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PubMed2002

Treatment-time-dependent difference of ketamine pharmacological response and toxicity in rats.

Circadian rhythms impact many physiological functions that may affect drug pharmacological response. Ketamine is a dissociative agent commonly used for surgical anesthesia in rats. The aim of the present study was to analyze the central nervous system (CNS) depression and lethality of ketamine injected intraperitoneally at different times during the 24 h. The study was conducted in October 2001, spring in the Southern hemisphere. Female prepuberal Sprague-Dawley rats synchronized to a 12h light: 12h dark cycle (light, 07:00h-19:00h) were studied. Ketamine (40 mg/kg) was administered to one of six different clock-time treatment groups (n = 6-7 rats each). Duration of latency period, ataxia, loss of righting reflex (LRR), post-LRR ataxia, and total pharmacological response were determined by visual assessment. To investigate acute toxicity, ketamine lethal dose 50 (148.0 mg/kg) was also administered as a single injection to six different treatment-time groups of rats. Significant temporal differences and circadian rhythms were detected in drug-induced post-LRR ataxia and total pharmacological response duration. The longest pharmacological response occurred in rats injected during the light (rest) phase and the shortest response in the dark (activity) phase. No circadian rhythm was detected in acute toxicity. The study findings indicate that the duration of CNS depression of ketamine in rats exhibits circadian rhythmic variation.

Anesthetics, Dissociative↗
PubMed1999

Pharmacologic properties of phenyl N-tert-butylnitrone.

Phenyl N-tert-butylnitrone (PBN) is the parent of a family of nitrones used as spin-trapping agents to trap free radicals. PBN's pharmacological effects in animal models are extensive, ranging from protection against death after endotoxin shock, protection from ischemia-reperfusion injury, to increasing the life span of mice. Recent additions to the list include protection from bacterial meningitis, thalidomide-induced teratogenicity, drug-induced diabetogenesis, and choline-deficient hepatocarcinogenesis. Because PBN reacts with oxygen radicals to produce less reactive species, it has been suggested that this is the basis of its pharmacological effects. However, there has been no hard evidence for this notation. Nevertheless, many investigators have used the presence of PBN's pharmacologic effect as evidence for free radical involvement in their models. Mechanistic studies on the PBN's antisepsis action revealed that PBN inhibits expression of various pro-inflammatory genes, suggesting that the protective action involves more than a straightforward free radical-scavenging mechanism. Previous and recent developments in the investigations on the pharmacologic properties of PBN are described in this review.

Aging↗
PubMed1993

Novel pharmacologic therapies in the treatment of experimental traumatic brain injury: a review.

Delayed or secondary neuronal damage following traumatic injury to the central nervous system (CNS) may result from pathologic changes in the brain's endogenous neurochemical systems. Although the precise mechanisms mediating secondary damage are poorly understood, posttraumatic neurochemical changes may include overactivation of neurotransmitter release or re-uptake, changes in presynaptic or postsynaptic receptor binding, or the pathologic release or synthesis of endogenous "autodestructive" factors. The identification and characterization of these factors and the timing of the neurochemical cascade after CNS injury provides a window of opportunity for treatment with pharmacologic agents that modify synthesis, release, receptor binding, or physiologic activity with subsequent attenuation of neuronal damage and improvement in outcome. Over the past decade, a number of studies have suggested that modification of postinjury events through pharmacologic intervention can promote functional recovery in both a variety of animal models and clinical CNS injury. This article summarizes recent work suggesting that pharmacologic manipulation of endogenous systems by such diverse pharmacologic agents as anticholinergics, excitatory amino acid antagonists, endogenous opioid antagonists, catecholamines, serotonin antagonists, modulators of arachidonic acid, antioxidants and free radical scavengers, steroid and lipid peroxidation inhibitors, platelet activating factor antagonists, anion exchange inhibitors, magnesium, gangliosides, and calcium channel antagonists may improve functional outcome after brain injury.

Animals↗
PubMed2006

Guidelines for the pharmacologic treatment of neurobehavioral sequelae of traumatic brain injury.

