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Blood pressure decrease prior to initiating pharmacological therapy in nonemergent hypertension.

In order to characterize the decrease in blood pressure that occurs in the emergency department (ED) setting in cases of nonemergent hypertension before beginning pharmacological therapy, 94 consecutive cases of hypertension seen at the University of Illinois Hospital were reviewed. Each patient in the analysis had a triage blood pressure recorded by the nursing staff and second blood pressure reading taken between 10 minutes and 2 hours after the triage pressure before pharmacological therapy was begun. Patients with diastolic pressures less than 90 mm Hg were excluded, as were patients with acute end-organ pathology secondary to hypertension. In the remaining 54 cases, the mean arterial pressure fell by 6% (P less than .003), the systolic pressure fell by 6% (P less than .022), and the diastolic pressure fell by 6.4% (P less than .003), suggesting that in nonemergent hypertension, a significant decrease in blood pressure occurs in the ED before pharmacological therapy is begun. The blood pressure decrease was not statistically different when sex and age were considered, but when patients were grouped into those with diastolic pressures between 90 mm Hg and 114 mm Hg and those with diastolic pressures greater than or equal to 115 mm Hg, there was a statistically significant decrease in systolic, diastolic, and mean arterial pressures only in patients with diastolic pressures greater than or equal to 115 mm Hg. Our findings suggest that patients with nonemergent hypertension do not always require immediate and aggressive pharmacological intervention in the ED setting and are best observed for a short period and then reassessed before beginning pharmacological therapy.

Adult↗

Marine pharmacology in 2001--2002: marine compounds with anthelmintic, antibacterial, anticoagulant, antidiabetic, antifungal, anti-inflammatory, antimalarial, antiplatelet, antiprotozoal, antituberculosis, and antiviral activities; affecting the cardiovascular, immune and nervous systems and other miscellaneous mechanisms of action.

During 2001--2002, research on the pharmacology of marine chemicals continued to be global in nature involving investigators from Argentina, Australia, Brazil, Canada, China, Denmark, France, Germany, India, Indonesia, Israel, Italy, Japan, Mexico, Netherlands, New Zealand, Pakistan, the Philippines, Russia, Singapore, Slovenia, South Africa, South Korea, Spain, Sweden, Switzerland, Thailand, United Kingdom, and the United States. This current article, a sequel to the authors' 1998, 1999 and 2000 marine pharmacology reviews, classifies 106 marine chemicals derived from a diverse group of marine animals, algae, fungi and bacteria, on the basis of peer-reviewed preclinical pharmacology. Anthelmintic, antibacterial, anticoagulant, antifungal, antimalarial, antiplatelet, antiprotozoal, antituberculosis or antiviral activities were reported for 56 marine chemicals. An additional 19 marine compounds were shown to have significant effects on the cardiovascular, immune and nervous system as well as to possess anti-inflammatory and antidiabetic effects. Finally, 31 marine compounds were reported to act on a variety of molecular targets and thus may potentially contribute to several pharmacological classes. Thus, during 2001--2002 pharmacological research with marine chemicals continued to contribute potentially novel chemical leads for the ongoing global search for therapeutic agents for the treatment of multiple disease categories.

Animals↗

Cloning and pharmacological characterization of the monkey histamine H3 receptor.

Species differences have been described previously for histamine H(3) receptor pharmacology. Rat selective histamine H(3) receptor ligands such as ciproxifan and A-304121 (2-amino-1-[4-[3-(4-cyclopropanecarbonyl-phenoxy)-propyl]-piperazin-1-yl]-propan-1-one) show over 100-fold selectivity for the rat receptor compared to the human receptor. To date, however, the pharmacology of the cloned monkey histamine H(3) receptor has not been examined. In this study, we cloned the monkey histamine H(3) receptor gene (H(3)R) and evaluated the receptor pharmacology in binding and functional assays. The monkey histamine H(3) receptor is highly homologous to the human receptor with 438 identities in their 445 amino acid sequences, but less homologous to the rat receptor. However, unlike the human or rat, we found no evidence for additional splicing for the monkey H(3)R. Pharmacological analysis indicated that the monkey receptor exhibited similar pharmacological profiles to those of the human receptor, providing critical information for characterizing histamine H(3) receptor ligands in monkey behavioral models.

