Comparative Study of the Pharmacokinetics and Bioequivalence of Meldonium and Mildronate® Preparations

Pharmaceutical Chemistry Journal - Acomparative study of the pharmacokinetics, bioequivalence, and safety of two marketed meldonium dosage forms Meldonium Organika (meldonium, 500 mg capsules,...     

Socio-economic status and the therapeutic effectiveness of antihypertensive treatment – the design of the LEO study

ABSTRACT

Objective: The risk of arterial hypertension and subsequent cardiovascular disease morbidity and mortality increases with low socio-economic status (SES). Even small differences in blood pressure, whether untreated or despite treatment, account for this substantial difference. Most of the increased risk in the low socio-economic group is due to traditional cardiovascular risk factors such as overweight and obesity, alcohol consumption and a sedentary life style. Intense treatment of arterial hypertension has been shown to overcome these prognostic inequalities. Therefore, drugs with high efficacy, optimal treatment adherence and a low potential for drug-related side effects are needed in order to reduce the cardiovascular risk burden of patients with a low SES. The angiotensin receptor blocker (ARB) olmesartan will be used to investigate the effectiveness of this drug in different socio-economic classes.

Research design and methods: The LEO (Long-term Effectiveness of Olmesartan in different Socioeconomic groups) study is a large observational long-term study which has been set up to test the effectiveness of olmesartan within this context. The study has a matched-pairs design (1403 patients in both the low and the high socio-economic classes).

Main outcome measures: The LEO study will test whether this regimen can reduce the SES-related difference in long-term blood pressure control and compliance in the low SES population.

Conclusions: The study may generate valuable information about the antihypertensive effectiveness of olmesartan alone or in combination with hydrochlorothiazide in different socio-economic classes. It will further test whether the drug helps to reduce the inherent inequalities in cardiovascular prognosis between different socio-economic groups.

Current status: The study commenced in July 2007. Results are anticipated in December 2008.     

Synthesis and Study of the Analgesic and Antiinflammatory Activity of α-Acetoxyphenylacetic Acid Amides

Pharmaceutical Chemistry Journal -     

Postexposure management and treatment of anthrax in dogs—Executive councils of the American academy of veterinary pharmacology and therapeutics and the American college of veterinary clinical pharmacology

Dogs are generally at low risk of developing disease following exposure to anthrax. When disease does occur, it appears associated with oral exposure to the bacteria leading to massive swelling of the head, neck, and mediastinal regions. Death is due to toxemia and shock. For animals at high risk, such as search and rescue dogs with a known exposure, doxycycline at 5 mg/kg orally once daily for 45 to 60 days is suggested as a prophylactic treatment. Additional information on the diagnosis, prevention, and treatment of the disease in dogs is presented.     

β-blockers and the risk of incident depression in the elderly

The hypothesis that β-blockers cause depression has been both confirmed and refuted in previous studies. However, in hardly any of these studies, depression was systematically and adequately assessed. The aim of this cohort study was to examine whether β-blockers, in general, highly lipid-soluble, nonselective, or serotonergic receptor-binding β-blockers, are associated with incident depression. Between 1993 and 2005, 5104 elderly persons were followed for incident depressions. Depressions were identified by regular interview and continuous monitoring of medical records. Cases were categorized as clinically relevant depressive symptoms or as depressive syndromes, the latter including Diagnostic and Statistical Manual of Mental Disorders-IV-defined depressive disorders. Pharmacies provided information on filled β-blockers. We used Cox regression with drug use as a time-dependent variable to analyze the data, adjusted for potential demographic covariates, activity of daily living, and (contra)indications for β-blockers. We found that use of β-blockers in general did not convey an increased risk of depressive symptoms (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.37-1.59) or depressive syndromes (HR, 0.99; 95% CI, 0.53-1.84). Highly lipid-soluble β-blockers, mostly propranolol in our study, were associated with depressive symptoms during the first 3 months of use (HR, 3.31; 95% CI, 1.03-10.6), but not with depressive syndromes. Nonselective or serotonergic receptor affinity was not associated with an increased risk of depressive symptoms or syndromes independent of high lipid solubility. We conclude that β-blockers in general do not convey an increased risk of depression. Lipophilic β-blockers are associated with an increased risk of depressive symptoms.     