There is currently a lack of evidence-based guidelines to guide the pharmacological treatment of neurobehavioral problems that commonly occur after traumatic brain injury (TBI). It was our objective to review the current literature on the pharmacological treatment of neurobehavioral problems after traumatic brain injury in three key areas: aggression, cognitive disorders, and affective disorders/anxiety/ psychosis. Three panels of leading researchers in the field of brain injury were formed to review the current literature on pharmacological treatment for TBI sequelae in the topic areas of affective/anxiety/ psychotic disorders, cognitive disorders, and aggression. A comprehensive Medline literature search was performed by each group to establish the groups of pertinent articles. Additional articles were obtained from bibliography searches of the primary articles. Group members then independently reviewed the articles and established a consensus rating. Despite reviewing a significant number of studies on drug treatment of neurobehavioral sequelae after TBI, the quality of evidence did not support any treatment standards and few guidelines due to a number of recurrent methodological problems. Guidelines were established for the use of methylphenidate in the treatment of deficits in attention and speed of information processing, as well as for the use of beta-blockers for the treatment of aggression following TBI. Options were recommended in the treatment of depression, bipolar disorder/mania, psychosis, aggression, general cognitive functions, and deficits in attention, speed of processing, and memory after TBI. The evidence-based guidelines and options established by this working group may help to guide the pharmacological treatment of the person experiencing neurobehavioral sequelae following TBI. There is a clear need for well-designed randomized controlled trials in the treatment of these common problems after TBI in order to establish definitive treatment standards for this patient population.

Aggression↗
PubMed1999

Bioavailability of biotin given orally to humans in pharmacologic doses.

BACKGROUND: Patients with carboxylase deficiency are treated with pharmacologic doses of biotin. OBJECTIVE: We sought to determine the bioavailability of biotin at pharmacologic doses. DESIGN: Biotin was administered orally (2.1, 8.2, or 81.9 micromol) or intravenously (18.4 micromol) to 6 healthy adults in a crossover design with > or =2 wk between each biotin administration. Before and after each administration, timed 24-h urine samples were collected. Urinary biotin and biotin metabolites were analyzed by an HPLC avidin-binding assay. RESULTS: Urinary recoveries of biotin plus metabolites were similar (approximately 50%) after the 2 largest oral doses and the 1 intravenous dose, suggesting 100% bioavailability of the 2 largest oral doses. For unexplained reasons, the apparent recovery of the smallest oral dose was about twice that of the other doses. For all 4 doses, biotin accounted for >50% of the total of biotin and biotin metabolites in urine. Bisnorbiotin (13-23%), biotin-d,l-sulfoxide (5-13%), bisnorbiotin methyl ketone (3-9%), and biotin sulfone (1-3%) accounted for the remainder. The percentage excretion of biotin was greater when biotin was administered intravenously and for the largest oral dose than for the 2 smallest oral doses. CONCLUSION: Our data provide evidence that oral biotin is completely absorbed even when pharmacologic doses are administered. Biotin metabolites account for a substantial portion of total urinary excretion and must be considered in bioavailability studies. We speculate that renal losses of biotin (as a percentage of the dose administered) are moderately elevated when pharmacologic doses of biotin are administered.

Administration, Oral↗
PubMed1990

Non-pharmacological treatment of hypertension: differences between health centres in patients' blood pressure and success at withdrawal from drugs.

Four hundred patients from eight health centres were recruited for this two-year study on the possibility of replacing antihypertensive drugs by non-pharmacological therapy. This consisted of monthly check-ups and blood pressure measurements at home by the patients plus advice about changes of lifestyle--salt restriction, weight reduction, physical activity, and reduction of alcohol and tobacco. The non-pharmacological treatment was effective and 44% had discontinued drugs after two years without any increase in diastolic blood pressure. Twenty-five per cent reduced their weight by 4% or more. There were no changes in sodium or potassium output. Thirty-five per cent increased their physical activity and 20% decreased it. When the results for each health centre were compared, striking differences in hypertensive characteristics of patients and the outcome of antihypertensive drug treatment were found. In one health centre 69% of patients were not taking drugs after two years. In some health centres the non-pharmacological treatment was quite successful, but in others the attempt failed. A prerequisite for successful use of pharmacological treatment is that the problem of non-compliance should be solved.