Amino Acid Sequence↗

Molecular and pharmacological characterization of serotonin 5-HT2A and 5-HT2B receptor subtypes in dog.

We report the cloning, molecular characterization, and pharmacological characterization of the canine 5-HT2A and 5-HT2B receptors. The canine and human 5-HT2A receptors share 93% amino acid homology. The canine and human 5-HT2B receptors are also highly conserved (87% homology) with the exception of the carboxyl termini where the canine protein is 62 amino acids shorter. Both the canine 5-HT2A and 5-HT2B receptors have high affinity for [3H]5-HT (KD=4.50+/-0.89 nM and 3.10+/-0.82 nM, respectively) and, in general, the pharmacology of these two receptors matches closely the pharmacology of their human homologs for the 19 serotonergic ligands tested. However, the functional response (Ca2+ mobilization) of the canine 5-HT2B receptor to several agonists was weaker compared to the human 5-HT2B receptor. Using quantitative reverse transcriptase polymerase chain reaction, a high expression level of canine 5-HT2A receptor mRNA was detected in the brain and lower levels in peripheral tissues, whereas the highest levels of canine 5-HT2B receptor mRNA were observed in lungs and smooth muscles. A significant level of canine 5-HT2B receptor mRNA was detected in brain tissue. The availability of the full sequence and pharmacology of the canine 5-HT2A and canine 5-HT2B receptors provides useful information for the interpretation of previous and future pharmacological studies of 5-HT2A/2B ligands in dog.

Amino Acid Sequence↗

Edinger-Westphal and pharmacologically stimulated accommodative refractive changes and lens and ciliary process movements in rhesus monkeys.

During accommodation, the refractive changes occur when the ciliary muscle contracts, releasing resting zonular tension and allowing the lens capsule to mold the lens into an accommodated form. This results in centripetal movement of the ciliary processes and lens edge. The goal of this study was to understand the relationship between accommodative refractive changes, ciliary process movements and lens edge movements during Edinger-Westphal (EW) and pharmacologically stimulated accommodation in adolescent rhesus monkeys. Experiments were performed on one eye each of three rhesus monkeys with permanent indwelling electrodes in the EW nucleus of the midbrain. EW stimulated accommodative refractive changes were measured with infrared photorefraction, and ciliary process and lens edge movements were measured with slit-lamp goniovideography on the temporal aspect of the eye. Images were recorded on the nasal aspect for one eye during EW stimulation. Image analysis was performed off-line at 30 Hz to determine refractive changes and ciliary body and lens edge movements during EW stimulated accommodation and after carbachol iontophoresis to determine drug induced accommodative movements. Maximum EW stimulated accommodation was 7.36+/-0.49 D and pharmacologically stimulated accommodation was 14.44+/-1.21 D. During EW stimulated accommodation, the ciliary processes and lens edge moved centripetally linearly by 0.030+/-0.001 mm/D and 0.027+/-0.001 mm/D, with a total movement of 0.219+/-0.034 mm and 0.189+/-0.023 mm, respectively. There was no significant nasal/temporal difference in ciliary process or lens edge movements. 30-40 min after pharmacologically stimulated accommodation, the ciliary processes moved centripetally a total of 0.411+/-0.048 mm, or 0.030+/-0.005 mm/D, and the lens edge moved centripetally 0.258+/-0.014 mm, or 0.019+/-0.003 mm/D. The peaks and valleys of the ciliary processes moved by similar amounts during both supramaximal EW and pharmacologically stimulated accommodation. In conclusion, this study shows, for the first time, that the ciliary processes and lens edge move centripetally, linearly with refraction during EW stimulated accommodation. During pharmacological stimulation, the ciliary processes move to a greater extent than the lens edge, confirming that in adolescent monkeys, lens movement limits the accommodative optical change in the eye.

Accommodation, Ocular↗

The prognostic value of pharmacologic stress myocardial perfusion imaging in patients with permanent pacemakers.

