Efficacy, safety, quality control, marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents)

This review highlights the current advances in knowledge about the safety, efficacy, quality control, marketing and regulatory aspects of botanical medicines. Phytotherapeutic agents are standardized herbal preparations consisting of complex mixtures of one or more plants which contain as active ingredients plant parts or plant material in the crude or processed state. A marked growth in the worldwide phytotherapeutic market has occurred over the last 15 years. For the European and USA markets alone, this will reach about $7 billion and $5 billion per annum, respectively, in 1999, and has thus attracted the interest of most large pharmaceutical companies. Insufficient data exist for most plants to guarantee their quality, efficacy and safety. The idea that herbal drugs are safe and free from side effects is false. Plants contain hundreds of constituents and some of them are very toxic, such as the most cytotoxic anti-cancer plant-derived drugs, digitalis and the pyrrolizidine alkaloids, etc. However, the adverse effects of phytotherapeutic agents are less frequent compared with synthetic drugs, but well-controlled clinical trials have now confirmed that such effects really exist. Several regulatory models for herbal medicines are currently available including prescription drugs, over-the-counter substances, traditional medicines and dietary supplements. Harmonization and improvement in the processes of regulation is needed, and the general tendency is to perpetuate the German Commission E experience, which combines scientific studies and traditional knowledge (monographs). Finally, the trend in the domestication, production and biotechnological studies and genetic improvement of medicinal plants, instead of the use of plants harvested in the wild, will offer great advantages, since it will be possible to obtain uniform and high quality raw materials which are fundamental to the efficacy and safety of herbal drugs.

High incidence of adverse reactions to initial antiretroviral therapy in Brazil

A concurrent prospective study was conducted from 2001 to 2003 to assess factors associated with adverse reactions among individuals initiating antiretroviral therapy at two public referral HIV/AIDS centers in Belo Horizonte, MG, Brazil. Adverse reactions were obtained from medical charts reviewed up to 12 months after the first antiretroviral prescription. Cox proportional hazard model was used to perform univariate and multivariate analyses. Relative hazards (RH) were estimated with 95% confidence intervals (CI). Among 397 charts reviewed, 377 (95.0%) had precise information on adverse reactions and initial antiretroviral treatment. Most patients received triple combination regimens including nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors. At least one adverse reaction was recorded on 34.5% (N = 130) of the medical charts (0.17 adverse reactions/100 person-day), while nausea (14.5%) and vomiting (13.1%) were the most common ones. Variables independently associated with adverse reactions were: regimens with nevirapine (RH = 1.78; 95% CI = 1.07-2.96), indinavir or indinavir/ritonavir combinations (RH = 2.05; 95% CI = 1.15-3.64), female patients (RH = 1.93; 95% CI = 1.31-2.83), 5 or more outpatient visits (RH = 1.94; 95% CI = 1.25-3.01), non-adherence to antiretroviral therapy (RH = 2.38; 95% CI = 1.62-3.51), and a CD4+ count of 200 to 500 cells/mm³ (RH = 2.66; 95% CI = 1.19-5.90). An independent and negative association was also found for alcohol use (RH = 0.55; 95% CI = 0.33-0.90). Adverse reactions were substantial among participants initiating antiretroviral therapy. Specially elaborated protocols in HIV/AIDS referral centers may improve the diagnosis, management and prevention of adverse reactions, thus contributing to improving adherence to antiretroviral therapy among HIV-infected patients.

Exercise may cause myocardial ischemia at the anaerobic threshold in cardiac rehabilitation programs

Myocardial ischemia may occur during an exercise session in cardiac rehabilitation programs. However, it has not been established whether it is elicited when exercise prescription is based on heart rate corresponding to the anaerobic threshold as measured by cardiopulmonary exercise testing. Our objective was to determine the incidence of myocardial ischemia in cardiac rehabilitation programs according to myocardial perfusion SPECT in exercise programs based on the anaerobic threshold. Thirty-nine patients (35 men and 4 women) diagnosed with coronary artery disease by coronary angiography and stress technetium-99m-sestamibi gated SPECT associated with a baseline cardiopulmonary exercise test were assessed. Ages ranged from 45 to 75 years. A second cardiopulmonary exercise test determined training intensity at the anaerobic threshold. Repeat gated-SPECT was obtained after a third cardiopulmonary exercise test at the prescribed workload and heart rate. Myocardial perfusion images were analyzed using a score system of 6.4 at rest, 13.9 at peak stress, and 10.7 during the prescribed exercise (P < 0.05). The presence of myocardial ischemia during exercise was defined as a difference ≥2 between the summed stress score and summed rest score. Accordingly, 25 (64%) patients were classified as ischemic and 14 (36%) as nonischemic. MIBI-SPECT showed myocardial ischemia during exercise within the anaerobic threshold. The 64% prevalence of ischemia observed in the study should not be looked on as representative of the whole population of patients undergoing exercise programs. Changes in patient care and exercise programs were implemented as a result of our finding of ischemia during the prescribed exercise.