Adult↗
PubMed1984

Nickel influences iron metabolism through physiologic, pharmacologic and toxicologic mechanisms in the rat.

A study involving three experiments was done to ascertain whether the beneficial effect of nickel on hematopoiesis in moderately iron-deficient rats was due to physiologic and/or pharmacologic mechanisms. Female Sprague-Dawley rats were fed nickel supplements ranging from 0 to 100 micrograms/g in iron-low (15 micrograms Fe3+/g), iron-adequate (65 micrograms Fe3+/g), or iron-luxuriant (100 micrograms Fe3+/g) diets. The basal diet contained from 2 ng (experiment 3) to 36 ng (experiment 1) of nickel/g. At 10 weeks, both nickel deficiency and toxicity (100 micrograms/g diet) tended to depress hematopoiesis and markedly altered femur and liver trace element content in marginally iron-deficient rats. The alterations included elevated copper, iron and nickel, and depressed calcium and manganese in femurs. The pharmacologic action of nickel was indicated by the finding that high dietary nickel (5, 10, 20 or 50 micrograms/g) apparently stimulated hematopoiesis in marginally iron-deprived rats to a greater extent than dietary levels of nickel (0.1, 0.5 or 1.0 microgram/g) considered adequate for nutritional needs. High dietary nickel also elevated the iron content in liver of marginally iron-adequate rats. The findings indicate that nickel influences iron metabolism at physiologic, pharmacologic and toxic levels of intake. They also indicate that many previously reported signs of nickel deprivation, including effects on hematopoiesis, may have been misinterpreted and might be manifestations of pharmacologic actions of nickel.

Animals↗
PubMed1994

Non-pharmacological therapy of hypertension.

Weight reduction, moderate sodium restriction and alcohol reduction all lower blood pressure significantly in the short-term, and appear feasible in the long-term. Dynamic exercise may have a useful role in selected patients. Cessation of cigarette smoking has no important effect on blood pressure itself but is likely to improve the prognosis. No other non-pharmacological intervention warrants a place in routine management on present evidence. Regimens involving combined reduction in weight, salt and alcohol have proved less effective than drug therapy in terms of blood pressure reduction. Hypertensive patients may be shifted from just above some arbitrary intervention level to just below it by non-pharmacological treatment, and the perceived benefits of non-pharmacological management may be offset by an increased risk of vascular complications related to suboptimal blood pressure control. Moreover even simple measures such as moderate sodium restriction may affect some aspects of quality of life adversely. Non-pharmacological measures should generally be regarded as useful adjuncts to antihypertensive drug therapy rather than alternatives to it.

Alcohol Drinking↗
PubMed2001

A human tissue-engineered vascular media: a new model for pharmacological studies of contractile responses.

Our method for producing tissue-engineered blood vessels based exclusively on the use of human cells, i.e., without artificial scaffolding, has previously been described (1). In this report, a tissue-engineered vascular media (TEVM) was specifically produced for pharmacological studies from cultured human vascular smooth muscle cells (VSMC). The VSMC displayed a differentiated phenotype as demonstrated by the re-expression of VSMC-specific markers and actual tissue contraction in response to physiological stimuli. Because of their physiological shape and mechanical strength, rings of human TEVM could be mounted on force transducers in organ baths to perform standard pharmacological experiments. Concentration-response curves to vasoconstrictor agonists (histamine, bradykinin, ATP, and UTP) were established, with or without selective antagonists, allowing pharmacological characterization of receptors (H1, B2, and P2Y1, and pyrimidinoceptors). Sustained agonist-induced contractions were associated with transient increases in cytosolic Ca2+ concentration, suggesting sensitization of the contractile machinery to Ca2+. ATP caused both Ca2+ entry and Ca2+ release from a ryanodine- and caffeine-sensitive store. Increased cyclic AMP or cyclic GMP levels caused relaxation. This human TEVM displays many of functional characters of the normal vessel from which the cells were originally isolated, including contractile/relaxation responses, cyclic nucleotide sensitivity, and Ca2+ handling mechanisms comparable to those of the normal vessel from which the cells were originally isolated. These results demonstrate the potential of this human model as a versatile new tool for pharmacological research.