BACKGROUND: The aim of this study is to assess the prognostic value of pharmacologic stress (adenosine or dipyridamole) myocardial perfusion imaging in patients with permanent electronic ventricular pacemakers. METHODS AND RESULTS: Between October 1986 and December 1995, 93 patients with pacemakers underwent pharmacologic stress testing with myocardial perfusion single photon emission computed tomography imaging. Follow-up information on 91 patients (98%) was obtained. Mean follow-up was 5.6 +/- 2.4 years. Previously published clinical and image variables were analyzed for their prognostic significance with regard to cardiac death, cardiac death/nonfatal myocardial infarction, and cardiac death/nonfatal myocardial infarction/late revascularization. The presence of a high-risk scan was a significant predictor of subsequent cardiac death by both univariate (chi 2 = 9.4, P < .001) and multivariate analysis (chi 2 = 6.5, P = .01) after adjustment for clinical score. Clinical score was not a significant predictor of cardiac death. CONCLUSION: This study demonstrates that pharmacologic stress myocardial perfusion imaging provides significant prognostic information in patients with permanent pacemakers. In this population, pharmacologic stress myocardial perfusion imaging can differentiate patients at high risk of a subsequent cardiac event from those at low risk. These results support the American College of Cardiology/American Heart Association guideline recommendations for pharmacologic stress perfusion imaging in patients with permanent pacemakers.

Adenosine↗

Role of pharmacological aids and social supports in smoking cessation associated with Quebec's 2000 Quit and Win campaign.

BACKGROUND: This evaluation of the 2000 Quit and Win campaign in the province of Quebec, Canada, assessed the use and effectiveness of pharmacological aids, social support, and support resources (clinic program, support groups, books, telephone support) among contest participants. The reach of the contest was 1.3% of adult smokers: 20,400 participants. METHODS: Six months after the contest ended, 3,033 randomly selected participants completed telephone interviews about their smoking status and their use of nonform aids, social support, support resources, and pharmacological aids during their cessation attempt. Those who were abstinent from smoking were then reinterviewed 6 months later, that is, 12 months after the contest. RESULTS: Cessation rates were 66% at contest end, 36% at 6 months, and 22% at 12 months. Heavier smokers were somewhat more likely to have quit. Overall, 41% of respondents used any form of aid (support resources and pharmacological aids) in the first 6 months; among these, 42% used bupropion and 38% used nicotine patches. Those using bupropion were more likely to successfully quit smoking. Successful quitters rated the social support received from their buddy as more useful than did relapsers, and social support was unrelated to the use of pharmacological aids. CONCLUSIONS: The results suggest that adequate investment in population-wide Quit and Win programs that provide a variety of appropriate aids to smokers, including social support and pharmacological products, can improve the reach of smokers.

Adolescent↗

Intraaortic balloon counterpulsation: its influence alone and combined with various pharmacological agents on regional myocardial blood flow during experimental acute coronary occlusion.

We investigated the separate and combined effects of pharmacological and intraaortic balloon pump (IABP) support on regional myocardial blood flow in an experimental model of acute myocardial ischemia. Chloralose-anesthetized dogs were ventilated with an oxygen-air mixture, and cardiac output, arterial pressure, and heart rate were held constant. Treatment was begun 20 minutes following permanent ligation of the left anterior descending coronary artery (LAD). We evaluated the following pharmacological interventions: 25% hypertonic mannitol, isosorbide dinitrate, methyl-prednisolone sodium succinate, and propranolol. We measured left ventricular hemodynamics and intramyocardial blood flow by the radioactive microsphere technique prior to treatment and at 15-minute intervals thereafter. Compared with control measurements 20 minutes following LAD ligation, collateral blood flow to ischemic myocardium tended to decrease with no treatment. Treatments with the four pharmacological interventions and with IABP alone produced no significant improvement in collateral blood flow to ischemic myocardium 15 minutes following treatment. In contrast, mannitol, isosorbide dinitrate, and propranolol, each combined with IABP support, produced significant improvements in collateral flow within the same time periods. In nonischemic myocardium, combined pharmacological and IABP treatment did not enhance myocardial blood flow above that obtained with the pharmacological agents alone. The most effective combination of mechanisms for improving the ischemic region's myocardial blood flow appeared to be a reduction of extravascular coronary flow resistance coupled with a simultaneous increase in diastolic arterial pressure.

Animals↗

Effects of conventional hypothermic ischemic arrest and pharmacological arrest on myocardial supply/demand balance during aortic cross-clamping.