Studies on the Syntheses and Properties of 5′-Branched-sugar Isonucleosides and the Related Oligonucleotides

The chemistry of nucleosides and oligonucleotides is an actively investigated field in the search for new drugs. The syntheses and the properties of isonucleosides and oligonucleotides have been investigated to improve their stability, antitumor and antiviral activities, and to reduce their toxicity.The syntheses and properties of isonucleosidesA new class of isonucleoside analogues with branched-sugar 2(-deoxy-2(-nucleobase-5(-deoxy-1(,4(-anhydro-D-altritol(21, 23a～c) has been synthesized fr…     

Effects of the Aconitum alkaloid mesaconitine in rat hippocampal slices and the involvement of α- and β-adrenoceptors

1. The effects of mesaconitine, the main alkaloid contained in Aconiti tuber, were investigated by use of extracellular recordings of stimulus-evoked population spikes and field excitatory postsynaptic potentials (e.p.s.ps) in the CA1 region of rat hippocampal slices.
2. At a concentration of 10 nM, mesaconitine evoked excitations, which were manifested as an increase in the amplitude of the orthodromic spike and the appearance of multiple spikes following the first postsynaptic spike, without affecting the magnitude of paired-pulse facilitation. The increase in spike amplitude was persistent and was not reversed by up to 90 min of washout. At concentrations of 30 and 100 nM, the alkaloid produced a biphasic effect, that is an excitation followed by an inhibition without having any effect upon the field e.p.s.p. At concentrations above 100 nM, mesaconitine suppressed the orthodromic population spike and the field e.p.s.p.
3. The excitatory effect was also observed when electrical stimulation was stopped completely during the application of mesaconitine (10 nM) and during the first 15 min of washout.
4. The enhancement of the population spike and the appearance of multiple spikes induced by mesaconitine (10–100 nM) were blocked by pretreatment with the β-adrenoceptor antagonists propranolol (1 μM) and timolol (1 μM), whereas the inhibitory effect was blocked by the α-adrenoceptor antagonists yohimbine (1 μM) and phentolamine (10 μM). However, when the β-adrenoceptor antagonist timolol was added 10 min after the application of mesaconitine, it failed to block the long-lasting enhancement of the spike amplitude and the appearance of multiple population spikes.
5. Application of the selective β-adrenoceptor agonist isoprenaline (500 nM) to the hippocampal slices induced an increase in the amplitude of the orthodromic population spike and elicited 2–3 additional spikes. Mesaconitine (10 nM) did not further potentiate this enhancement of the spike amplitude when added after a 15 min pretreatment with isoprenaline.
6. Perfusion of forskolin, which directly activates adenylate cyclase, enhanced the population spike. Mesaconitine had no additional effect when applied after pretreatment with forskolin.
7. It is concluded that the excitatory effects evoked by lower concentrations of the plant alkaloid mesaconitine are mediated by stimulation of β-adrenoceptors and the consequent activation of intracellular processes which lead to the long-lasting changes in excitability.

     

Do gender and year of study affect the ability of the theory of planned behaviour to predict binge-drinking intentions and episodes?

Background: The present study tested the utility of the theory of planned behaviour (TPB), augmented with anticipated regret, as a model to predict binge-drinking intentions and episodes among female and male undergraduates and undergraduates in different years of study. Method: Undergraduate students (N?=?180, 54 males, 126 females, 60 per year of study) completed baseline measures of demographic variables, binge-drinking episodes (BDE), TPB constructs and anticipated regret. BDE were assessed one-week later. Results: The TPB accounted for 60% of the variance in female undergraduates' intentions and 54% of the variance in male undergraduates' intentions. The TPB accounted for 57% of the variance in intentions in first-year undergraduates, 63% of the variance in intentions in second-year undergraduates and 68% of the variance in intentions in final-year undergraduates. Follow-up BDE was predicted by intentions and baseline BDE for female undergraduates as well as second- and final-year undergraduates. Baseline BDE predicted male undergraduates’ follow-up BDE and first-year undergraduates’ follow-up BDE. Conclusion: Results show that while the TPB constructs predict undergraduates’ binge-drinking intentions, intentions only predict BDE in female undergraduates, second- and final-year undergraduates. Implications of these findings for interventions to reduce binge drinking are outlined.     

Studies on the Syntheses and Properties of 5＇-Branched-sugar Isonucleosides and the Related Oligonucleotides

The chemistry of nucleosides and oligonucleotides is an actively investigated field in the search for new drugs. Thesyntheses and the properties of isonucleosides and oligonucleotides have been investigated to improve their stability,antitumor and antiviral activities, and to reduce their toxicity.     