Adenosine Triphosphate↗
PubMed2001

Relevance of clinical pharmacological models for the evaluation of therapeutic dose range of an AT1-receptor antagonist.

Clinical pharmacological models Antihypertensive drugs affecting the renin-angiotensin system (RAS) can be evaluated in single-dose studies in healthy volunteers challenged with angiotensin I or II, or in subjects in whom the RAS has been activated by salt depletion. Such pharmacological studies can be used to investigate dose-response relationships. Objective The relevance of these models in predicting therapeutic dose range has been evaluated by comparing the results of pharmacological studies with those of a conventional dose-finding study in hypertensive patients with the new AT1-receptor antagonist olmesartan medoxomil. Results In healthy volunteers, 2.5-40 mg olmesartan medoxomil single doses significantly inhibited the pressor response to exogenous angiotensin I. A dose-response relationship was observed, with relevant (> 75%) inhibition occurring at doses of 10 mg and above. In a single-dose crossover study in patients with mild-to-moderate hypertension receiving a sodium-restricted diet, statistically significant lowering of mean 24-h blood pressure, measured by ambulatory blood pressure monitoring, was observed at doses of 10-80 mg. By comparison, a large-scale (n = 792), placebo-controlled, dose-ranging study in patients with mild-to-moderate hypertension likewise showed significant superiority over placebo for 10-80 mg olmesartan medoxomil once-daily doses. Conclusion Single-dose clinical pharmacology studies provided an accurate indication of the effective dose range of a new AT1-receptor antagonist Such models can be useful in identifying, for more detailed study, the likely therapeutic dose range of new drugs acting on the RAS. However, the dose-response still requires testing in large target populations.

Adult↗
PubMedDate not supplied

Neonatal seizures: diagnosis, pharmacologic interventions, and outcomes.

Neonatal seizures are difficult to detect, diagnose, and manage. Infants with a history of seizures often have long-term neurologic sequelae. Controversy exists as to whether neonatal seizures themselves cause damage to the developing brain, and thus, subsequent sequelae; or if these sequelae are due primarily to the underlying cause of the seizures. Treatment of seizures involves identifying and treating the underlying etiology of the seizure and appropriate use of pharmacologic interventions. To provide the context for pharmacological management of seizures in newborns, this article examines the pathophysiology and etiology of seizures and discusses pharmacological agents and issues, short- and long-term outcomes, clinical implications, and directions for future research. Understanding pharmacological issues within this context provides a comprehensive foundation for decision making and management of neonatal seizures.

Anticonvulsants↗
PubMed1999

Pathogenesis and pharmacological strategies for mitigating secondary damage in acute spinal cord injury.

OBJECTIVE: Experimental models and clinical observations of acute spinal cord injury (SCI) support the concepts of primary and secondary injury, in which the initial mechanical insult is succeeded by a series of deleterious events that promote progressive tissue damage and ischemia. Whereas the primary injury is fated by the circumstances of the trauma, the outcome of the secondary injury may be amenable to therapeutic modulation. This article reviews the pathogenetic determinants of these two phases of injury and summarizes the pharmacological manipulations that may restore neurological function after SCI. METHODS: Experimental models of SCI and their inherent limitations in simulating human SCI are surveyed. The pathogenesis of primary and secondary injury, as well as the theoretical bases of neurological recovery, are examined in detail. The effects of glucocorticoids, lazeroids, gangliosides, opiate antagonists, calcium channel blockers, glutamate receptor antagonists, antioxidants, free radical scavengers, and other pharmacological agents in both animal models and human trials are summarized. Practical limitations to inducing neural regeneration are also addressed. RESULTS: The molecular events that mediate the pathogenesis of SCI are logical targets for pharmacological manipulation and include glutamate accumulation, aberrant calcium fluxes, free radical formation, lipid peroxidation, and generation of arachidonic acid metabolites. Enhancement of neural regeneration and plasticity comprise other possible strategies. CONCLUSION: Pharmacological agents must be given within a narrow window of opportunity to be effective. Although many therapeutic agents show potential promise in animal models, only methylprednisolone has been shown in large, randomized, double-blinded human studies to enhance the functional recovery of neural elements after acute SCI. Future therapy is likely to involve various combinations of these agents.