Aortic cross-clamping may produce ischemic damage due to a discrepancy between supply and demand. Supply is determined by noncoronary collateral flow and substrate stores, and demand by electromechanical activity, wall tension, and temperature. The effects of 60 minutes of conventional hypothermic ischemic arrest were compared to those of pharmacological arrest. Noncoronary collateral blood supply was comparable in both groups during cross-clamping. With ischemic arest, mechanical activity and endocardial electrical activity persisted and wall tension fell progressively. With pharmacological arrest, electromechanical activity stopped in less than 1 minute but returned (with increased wall tension) nearly 1 hour. Thirty minutes following reperfusion, coronary flow was redistributed away from subendocardium after ischemic arrest and toward endocardium after pharmacological arrest. Myocardial performance was depressed severely after conventional arrest and only mildy after pharmacological arrest. We conclude that aortic cross-clamping is safer with pharmacological arrest than with ischemic arrest. The cardioplegic solution modifies the supply/demand balance favorably, but it is washed out by noncoronary collateral blood supply.

Animals↗

The pharmacology of a dopamine receptor in the locust nervous tissue.

A dopamine receptor in the nervous tissue of the desert locust (Schistocerca gregaria Forskâl) was studied using ¿3Hlysergic acid diethylamide (LSD) as the radioligand. Its expression is almost entirely restricted to the mushroom bodies, centres for learning and memory in the insect brain. This G-protein coupled receptor is present in relatively low concentrations in the locust brain (35 fmol/mg protein). The pharmacological characterisation reveals high affinity for the putative natural agonist dopamine (K(i)=28 nM). Substances with high subtype specificity for vertebrate dopamine receptors such as SCH 23390 (K(i)=639 nM) and sulpiride (K(i)=21,200 nM) have low affinity for the locust neuronal dopamine receptor. In opposite, substances with a broad pharmacological profile such as LSD, spiperone (K(i)=7.26 nM), and chlorpromazine (K(i)=9.52 nM) have high affinity properties. Comparison of the pharmacological data reveals no significant homology to any vertebrate dopamine receptor class characterised so far. This uncertainty about the pharmacological relatedness of insect dopamine receptors mirrors the available molecular data. It is almost impossible to classify cloned insect dopamine receptors into vertebrate dopamine receptor schemes. This lack of pharmacological relatedness opens the opportunity to develop highly specific insecticides against insect dopamine receptors.

Animals↗

Molecular and pharmacological characterization of the mouse histamine H3 receptor.

Human, guinea pig and rat histamine H(3) receptors have been investigated at both pharmacological and molecular levels in recent years. Here we report the cloning, molecular, and pharmacological characterization of the mouse histamine H(3) receptor. The amino acid sequence of the mouse histamine H(3) receptor exhibits high homology to rat, guinea pig and human histamine H(3) receptors with 98%, 95%, 94% identities, respectively. The distribution of the mRNA encoding the mouse histamine H(3) receptor was predominant in the brain as detected by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and RNase protection assay. Although several splice forms have been reported for human, guinea pig and rat histamine H(3) receptor mRNAs, we did not detect equivalent isoforms in the mouse in several tissues by either RNase protection assay or robust Polymerase Chain Reaction (PCR) amplifications. Human embryonic kidney (HEK)-293 cells transiently transfected with mouse histamine H(3) receptor cDNA and Gq(i5) exhibited increases of intracellular Ca(2+) in response to histamine and several histamine H(3) receptor agonists. COS-7 (African green monkey kidney) cells transfected with mouse histamine H(3) receptor cDNA showed high affinity binding for histamine H(3) receptor ligands in competition binding assays. The pharmacological comparison of human, guinea pig, rat and mouse histamine H(3) receptors indicated that, as expected, the mouse histamine H(3) receptor exhibited a more similar pharmacological profile to the rat histamine H(3) receptor than to either the human or the guinea pig histamine H(3) receptor. Taken together, these findings allow a further appreciation of the histamine H(3) receptor at the molecular level and provide an additional species to assist in the pharmacological assessment of histamine H(3) receptor function.

