of diazepam is not induced through benzodiazepine receptors. Induction of tolerance to diazepam on its observed effects on potential difference and short-circuit current was obtained by the administration of a single dose of the drug in a slow release preparation. Skins tolerant to diazepam were also tolerant to the acute effects of verapamil on both electric parameters. Tolerance to diazepam effects was partly reversed by increasing Ca 2+ concentration in the inner bathing solution. The results are consistent with a Ca 2+ channel blocking effect of diazepam in the P. thaul skin.

Delivery and fate of oral mesalamine microgranules within the human small intestine

Background/Aims Oral use of mesalamine in inflammatory bowel disease requires slow-release preparations to prevent premature absorption and inactivation. Resulting luminal concentrations within the human small intestine are unknown. The aim of this study was to determine human intestinal delivery patterns of mesalamine from a microgranule preparation (Pentasa; Ferring Arzneimittel, Kiel, Germany) effective in Crohn's disease with small bowel involvement. Methods A multilumen tube for duodenal, jejunal, and ileal aspiration and marker perfusion was placed in 6 normal subjects. Levels of luminal, plasma, and urinary mesalamine and its main metabolite, acetyl mesalamine, were measured for 7 hours after ingestion of mesalamine (500 mg) with a labeled meal. Results Gastric emptying of mesalamine paralleled the meal, and its release occurred throughout the small intestine (cumulative, 20% of dose). For 4 hours, mean luminal mesalamine and acetyl mesalamine concentrations were 52 and 38 μg/mL (duodenum), 59 and 82 μg/mL (jejunum), and 64 and 104 μg/mL (ileum). Cumulative colonic delivery was 82% (7% dissolved, 75% in microgranules), and urinary excretion was 3.5%. Conclusions Although the major part of continuous-release mesalamine is delivered to the colon, large proportions are liberated and available at high concentrations within the small intestinal lumen, thus explaining its therapeutic efficacy in small intestinal Crohn's disease.

New steroids for inflammatory bowel disease

: The antiinflammatory effects of glucocorticosteroids (GCS) in inflammatory bowel disease (IBD) are unsurpassed by those of any other type of drug, but the beneficial effects are often offset by troublesome, and sometimes irreversible, systemic side effects. Improved GCS have been developed with the aim of obtaining improved topical action, with reduced systemic side effects. A high tissue uptake and a high affinity for the GCS-receptor in combination with a rapid and extensive biotransformation in the liver are key prerequisites. Budesonide appears to be the most promising of the new topical GCS for IBD. In enema form it is already in clinical use for active distal ulcerative colitis (UC), with efficacy similar to that of conventional GCS but with no appreciable impact on adrenal gland function. Oral, slow release preparations of budesonide are efficacious in the treatment of active ileocecal Crohn's disease (CD), causing less suppression of endogenous plasma cortisol levels than does oral prednisolone, and giving rise to fewer, and less severe, side effects. Budesonide may also have a role for prevention of clinical relapse in certain groups of patients with CD, and is currently under evaluation for extensive and left-side UC. Long-term studies addressing issues such as impact on bone metabolism are currently in progress. Future development of GCS for IBD includes factors such as improved topical delivery systems, enhanced tissue uptake, and even more extensive first pass metabolism.

Spontaneous reporting of adverse drug reactions to non-steroidal anti-inflammatory drugs. A report from the Spanish System of Pharmacovigilance, including an early analysis of topical and enteric-coated formulations.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the third most commonly prescribed group of drugs in Spain. We present here the profile of adverse drug reactions (ADRs) attributed to them and reported to the Spanish System of Pharmacovigilance (SSPV) between 1983 and 1991, together with a preliminary analysis of topical, slow-release (SR) and enteric-coated (EC) preparations. Out of 18,348 reports of ADRs included in the SSPV database, 1609 (8.8%) implicated an NSAID. NSAIDs ranked second after antibiotics (15.1% of all reports) among the most commonly implicated drugs. Half of the patients were more than 55 years old, and 60% were women. Diclofenac (364 reports), piroxicam (282), indomethacin (197), naproxen (155), and ketoprofen (137) were the most commonly implicated NSAIDs in reports of ADRs. The most commonly reported ADRs were gastrointestinal (39%), cutaneous (20%), and those affecting the central and peripheral nervous system (9%). Seven reactions had a fatal outcome, and 138 were considered life threatening. Forty-nine reports included previously undescribed ADRs. There were 98 reports describing ADRs attributed to topical NSAIDs; 5 of these described 11 general reactions, such as duodenal ulcer, gastrointestinal bleeding, diarrhoea, dyspnoea, facial oedema, aggravation of bronchospasm, and angioedema. One hundred and sixty-eight reports referred to SR and EC preparations. The ratio of gastrointestinal to non-gastrointestinal reactions to SR-EC diclofenac was higher in the case of SR-EC diclofenac than in the case of plain diclofenac (P = 0.037); similarly, the ratio of CNS to non-CNS reactions to SR-EC indomethacin was also higher than the corresponding ratio with plain indomethacin (P = 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)

Gastric microcirculatory changes of portal-hypertensive rats can be attenuated by long-term estrogen-progestagen treatment.