Acute Disease↗
PubMed1994

Pharmacological cardiac stress: when and how?

Pharmacological stress is vital to the modern nuclear cardiological laboratory. In clinical practice only adenosine, dipyridamole and dobutamine are used. Both adenosine (directly) and dipyridamole (indirectly) work via activation of alpha 2 receptors, which causes vasodilatation. Adenosine has a very short half-life and any adverse effects can be rapidly controlled. It is however more expensive and not yet commercially available in the UK when compared with dipyridamole, which has a prolonged 30-min half-life. Dobutamine is a beta-agonist which mimics exercise by raising the rate pressure product, and it also has a short half-life. Adenosine and dipyridamole share some contraindications which include asthma. Dobutamine has been shown to be safe in these patients. Exaggerated responses to adenosine are seen in sinoatrial disease and in patients taking maintenance dipyridamole treatment orally. The adenosine receptor antagonists must be avoided prior to the use of the vasodilators (caffeine 12 h, aminophylline/theophylline 24 h). There is no evidence to suggest any significant difference between pharmacological stress and maximal exercise for myocardial perfusion imaging, but pharmacological stress is necessary for patients who have no exercise capability. Studies which show that submaximal exercise reduces sensitivity suggest that pharmacological stress should also be used in patients whose exercise capacity is suboptimal. The addition of exercise to the vasodilator infusion has been shown to reduce non-cardiac side effects and improve imaging.

Adenosine↗
PubMed1998

Towards a cross-species pharmacology of sensorimotor gating: effects of amantadine, bromocriptine, pergolide and ropinirole on prepulse inhibition of acoustic startle in rats.

Animal models in behavioral pharmacology can be evaluated based on their face, predictive and construct validity. A further level of validity may be achieved if a model is reproduced precisely across species--from laboratory animal to human--using identical conditions and manipulations to elicit identical behavioral changes. Under circumstances in which a model achieves 'homologous' validity, it should be possible to demonstrate that the same pharmacological agents produce parallel changes in the same behavior (as distinct from the clinical condition that the animal behaviors are hypothesized to model), when studied in laboratory animals and in humans. Studies have demonstrated that the disruption of sensorimotor gating of the startle reflex, measured by prepulse inhibition (PPI), in rats by dopamine agonists exhibits face, predictive and construct validity for the relative loss of PPI in schizophrenia patients. To assess the homologous validity of this model, and to expand its utility in understanding the pathophysiology of sensorimotor gating deficits and in developing novel antipsychotic agents to reverse these deficits, it will be important to study PPI across species, comparing response profiles to identical pharmacological manipulations. In the present studies, we report that PPI in rats is reduced in a dose-dependent manner by four dopamine agonists that can be administered with relative ease to humans. We also report that the PPI-disruptive effects of the clinically useful dopamine agonist pergolide are reversed by both typical and atypical antipsychotics. These studies establish a foundation for pursuing human pharmacological studies of PPI, and for extrapolating the substantial neurochemical and neurophysiological information from animal studies of PPI, towards understanding the neural basis for deficient sensorimotor gating in specific neuropsychiatric disorders.

Acoustic Stimulation↗
PubMed2005

Pharmacology of vertigo/nystagmus/oscillopsia.