Alternative Splicing↗

Adrenal dynamic responses to physiologic and pharmacologic adrenocorticotropic hormone stimulation before and after ovarian steroid modulation in women with polycystic ovary syndrome.

OBJECTIVE: To test the hypothesis that in women with polycystic ovary syndrome (PCOS), adrenal cytochrome P450c 17alpha activity is different after physiologic vs. pharmacologic ACTH stimulation and that ovarian activity promotes adrenal hyperactivity that is different after physiologic vs. pharmacologic ACTH stimulation. DESIGN: Prospective controlled pilot study. SETTING: Reproductive endocrinology unit of an academic medical center. PATIENT(S): Six women with PCOS who had adrenal hyperandrogenism were compared with four women with normal ovulation. INTERVENTION(S): Adrenal dynamic blood sampling was performed before and after 6 months of GnRH agonist administration. MAIN OUTCOME MEASURE(S): Comparison of physiologic and pharmacologic ACTH-stimulated levels of progesterone, 17-hydroxyprogesterone, and androgens before and after ovarian steroid modulation. RESULT(S): In women with PCOS, exaggerated responses of androstenedione and 11beta-hydroxyandrostenedione as well as elevated ratios of 17-hydroxyprogesterone to progesterone and of androstenedione to 17-hydroxyprogesterone after physiologic ACTH stimulation did not persist after GnRH-agonist administration. Three of the six women with PCOS had an increased response of androstenedione and a ratio of androstenedione to 17-hydroxyprogesterone that were >2 SD above the mean of those in the women with normal ovulation after pharmacologic ACTH stimulation; this finding persisted after GnRH-agonist administration. CONCLUSION(S): In women with PCOS, increases in adrenal androgen sensitivity after physiologic ACTH stimulation reflected in both arms of cytochrome P450c 17alpha activity may be influenced by ovarian activity. However, 17,20-lyase hyperactivity in a subset after pharmacologic ACTH stimulation may be an intrinsic adrenal disorder.

Adrenocorticotropic Hormone↗

Effects of speech therapy and pharmacologic and surgical treatments on voice and speech in Parkinson's disease: a review of the literature.

The purpose of this review was to examine the different treatment approaches for persons with Parkinson's Disease (PD) and to examine the effects of these treatments on speech. Treatment methods reviewed include speech therapy, pharmacological, and surgical. Research from the 1950s through the 1970s had not demonstrated significant improvements following speech therapy. Recent research has shown that speech therapy (when persons with PD are optimally medicated) has proven to be the most efficacious therapeutic method for improving voice and speech function. Pharmacological methods of treatment in isolation do not appear to significantly improve voice and speech function in PD across research studies. Surgical treatment methods including pallidotomy and deep brain stimulation may be significant treatment options which improve voice and speech function in some persons with PD. Possible explanations for the differential responses to treatment are discussed. Future studies should investigate the effects of combined treatment approaches. Perhaps the combination of pharmacological, surgical and speech treatment will prove superior to treatments combining pharmacological and surgical or pharmacological and speech therapy in improving the communication abilities of persons with PD.

Antiparkinson Agents↗

Pharmacology of antidepressants--characteristics of the ideal drug.

OBJECTIVE: To describe the clinical and basic pharmacologic properties of antidepressants and thus define the pharmacologic criteria for the ideal antidepressant. DESIGN: A review of the pharmacologic characteristics of the newer second-generation antidepressants is presented in relationship to those of the older compounds. MATERIAL AND METHODS: Clinical pharmacologic and in vitro data on the synaptic effects of antidepressants (inhibition of synaptosomal uptake and blockade of neurotransmitter receptors) were obtained for the older antidepressants and for the more recently marketed and approved drugs. The group of antidepressants includes six new antidepressants approved for marketing since 1988 and two additional drugs marketed outside the United States as antidepressants but approved for use in the United States for obsessive-compulsive disorder. Thus, 18 antidepressant drugs are discussed. RESULTS: All antidepressants seem to be equally efficacious in treating depression, and no drug seems to work more rapidly than another. Nonetheless, antidepressant drugs differ substantially in pharmacokinetic variables (elimination half-lives); in their effects on the metabolism of other drugs (by inhibiting the cytochrome P450 system); in their potencies for blocking the reuptake of norepinephrine, serotonin, and dopamine; and in their affinities for blocking histamine H1, muscarinic acetylcholine, alpha 1-adrenergic, and dopamine D2 receptors. Most side effects of antidepressants can be explained by their effects on blocking uptake and on blocking neurotransmitter receptors. CONCLUSION: The newer second-generation antidepressants have distinct pharmacologic advantages in comparison with the tricyclic antidepressants and the older second-generation compounds. These advantages are clearly seen from their synaptic effects, in which most newer second-generation antidepressants are practically devoid of blocking effects at neurotransmitter receptors. Although the newer second-generation antidepressants are much closer to being the ideal antidepressant than are the older compounds, none completely fulfills the criteria for being the ideal drug.

