Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085631 (agitation)
 12,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypoglycaemia is possibly the most frequent metabolic emergency, in that insulin-induced hypoglycaemia is a common side-effect of treatment of a common disease. The symptoms are partly sympathetic and related to the release of catecholamines. These symptoms include sweating, tremor, palpitations, sensation of hunger, restlessness and anxiety. Other symptoms are caused by an insufficient supply of glucose to the brain, resulting in neuroglucopenia with symptoms like blurred vision, weakness, slurred speech, vertigo and difficulties in concentration. Symptom recognition is the primary and most effective defence against cerebral dysfunction which is the ultimate consequence of hypoglycaemia. Even in insulin-treated diabetic patients symptom failure might occur. Patients who experience severe episodes of hypoglycaemia do not constitute a special subgroup of patients. However, near-normalization of blood glucose levels have resulted in an increase in the incidence of severe hypoglycaemia. Moreover, the threshold for hormonal counter-regulatory responses in adrenaline, growth hormone and cortisol is lowered after a period of strict metabolic control in insulin-dependent diabetic patients. The glucose level at which the patients become subjectively aware of hypoglycaemia is correspondingly reduced. Other reasons for hypoglycaemia to occur are oral hypoglycaemic agents, especially sulfonylureas which may be potentiated by other drugs. Prolonged hypoglycaemia may be seen after first-order sulfonylureas, and may indicate glucose infusion as treatment. Next to insulin and sulfonylurea, ethanol is the most common cause of hypoglycaemia. In non-diabetics, hypoglycaemia will typically develop 6-24 h after a moderate or heavy intake of ethanol by a person who has had an insufficient intake of food for 1 or 2 days. Insulin-producing tumours, insulinomas and non-islet cell tumours may also be reasons for hypoglycaemia in non-diabetics. Treatment of mild episodes of hypoglycaemia is intake of fast-absorbing carbohydrates. Severe episodes can be treated with either i.v. dextrose or glucagon injected i.m. or i.v. The glycaemic response and recovery of a normal level of consciousness is 1-2 min slower after glucagon than after glucose.
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PMID:Endocrine emergencies. Hypoglycaemia. 173 95

Eight males were studied during 27 weeks, including two periods of five weeks during which they received clinical doses of sodium amylobarbitone and benzoctamine. Substitution of placebo for either drug caused raised anxiety and impairment of mental concentration. The drugs reduced restlessness during sleep and reduced paradoxical sleep. By the fifth week of sodium amylobarbitone, although sleep was still less restless in the early night it was more restless than normal in the late night.Blood samples were taken half-hourly during sleep by indwelling venous catheter. Plasma growth hormone concentration was little affected during drug administration but rose temporarily after withdrawal. There was a reduction of plasma corticosteroid concentration during sleep throughout administration of the drugs and a rebound above normal during the first withdrawal week.
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PMID:Two anti-anxiety drugs: a psychoneuroendocrine study. 434 14

The effects of local infusion of a 16 mM K+ solution or of a nociceptive stress on the release of somatostatin (SRIF) from the hypothalamus was measured in unanesthetized male rats implanted with a push-pull cannula in the median eminence. Although the baseline secretion rate of SRIF was increased in animals displaying agitation as a result of handling stress, both treatments induced fast doubling of SRIF release lasting for 15-30 min. Neither an equimolar Na+ infusion into the median eminence nor a similar K+ infusion into the 3rd ventricle had any affect on this release. The possible role of SRIF release in the mechanism of growth hormone inhibition following nociceptive stress is discussed.
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PMID:In vivo release of somatostatin from rat median eminence after local K+ infusion or delivery of nociceptive stress. 614 8

Three denaturing techniques have been evaluated for their ability to induce irreversible aggregation and precipitation of recombinant porcine growth hormone (pGH). The denaturing stimuli included thermal denaturation, interfacial denaturation through the introduction of a high air/water interface by vortex agitation, and a guanidine (Gdn) HCl technique which involved rapid dilution of a partially unfolded state of pGH to nondenaturing conditions. Soluble and insoluble pGH fractions were evaluated for the presence of covalently modified species and soluble aggregates by size exclusion chromatography (SEC), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and isoelectric focusing (IEF). In each of the three denaturation methods, precipitation was found to be irreversible, as the precipitated pellet could not be solubilized upon resuspending in buffer. The soluble pGH fractions consisted of only monomeric material and the insoluble protein pellet could be completely solubilized with Gdn HCl or SDS. There was no evidence of detectable covalent modifications in the precipitated protein pellet following any of the three denaturation techniques. Three excipients, Tween 20, hydroxypropyl-beta-cyclodextrin (HPCD), and sorbitol were evaluated for their stabilizing ability using each of the three denaturation methods and the degree of stabilization was found to be dependent upon the denaturing stimulus incorporated. Tween 20 was found to be highly effective in preventing pGH precipitation using the interfacial and Gdn techniques and was moderately effective using the thermal denaturation method. Inclusion of HPCD in the sample buffer significantly reduced precipitation using the thermal and interfacial methods but was ineffective in the Gdn technique.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Techniques for assessing the effects of pharmaceutical excipients on the aggregation of porcine growth hormone. 837 57