PURPOSE OF REVIEW: To describe recent developments in the pharmacological treatment of vertigo and nystagmus while focusing on vestibular neuritis, Meniere's disease, downbeat nystagmus, periodic alternating nystagmus, acquired pendular nystagmus, and superior oblique myokymia. RECENT FINDINGS: In the last 2 years several studies have been published on possible pharmacological treatment options for nystagmus and oscillopsia. In the treatment of vestibular neuritis two studies showed that cortisone treatment was effective for restoring labyrinthine function. This benefit seems more likely if treatment is started within the first 2 days of onset. For recurrent vertigo attacks due to Meniere's disease, the titration technique with daily or weekly doses of intratympanic gentamicin until onset of vestibular symptoms, change in vertigo or hearing loss rated best for complete vertigo control. A new pharmacological treatment option for downbeat nystagmus is the administration of potassium channel blockers (e.g. 4-aminopyridine). They are thought to reinforce the inhibitory action of cerebellar Purkinje cells. Several case reports have proven the beneficial effect of baclofen on periodic alternating nystagmus, of gabapentin and memantine on acquired pendular nystagmus, and of carbamazepine and gabapentin on superior oblique myokymia. SUMMARY: There have been several new developments in the treatment of nystagmus and vertigo over the last 2 years. These include potassium channel blockers for the treatment of downbeat nystagmus, early cortisone treatment to improve recovery of the labyrinth function in vestibular neuritis, and intratympanic gentamicin treatment for Meniere's disease. Other pharmacological treatment options are baclofen for periodic alternating nystagmus, gabapentin and memantine for acquired pendular nystagmus, and carbamazepine for superior oblique myokymia.

Amines↗
PubMed2003

Induction of coronary artery spasm by two pharmacological agents: comparison between intracoronary injection of acetylcholine and ergonovine.

BACKGROUND AND OBJECTIVES: There have been few studies comparing the clinical usefulness for the induction of coronary artery spasm (CAS) between acetylcholine (ACh) and ergonovine (ER). This study is designed: (1) to examine the duration of effect after intracoronary injection of ACh on the responsible vessels using a 0.014 inch, 15 MHz Doppler guide wire, and (2) to evaluate the efficacy of two pharmacological agents, ACh and ER, for the induction of CAS in patients with <50% stenosis in the cardiac laboratory. METHODS: Phasic coronary flow velocity patterns were recorded at rest and during ACh tests in 22 patients with normal or near-normal coronary arteries. The tip of the guide wire was placed on the proximal right coronary artery (RCA) and mid-left anterior descending artery. We measured the time required to baseline level of average peak velocity after intracoronary injection of ACh. We performed selective intracoronary administration of both ER and ACh in the same 171 patients (106 men, 65 women, mean age of 62+/-10 years) with <50% stenosis. Under no medication, ACh was injected first in incremental doses of 20, 50, and 80 microg into the RCA and of 20, 50, and 100 microg into the left coronary artery (LCA). Ten minutes later, ER was administered at 10 microg/min for four minutes for a maximal dose of 40 microg on the RCA and at 16 microg/min over four minutes for a total dose of 64 microg on the LCA. Positive spasm was defined as > or =99% luminal narrowing. RESULTS: The time-averaged peak velocity returned to baseline after intracoronary injection of ACh within 10 minutes in all 120 procedures, consisted of 19 with positive spasm (RCA (n=10): 245+/-33 s; LCA (n=9): 351+/-187 s) and 101 with negative spasm (RCA (n=48): 155+/-62 s, LCA (n=53): 248+/-106 s). In the overall results, there was no difference concerning the incidence of provoked spasm between the two pharmacological agents (ACh: 33% versus ER: 32%, NS). Coronary spasms were induced by either pharmacological agent in 134 vessels. Concordance in this study was 94% in all vessels, whereas the remaining 6% of vessels were different from each other. The non-concordance rate of the right coronary artery was significantly higher than that of the left coronary artery (10% versus 4%, p<0.01). However, ER provoked more focal spasms, whereas ACh provoked more diffuse and distal spasms, compared with each other. Seventy-four (55%) of the 134 vessels had coronary spasms in the same coronary arteries. Concordance of both provoked spasm sites and spasm configurations in the same coronary artery was observed in only 18 (13%) vessels. No serious or irreversible complications were observed during the two sequential tests. CONCLUSIONS: As a spasm provocation test, there were no differences between ACh and ER. We recommend the supplementary use of these two pharmacological agents for the induction of CAS in the cardiac laboratory, if available.