Antidepressive Agents↗

Cloning and characterization of the guinea pig 5-HT1F receptor subtype: a comparison of the pharmacological profile to the human species homolog.

The anti-migraine compound, sumatriptan, has been shown to have substantial affinity for the cloned human 5-HT1F receptor suggesting that, in addition to 5-HT1B/5-HT1D receptor subtypes, the 5-HT1F receptor may be a therapeutic target for the treatment of migraine. Several investigators have used the guinea pig plasma extravasation model to evaluate potential anti-migraine drugs. Since species differences in the pharmacology of serotonin receptors are well known, we compared the pharmacological profiles of the cloned human and guinea pig 5-HT1F receptors in order to validate the usefulness of the in vivo model in predicting anti-migraine activity of compounds targeted for humans. We have cloned the guinea pig 5-HT1F by homology to the human 5-HT1F receptor and evaluated its pharmacological profile using radioligand binding assays. The cloned guinea pig 5-HT1F gene exhibited 94% amino acid identity to the corresponding human homolog. High affinity (Kd approximately 10 nM) [3H]5-HT binding was detected to membranes obtained from Cos-7 cells transiently expressing the guinea pig 5-HT1F receptor. The cloned guinea pig receptor displayed typical 5-HT1F receptor pharmacology with the following rank order of binding affinities: 5-HT > sumatriptan > 1-NP = DHE > alpha-methyl 5-HT > metergoline > methiothepin > 5-CT. The pharmacological profiles of the cloned guinea pig and human 5-HT1F receptors were very similar as reflected by the high correlation (r2 = 0.72, slope = 0.76) observed between the binding affinities of compounds for these two species homologs. In situ hybridization studies in guinea pig tissue revealed 5-HT1F receptor mRNA expression in the neurons of the trigeminal ganglion, suggesting that the 5-HT1F receptor may play a role in the presynaptic inhibition of neuropeptide release at the level of the intracranial vasculature, thereby blocking the development of neurogenic inflammation. Dorsal root ganglion cells also moderately expressed the 5-HT1F transcripts. The localization of the 5-HT1F receptor to areas involved in the mediation and transfer of nociceptive information implies a role for this receptor in pain processing. These findings indicate that a selective 5-HT1F agonist may be a novel approach to treat migraine.

Amino Acid Sequence↗

Patterns of pharmacologic treatment of congestive heart failure in elderly nursing home residents and related issues: a review of the literature.