Nonprofessionals’ perceptions of the causes of behavioral and substance addictions

We assessed nonprofessionals' perceptions of etiological explanations of behavioral and substance addictions in a nationwide sample. A total of 612 adults (51% male) residing in the United States were recruited using Mechanical Turk. Participants rated the perceived likelihood of seven psychosocial and biological etiologies for one of five randomly assigned types of “addiction” (i.e., alcohol, marijuana, heroin, gambling, or pornography). Significantly fewer participants rated social pressure a likely cause of addiction to pornography (31%) than to marijuana (53%), alcohol (55%), and heroin (64%); significantly fewer rated traumatic childhood events a likely cause of addiction to gambling (33%) and marijuana (36%) than to pornography (56%), heroin (57%), and alcohol (64%); significantly fewer rated the way a person was raised a likely cause of addiction to marijuana (37%) than to heroin (55%) and alcohol (65%); and significantly more rated genetics a likely cause of an addiction to alcohol (65%) than to pornography (26%), marijuana (33%), gambling (41%), and heroin (45%). The proportions who rated stressful circumstances and character problem as likely causes were not significantly associated with type of addiction. In addition, participants rated an average of three or four separate etiologies as likely causes of each target addiction. Our results suggest that lay individuals recognize the multi-determined nature of addictive disorders and rate some causes as more or less likely depending on the specific addictive substance or behavior.     

A review of the clinical pharmacokinetics and metabolism of the α1-adrenoceptor antagonist indoramin

1. The α₁-adrenoceptor antagonist indoramin is rapidly and extensively absorbed after oral administration, but with only low to moderate bioavailability (8-24% median) from the tablet (Baratol®). Although plasma protein binding is high (72-86%), the drug is widely distributed into tissues (with median V_z 6.3.7.71/kg after i.v. dosage).

2. Elimination of indoramin is rapid in most healthy volunteers, with median plasma clearances of 18-26ml/min per kg, after i.v. dosage. Elimination occurs principally by metabolism, the major route being indole 6-hydroxylation, followed by sulphate conjugation of 6-hydroxyindoramin. The faecal route of excretion predominates (45-50% of dose), with a further 35-40% in the urine.

3. Extensive variation in single-dose oral pharmacokinetics of indoramin is due largely to the existence of a poor metabolizer phenotype which co-segregates with that of debrisoquine.

4. On repeated administration (37.5 mg twice daily) to healthy volunteers, plasma concentrations of indoramin accumulate 3-4-fold above those anticipated from single-dose kinetics. However, steady state is achieved within the first week of dosing.

5. The pharmacokinetics of indoramin are substantially altered in the elderly. The oral AUC for a 50mg dose is increased approx. 5-fold and the t_1/2 2-5-fold.

6. Cirrhotic liver disease enhances bioavailability and decreases clearance, approx. 2-fold in each case for single oral and i.v. doses of 50mg and 0.15mg/kg respectively.

7. After oral indoramin C_max and AUC are both raised (58% and 25%, respectively, for a 50 mg dose) by co-ingested ethanol (0.5 g/kg). After i.v. indoramin, kinetics are unaffected by alcohol, but indoramin (0.175 mg/kg) slightly increases (26%) blood ethanol concentrations during the first hour after dosing.

8. The pharmacodynamics of indoramin appear to be related to the combined pharmacokinetics of the drug and its 6-hydroxylated metabolite, which contributes to the antihypertensive effect.     

The Integration of the Glutamatergic and the White Matter Hypotheses of Schizophrenia��s Etiology

Background:

schizophrenia''s endophenotipic profile is not only generally complex, but often varies from case to case. The perspective of trying to define specific anatomic correlates of the syndrome has led to disappointing results. In that context, neurophysiologic hypotheses (e.g. glutamatergic hypothesis) and connectivity hypotheses became prominent. Nevertheless, despite their commitment to the principle of denying ''localist'' views and approaching the syndrome''s endophenotype from a whole brain perspective, efforts to integrate both have not flourished at this moment in time.

Objectives:

This paper aims to introduce a new etiological model that integrates the glutamatergic and the WM (WM) hypotheses of schizophrenia’s etiology. This model proposes to serve as a framework in order to relate to patterns of brain abnormalities from the onset of the syndrome to stages of advanced chronification.

Highlights:

Neurotransmitter abnormalities forego noticeable WM abnormalities. The former, chiefly represented by NMDAR hypo-function and associated molecular cascades, is related to the first signs of cell loss. This process is both directly and indirectly integrated to the underpinning of WM structural abnormalities; not only is the excess of glutamate toxic to the WM, but its disruption is associated to the expression of known genetic risk factors (e.g., NRG-1). A second level of the model develops the idea that abnormal neurotransmission within specific neural populations (''motifs'') impair particular cognitive abilities, while subsequent WM structural abnormalities impair the integration of brain functions and multimodality. As a result of this two-stage dynamic, the affected individual progresses from experiencing specific cognitive and psychological deficits, to a condition of cognitive and existential fragmentation, linked to hardly reversible decreases in psychosocial functioning.     