Acetylcholine↗
PubMed2003

Reinforcement from pharmacological effects of ethanol in newborn rats.

BACKGROUND: The preweanling period in the rat is characterized by acceptance of substantial amounts of ethanol and susceptibility to its reinforcing effects. It has been unclear, however, whether the neurobiological basis of ethanol reinforcement properties at this age is in ethanol's olfactory, gustatory, or pharmacological effects. METHODS: The effectiveness of intraperitoneal (ip) ethanol as a reinforcer for newborn (3-hr-old) rats was tested toward separation of the orosensory and pharmacological sources of ethanol reinforcement. Responsiveness to a test nipple by pups given such pairings was compared with that of pups given unpaired presentations of the nipple and ethanol. RESULTS: Reinforcement was assessed in terms of response to a surrogate nipple 1 hr after a single pairing of a similar nipple providing water (conditioned stimulus) and ip injection of ethanol (0.125, 0.25, 0.50, or 0.75 g/kg; unconditioned stimulus). Significant effects of ethanol reinforcement occurred with the lower doses (0.125 and 0.25 g/kg); higher doses of ethanol (0.50 and 0.75 g/kg) had no significant reinforcement effect. A second experiment determined that for conditioning with ip ethanol as the unconditioned stimulus, a conditioned stimulus consisting of only ingesting water or only suckling on an empty nipple also yielded significant reinforcing effects of ethanol, although with less strength than their combination. Both reinforcing doses of ethanol, 0.125 and 0.25 g/kg, yielded detectable concentrations of ethanol in the blood 5 min after injection, which were sustained at a significantly lower level 60 min after administration. CONCLUSIONS: These data indicate that aside from possible, and likely weak, hematogenic sources of gustatory and olfactory attributes of ethanol, the basis of ethanol's reinforcement effect in neonatal rats is primarily pharmacological. For the pharmacological effects of ethanol to be reinforcing for the neonatal rat, concurrent appetitive activity on a nipple providing a fluid may be necessary for a substantial effect with this paradigm.

Animals↗
PubMed2006

Pharmacology of ocular allergy.

PURPOSE OF REVIEW: To evaluate the pharmacology of current drug development directed towards ocular allergy. Increased worldwide prevalence of ocular allergy has stimulated expansion of management strategies towards physiologic and immunologic drug targets. RECENT FINDINGS: Present drug targets are located in the conjunctival mucosal surface at the initial site of allergen exposure. Pharmacologic intervention attends to early and late phase reactions. Targets generating a response include mast cells, IgE, released preformed mediator histamine, and newly formed mediators, such as prostaglandins, leukotrienes and cytokines. Methods to simulate allergy and measure efficacy of drugs are the conjunctival allergen challenge and the conjunctival provocation test. Pharmacologic outcome is measured via cytologic biomarkers and clinical signs/symptoms of redness, itching, lid swelling and chemosis. Endpoint instruments such as the Ocular Allergy Index and Eye Allergy Patient Impact Questionnaire have emerged from the field of pharmacoeconomics. SUMMARY: Important pharmacologic properties of targets have been revealed. First, histamine is more specifically antagonized by second generation antihistamines. Second, newly formed mediators and downstream responders (prostaglandins, leukotrienes, interleukins, intercellular adhesion molecule 1, tumor necrosis factor, vascular cell adhesion molecule, eosinophils and neutrophils) are more selectively antagonized by dual/multiple-action agents.

Conjunctivitis, Allergic↗