BACKGROUND: Congestive heart failure (CHF) is a serious clinical syndrome associated with increased morbidity, mortality, and health-related expenditure. In the United States, the incidence and prevalence of CHF have been shown to increase with age, particularly among the elderly (age >/=65 years). In addition, more elderly persons are living in or will be living in nursing homes. Given these trends, it is important to consider the quality of care, including pharmacologic treatment, received by elderly nursing home residents with a diagnosis of CHE There is currently a lack of clinical trial data on the pharmacologic treatment of CHF among elderly nursing home residents and, therefore, no standard of care. In lieu of clinical trial data, empiric studies based on nursing home populations may be useful. OBJECTIVE: This article reviews empiric studies concerning the pharmacologic treatment of CHF in elderly nursing home residents. METHODS: Empiric studies on the use of angiotensin-converting enzyme (ACE) inhibitors, digoxin, and diuretics in elderly nursing home residents with a diagnosis of CHF were identified through searches of MEDLINE, Cochrane Trials, and International Pharmaceutical Abstracts using the terms elderly, nursing home, geriatric, and heart failure. The search was limited to the past 11 years (1991-2002) to identify current patterns of treatment in the population of interest. Additional studies were identified through a manual search of the reference lists of the retrieved articles. RESULTS: Thirteen empiric studies were identified: 9 examined ACE-inhibitor use, 4 digoxin use, and 7 diuretic use. The findings of these studies indicated that ACE inhibitors are underused, are often prescribed at clinically inefficient doses, and are used more often in "young" elderly nursing home residents (age 65-74 years). Among patients who received a prescription for digoxin, many did not have an appropriate indication (eg, no documented atrial fibrillation, normal sinus rhythm). Similarly, diuretics were found to be inappropriately prescribed to elderly nursing home residents for the treatment of CHF. CONCLUSIONS: Based on the available empiric studies, elderly nursing home residents with a diagnosis of CHF do not appear to receive adequate treatment with ACE inhibitors, digoxin, or diuretics based on the recommendations of clinical or als or clinical guidelines. However, the clinical trials and clinical guidelines target the general elderly population and thus may not be applicable to elderly nursing home residents. Future research should explore factors influencing the pharmacologic treatment of CHF in elderly nursing home residents, and trials of new pharmacologic treatments for CHF should include elderly nursing home residents.

Aged↗

Preclinical research on cocaine self-administration: environmental determinants and their interaction with pharmacological treatment.

It has been asserted that any comprehensive understanding of cocaine abuse and its treatment will require attention to both behavioral and pharmacological variables. Although the preclinical literature evaluating the effects of pharmacological variables on cocaine self-administration has been extensively reviewed, no comprehensive review of the effects of environmental variables on cocaine self-administration has been published. The present review summarizes and critiques the preclinical findings on environmental determinants of cocaine self-administration. The influence of environmental variables on the effects of pharmacological interventions on cocaine self-administration are also described. Several environmental variables have been shown to affect cocaine self-administration, including unit dose, schedule of cocaine delivery, schedules of nondrug stimuli, behavioral history, conditioned stimuli, food deprivation, exposure to stress, and rearing environment. Among these variables, unit dose, schedule of cocaine delivery, availability of alternative nondrug reinforcers, food deprivation, and rearing environment have also been shown to alter pharmacological treatment effects on cocaine self-administration. Thus, drug effects on cocaine self-administration are malleable and dependent upon the environmental context within which they occur. Suggestions for future research on the effects of these and other environmental variables on cocaine self-administration and its pharmacological treatment are presented.

Animals↗

Clinical and cellular pharmacology in relation to solid tumours of childhood.

Our understanding of the clinical and cellular pharmacology of drugs commonly used in the treatment of childhood cancer have increased greatly over the past two decades. However, with the exception of childhood acute lymphoblastic leukaemia (ALL), our current knowledge of factors such as inter-patient pharmacokinetic variability and cellular determinants of chemosensitivity has not been utilized in the design of integrated clinical studies. Recent pre-clinical and clinical evaluation of the topoisomerase I inhibitors topotecan and irinotecan has highlighted the potential importance of pharmacological factors in their effectiveness as cytotoxics. In this review, the clinical and cellular pharmacology of vincristine, actinomycin D, doxorubicin, cyclophosphamide, ifosfamide, cisplatin, carboplatin and etoposide will be discussed in relation to the major paediatric solid tumours. For each disease type, knowledge of the clinical and cellular pharmacology of a candidate drug will be related to pharmacodynamic responses such as response, toxicity and prognosis. For diseases such as Wilms' tumour, osteogenic sarcoma and Ewing's tumour, histological response to initial induction chemotherapy is of prognostic significance, and the depth of response is increasingly recognised as an important determinant of prognosis for high-risk neuroblastoma. For several of these tumour types, the dose-intensity of chemotherapy may be an important variable in determining prognosis. However the relationship between pharmacokinetic variability, cellular pharmacology and the major determinants of chemosensitivity to those drugs employed in first line therapy is unknown. The study of these relationships, by means of up front window studies in children who present with high-risk disease, may be as important as the introduction of new agents. Indeed, the optimisation of current therapies may be required to allow a fully informed selection of those children for whom novel therapies are truly needed. Funding and international collaboration at the clinical and scientific level would be required to achieve these aims.

Antineoplastic Agents↗