Pharmacokinetic–Pharmacodynamic Modeling of the Effectiveness and Safety of Buprenorphine and Fentanyl in Rats

Objective Respiratory depression is a serious and potentially life-threatening side-effect of opioid therapy. The objective of this investigation was to characterize the relationship between buprenorphine or fentanyl exposure and the effectiveness and safety outcome in rats. Methods Data on the time course of the antinociceptive and respiratory depressant effect were analyzed on the basis of population logistic regression PK–PD models using non-linear mixed effects modeling software (NONMEM). The pharmacokinetics of buprenorphine and fentanyl were described by a three- and two-compartment model, respectively. A logistic regression model (linear logit model) was used to characterize the relationship between drug exposure and the binary effectiveness and safety outcome. Results For buprenorphine, the odds ratios (OR) were 28.5 (95% CI, 6.9–50.1) and 2.10 (95% CI, 0.71–3.49) for the antinociceptive and respiratory depressant effect, respectively. For fentanyl these odds ratios were 3.03 (95% CI, 1.87–4.21) and 2.54 (95% CI, 1.26–3.82), respectively. Conclusion The calculated safety index (OR_{antinociception}/OR_{respiratory depression}) for fentanyl of 1.20 suggests that fentanyl has a low safety margin, implicating that fentanyl needs to be titrated with caution. For buprenorphine the safety index is 13.54 suggesting that buprenorphine is a relatively safe opioid.     

Antiproliferative and teratogenic activities of the bishemisuccinates of 7α-hydroxycholesterol and 7β-hydroxycholesterol

1. The bishemisuccinates of 7α-hydroxycholesterol and 7β-hydroxycholesterol induced a dose-dependent decrease in the incorporation of [³H]thymidine into fibroblast cell line (3T3), macrophagelike cell line (P388D1) and rat hepatoma cell line (H35). Concomitantly there was a reduction in cell viability.2. The 3T3 cells were less susceptible than P388D1 and H35 cells.3. The aforementioned derivatives of 7α-hydroxycholesterol and 7β-hydroxycholesterol produced malformations in cultured embryos including abnormalities in yolk sac circulation, heartbeat, body axis, otic vesicle, branchial apparatus, cranial neural tube and forelimb bud. Axial length and somite number were reduced.     

Care of the stroke patient—communication between the community pharmacist and prescribers in the Republic of Ireland

Objective This study sought to examine the perceptions that community pharmacists have of communication with prescribers in both primary and secondary care in Ireland, with respect to care of stroke patients. Setting Community pharmacies across Ireland, stratified into the four representative administrative regions. Method Survey using a structured postal questionnaire. Main outcome measure Perceptions of communication with prescribers based in primary and secondary care; pharmacy and pharmacy premises demographics. Results A response rate of 52% (n = 314) was achieved. Community pharmacists’ perceptions of information provision from secondary care were low, the majority (83%) never received any information from the hospital, although they would welcome it. Communication with hospital based prescribers was considered by most (93%) to be poor. The majority (greater than 75%) of respondents expressed a desire for greater information provision concerning a stroke patient’s medication and diagnostic information. Pharmacists’ perceptions of interaction with general practitioners were generally regarded as good (63%) although information provision in both directions between pharmacist and general practitioner could be improved. Conclusion The findings of this study indicated that community pharmacists perceive that there is room for improvement in the communication between themselves and prescribers in the primary and secondary care settings, concerning the care of the stroke patient. This highlights the need for the development of formal communication channels between community pharmacists and other members of the healthcare team involved in the care of the stroke patient. However, the challenges of communicating patient information across healthcare sectors are recognized.     

Effects of sympathectomy on the in vitro α and β-responses of the parotid gland

Summary Amylase and K⁺ release were measured in slices obtained from innervated and sympathetically denervated rat parotid glands. Amylase release induced by noradrenaline was found to be increased after chronic denervation. The postjunctional component of supersensitivity to noradrenaline was evidenced by an increase in the maximal response to this agonist. The maximal response of denervated glands was blocked by propranolol 10^–5 M. On the other hand, chronic denervation did not modify the -adrenoceptor-mediated response, K⁺ release, either in the presence or in the absence of ouabain. It is concluded that, after sympathetic denervation, postjunctional supersensitivity develops for the -adrenoceptor-mediated but not for the -adrenoceptors-mediated effects of noradrenaline.