Selective dopamine D1-receptor antagonists have been shown to exhibit similar effects in animal models for antipsychotic action as the selective D2 antagonists. NNC 01-0687, a benzazepine with selective and high affinity to the D1-receptor, was well tolerated by healthy subjects allocated to double blind, placebo controlled studies. Complaints of moderate restlessness and drowsiness were reported after administration of 25 mg NNC 01-0687, indicating the dose to be the maximum tolerated single dose. The highest multiple dose level of a daily dose of 45 mg NNC 01-0687 administered t.i.d. for 14 days was assessed as safe and well-tolerated with few reports of adverse events. Some alanine aminotransferase (ALT) elevations appeared in both treatment groups (active and placebo) and no evident influence of NNC 01-0687 on the liver function could be derived. No statistically significant or clinically relevant effects were observed in haematological parameters, urinalyses, blood pressure, heart rate, ECG or plasma levels of prolactin, cortisol or growth hormone. The plasma drug concentration curves indicated a fast absorption with tmax at 0.5-1 h and an apparent elimination half-life of 3-4 h. Both AUC and Cmax appeared to be linearly correlated to the dose, indicating linear pharmacokinetics. With similar Cmax and AUC on day 1 and day 10 no accumulation was observed. When administered just after lunch, the Cmax was reduced by 50-60% and the tmax increased to 3 h, but without change of AUC.
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PMID:Tolerability, safety and pharmacokinetics of single dose and multiple dosing of the selective D1 antagonist NNC 01-0687 in healthy subjects. 858 9

A combined anterior pituitary (CAP) function test was assessed in eight healthy male beagle dogs. The CAP test consisted of sequential 30-second intravenous administrations of four hypothalamic releasing hormones in the following order and doses: 1 microgram of corticotropin-releasing hormone (CRH)/kg, 1 microgram of growth hormone-releasing hormone (GHRH)/kg, 10 micrograms of gonadotropin-releasing hormone (GnRH)/kg, and 10 micrograms of thyrotropin-releasing hormone (TRH)/kg. Plasma samples were assayed for adrenocorticotropin, cortisol, GH, luteinizing hormone (LH), and prolactin (PRL) at multiple times for 120 min after injection. Each releasing hormone was also administered separately in the same dose to the same eight dogs in order to investigate any interactions between the releasing hormones in the combined function test. Compared with separate administration, the combined administration of these four hypothalamic releasing hormones caused no apparent inhibition or synergism with respect to the responses to CRH, GHRH, and TRH. The combined administration of these four hypothalamic releasing hormones caused a 50% attenuation in LH response compared with the LH response to single GnRH administration. The side effects of the combined test were confined to restlessness and nausea in three dogs, which disappeared within minutes after the administration of the releasing hormones. It is concluded that with the rapid sequential administration of four hypothalamic releasing hormones (CRH, GHRH, GnRH, and TRH), the adenohypophyseal responses are similar to those occurring with the single administration of these secretagogues, with the exception of the LH response, which is lower in the CAP test than after single GnRH administration.
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PMID:Assessment of a combined anterior pituitary function test in beagle dogs: rapid sequential intravenous administration of four hypothalamic releasing hormones. 866 4

In the absence of surfactants, recombinant human growth hormone (rhGH) rapidly forms insoluble aggregates during agitation. The nonionic surfactant Tween 20, when present at Tween:protein molar ratios >4, effectively inhibits this aggregation. Differential scanning calorimetry (DSC) of rhGH solutions showed melting transitions that decreased by ca. 2 degrees C in the presence of Tween. Circular dichroism (CD) studies of the same thermal transition showed that the decrease is specific to the relatively high protein concentrations required for DSC. CD studies showed melting transitions that decreased with lower protein concentrations. Tween has an insignificant effect on the melting transition of rhGH at lower protein concentrations (0.18 mg/mL). Injection titration microcalorimetry showed that the interaction of Tween with rhGH is characterized by a weak enthalpy of binding. For comparison, interferon-g, another protein which has been shown to bind Tween, also shows weak enthalpy of binding. Fluorescent probe binding studies and infrared spectroscopic investigations of rhGH secondary structure support suggestions in the literature (Bam, N. B.; Cleland, J. L., Randolph, T. W. Molten globule intermediate of recombinant human growth hormone: stabilization with surfactants. Biotechnol. Prog. 1996. 12, 801-809) that Tween binding is driven by hydrophobic interactions, with little perturbation of protein secondary structure.
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PMID:Tween protects recombinant human growth hormone against agitation-induced damage via hydrophobic interactions. 1018 66