It has been suggested that estrogen-progestagen therapy may be useful in preventing bleeding from gastric angiodysplasia, a vascular lesion similar to that described in portal-hypertensive gastropathy. In this study we assessed the effects of estrogen-progestagen therapy on gastric microcirculation and systemic and splanchnic hemodynamics in portal-hypertensive and sham-operated rats. One week after the surgical procedure (partial portal vein ligation or sham surgery), animals were given an intramuscular injection of a slow-release preparation of estrogen-progestagen or its vehicle. Two weeks later, gastric mucosal blood flow was measured by means of hydrogen gas clearance, a morphometrical analysis of gastric mucosal blood vessels was performed and systemic and splanchnic hemodynamics were evaluated with a radiolabeled-microspheres technique. In portal-hypertensive rats, estrogen-progestagen therapy induced a significant reduction in gastric mucosal blood flow, number of blood vessels and relative area of vessels. Similar changes, although of lesser magnitude, were achieved with estrogen or progestagen given separately and with the low dose of combined estrogen-progestagen. Estrogen-progestagen treatment also induced significant reductions in portal pressure and porto-collateral resistance without changing systemic or splanchnic hemodynamics. In contrast, estrogen-progestagen treatment did not induce changes in any of the parameters studied in sham-operated rats. We conclude that long-term estrogen-progestagen therapy reduces the gastric hyperemia, increased mucosal vessel density and portal pressure in portal-hypertensive rats.

Effectiveness and plasma levels of valproic acid with use of new slow-release preparation of sodium valproate

Effectiveness and plasma levels of valproic acid with use of new slow-release preparation of sodium valproate

Long term increases in coronary arterial conductance during five day infusion of low dose nicorandil.

The aim was to test the effects of nicorandil on coronary arterial conductance and on a possible development of tolerance or cross tolerance with glyceryl trinitrate during a 5 d continuous intravenous infusion of this hybrid molecule (consisting of a combination of potassium channel activation and simultaneous nitro-ester induced soluble guanylyl-cyclase activation). Continuous intravenous infusions of nicorandil at 2.5 micrograms.kg-1.min-1 and 10 micrograms.kg-1.min-1 into conscious chronically instrumented dogs were carried out for 5 d using a special portable infusion system. Employing additional short term infusions, dose-response curves were obtained by giving nicorandil or glyceryl trinitrate at increasing dosages both in the preinfusion control state and 4 h after terminating the nicorandil infusion. The 5 d infusion of 2.5 or 10.0 micrograms.kg-1.min-1 nicorandil resulted in a significant increase in large coronary artery diameter by 4.21 (SEM 0.14)% or 9.20(0.28)%, respectively. At the lower dose no significant tolerance or cross tolerance with glyceryl trinitrate was observed. However, at the higher dose there was a shift of the dose-response curve of both nicorandil and glyceryl trinitrate to the right, indicating some tolerance. The smaller dose did not induce hypotension or reflex increase in heart rate, whereas the larger resulted in a 42(2.5)% increase in heart rate. A dose regimen of 2.5 micrograms.kg-1.min-1 continuously administered for 5 d is capable of inducing a significant increase in coronary arterial conductance which was well maintained over the whole infusion period. Thus nicorandil can exert a selective large coronary artery dilatation and may bring about a well maintained increase in epicardial coronary conductance, especially when applied as a low dose slow release preparation which circumvents hypotension and increase in heart rate.

Effects of photoperiod and slow-release preparations of bromocryptine and melatonin on reproductive activity and prolactin secretion in female goats2

The present study was conducted to investigate seasonal reproductive patterns in a Boer Goat x German Fawn cross and ways to modulate these patterns by injecting slow-release bromocryptine and melatonin preparations. Twenty does were exposed to a light program of alternating periods of 90 long days (LD) followed by 100 short days (SD) twice in succession (LD1, SD1, LD2, SD2). At the beginning of LD2, does were treated as follows: vehicle injection (CTR, n = 7), slow-release bromocryptine (BCR, n = 6), or slow-release melatonin (MLT, n = 7). Blood samples were collected twice weekly, and from October 5 to December 14, 1989, weekly, to be analyzed for progesterone, prolactin, and melatonin. Long days inhibited cyclicity, and short days stimulated it. Prolactin was increased during long days and decreased during short days. High ambient temperature resulted in increased prolactin concentrations. Under long photoperiod, long-acting BCR suppressed prolactin secretion for 68 d, and the estrous season was extended compared with CTR. Under long photoperiod, long-acting MLT increased serum melatonin for 96 d, suppressed prolactin concentration, and substantially lengthened the period of cyclicity compared with the CTR- and BCR-treated groups. The resumption of cyclicity during the subsequent short day period occurred later in MLT- than in CTR- and BCR-treated groups. In conclusion, we modulated the day length-controlled seasonal cyclicity of goats by treating them with injectable slow-release preparations of BCR and MLT, the latter being more effective.