Two different types of insoluble, non-native aggregates of recombinant human growth hormone were formed by agitation in buffer or buffer containing 0.75 m guanidine HCl (GdnHCl) and characterized by infrared and second derivative UV spectroscopies. The degree of secondary structural perturbation was greater in the aggregates formed in 0.75 m GdnHCl. Both aggregate types were dissolved and refolded using high hydrostatic pressures in combination with either elevated temperature or non-denaturing levels of guanidine HCl or urea. The effects of a range of temperature, pressure, and chaotrope concentrations were tested and led to optimal conditions that approached 100% yield of native protein. The aggregates formed in 0.75 m GdnHCl required higher concentrations of urea or GdnHCl, or higher temperature or pressure for a yield equivalent to that for aggregates formed in buffer alone. Investigation of the effects of pressure, temperature, and chaotrope on unfolding of rhGH documented that under conditions used for optimal high pressure disaggregation and refolding, the native state is greatly favored thermodynamically (e.g. 25 kJ/mol at 2000 bar and 0.75 m GdnHCl). Dissolution of aggregates under pressure is a kinetically limited process. Comparison of refolding yields in GdnHCl and urea solutions suggest that pressure effects on electrostatic interactions do not dominate pressure effects on disaggregation. We suggest that non-native hydrogen bonds between protein molecules within aggregates of recombinant human growth hormone are responsible for the rate-limiting kinetic barrier in pressure-induced disaggregation.
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PMID:High pressure refolding of recombinant human growth hormone from insoluble aggregates. Structural transformations, kinetic barriers, and energetics. 1159 10

The objectives of this work were to determine the effects of nonionic surfactants (Tween 20 and Tween 80) on agitation-induced aggregation of the recombinant fusion protein, Albutropintrade mark (human growth hormone genetically fused to human albumin), and to characterize the binding interactions between the surfactants and the protein. Knowing the binding stoichiometry would allow a rational choice of surfactant concentration to protect the protein from surface-induced aggregation. Fluorescence spectroscopy and isothermal titration calorimetry (ITC) were employed to study Albutropin surfactant binding. Albutropin was agitated at 25 +/- 2 degrees C to induce aggregation, and samples were taken during a 96-h incubation. Size-exclusion chromatography (SEC-HPLC) (HPLC, high-performance liquid chromatography) was used to detect and quantify the extent of protein aggregation. The effect of surfactants on the protein's free energy of unfolding was determined using guanidine HCl as a denaturant. Tween 20 and Tween 80 had saturable binding to Albutropin with a molar binding stoichiometry of 10:1 and 9:1 (surfactant:protein), respectively. Binding of the surfactants to Albutropin increased the free energy of unfolding by over 1 and 0.6 kcal/mol, respectively. In protein samples that were agitated in the absence of surfactant, soluble aggregates were detected within 24 h, and there was almost complete loss of monomer to soluble aggregates by the end of the 96-h experiment. At the molar binding stoichiometry, Tween 20 and Tween 80 prevented the formation of soluble aggregates, even though the concentrations of surfactants were well below their critical micelle concentrations (CMC). Tween 20 and Tween 80 protected Albutropin against agitation-induced aggregation, even at concentrations below the CMC. Equilibrium unfolding data indicate that Tween confer protection by increasing the free energy of unfolding of Albutropin.
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PMID:Effects of Tween 20 and Tween 80 on the stability of Albutropin during agitation. 1585 48

Somatropin, human growth hormone (hGH), is an unstable protein, posing challenging problems for its formulation and long-term stability. Since hGH formed insoluble adducts with heparin our aim was to evaluate heparin as a stabilizing agent for the drug. These adducts were characterized by particle diameter, tertiary structure variations and release studies. Studies were also carried out to determine the stability of hGH in the presence and absence of heparin by an interfacial denaturation method and real-time stability studies by measuring hGH activity and particle diameter. Moreover, biological activity of hGH and hGH/UH (unfractionated heparin) adducts was identified by daily subcutaneous injections to hypophysectomized rats. There was a decrease in mean hydrodynamic particle diameter of hGH/UH adducts with increased pH (54.4 to 12.2 nm from pH 3 to pH 7) indicating that the adducts were either dissociating or dissolving at high pH. Furthermore, second-derivative spectroscopy indicated that complexation of hGH with heparin did not cause a major disruption in the tertiary structure of hGH but decreased the hydrophilic environment around the tyrosine residues. Release of hGH from hGH/UH adducts was pH and ionic strength dependent with the highest release at pH 8 (93%) and lowest release at pH 3 (0%) over the first hour. Interfacial denaturation methods indicated that vortex agitation over 120 s resulted in no change in the optical density of hGH/UH adducts compared with a substantial increase for hGH alone at pH 6.8. Real-time stability studies over 93 days demonstrated that hGH/UH adducts at both pH 3 and 7 with an excess of heparin produced the highest percent of active hGH remaining in the solution at 4 degrees C and 37 degrees C. The higher stability of hGH/UH adducts with excess heparin compared with the stoichiometric ratio was also confirmed by particle size measurements during storage. The biological activity of these adducts was comparable with hGH alone by weight-gain studies in hypophysectomized rats. The findings suggest the value of using hGH/heparin adducts to stabilize the protein.
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PMID:Stabilization of somatropin by heparin. 1590 44


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