Acute exercise performed close to the anaerobic threshold improves cognitive performance in elderly females

The objective of the present study was to compare the effect of acute exercise performed at different intensities in relation to the anaerobic threshold (AT) on abilities requiring control of executive functions or alertness in physically active elderly females. Forty-eight physically active elderly females (63.8 ± 4.6 years old) were assigned to one of four groups by drawing lots: control group without exercise or trial groups with exercise performed at 60, 90, or 110% of AT (watts) and submitted to 5 cognitive tests before and after exercise. Following cognitive pretesting, an incremental cycle ergometer test was conducted to determine AT using a fixed blood lactate concentration of 3.5 mmol/L as cutoff. Acute exercise executed at 90% of AT resulted in significant (P < 0.05, ANOVA) improvement in the performance of executive functions when compared to control in 3 of 5 tests (verbal fluency, Tower of Hanoi test (number of movements), and Trail Making test B). Exercising at 60% of AT did not improve results of any tests for executive functions, whereas exercise executed at 110% of AT only improved the performance in one of these tests (verbal fluency) compared to control. Women from all trial groups exhibited a remarkable reduction in the Simple Response Time (alertness) test (P = 0.001). Thus, physical exercise performed close to AT is more effective to improve cognitive processing of older women even if conducted acutely, and using a customized exercise prescription based on the anaerobic threshold should optimize the beneficial effects.

The fallacy of racial pharmacogenomics

Personalized pharmacogenomics aims to use individual genotypes to direct medical treatment. Unfortunately, the loci relevant for the pharmacokinetics and especially the pharmacodynamics of most drugs are still unknown. Moreover, we still do not understand the role that individual genotypes play in modulating the pathogenesis, the clinical course and the susceptibility to drugs of human diseases which, although appearing homogeneous on the surface, may vary from patient to patient. To try to deal with this situation, it has been proposed to use interpopulational variability as a reference for drug development and prescription, leading to the development of "race-targeted drugs". Given the present limitations of genomic knowledge and of the tools needed to fully implement it today, some investigators have proposed to use racial criteria as a palliative measure until personalized pharmacogenomics is fully developed. This was the rationale for the FDA approval of BiDil for treatment of heart failure in African Americans. I will evaluate the efficacy and safety of racial pharmacogenomics here and conclude that it fails on both counts. Next I shall review the perspectives and the predicted rate of development of clinical genomic studies. The conclusion is that "next-generation" genomic sequencing is advancing at a tremendous rate and that true personalized pharmacogenomics, based on individual genotyping, should soon become a clinical reality.

Vancomycin-resistant enterococcus outbreak in a pediatric intensive care unit: report of successful interventions for control and prevention

The objective of this study is to retrospectively report the results of interventions for controlling a vancomycin-resistant enterococcus (VRE) outbreak in a tertiary-care pediatric intensive care unit (PICU) of a University Hospital. After identification of the outbreak, interventions were made at the following levels: patient care, microbiological surveillance, and medical and nursing staff training. Data were collected from computer-based databases and from the electronic prescription system. Vancomycin use progressively increased after March 2008, peaking in August 2009. Five cases of VRE infection were identified, with 3 deaths. After the interventions, we noted a significant reduction in vancomycin prescription and use (75% reduction), and the last case of VRE infection was identified 4 months later. The survivors remained colonized until hospital discharge. After interventions there was a transient increase in PICU length-of-stay and mortality. Since then, the use of vancomycin has remained relatively constant and strict, no other cases of VRE infection or colonization have been identified and length-of-stay and mortality returned to baseline. In conclusion, we showed that a bundle intervention aiming at a strict control of vancomycin use and full compliance with the Hospital Infection Control Practices Advisory Committee guidelines, along with contact precautions and hand-hygiene promotion, can be effective in reducing vancomycin use and the emergence and spread of vancomycin-resistant bacteria in a tertiary-care PICU.

Reseptikeskuksen lääkekohtaisen tiedon laadun kartoitus toiminnallisesta näkökulmasta

Diplomityössä kartoitetaan tiedon laatuun vaikuttavia tekijöitä kirjallisuuden pohjalta sekä tutkitaan empiirisesti sähköisen reseptin tietosisällön laatua toiminnallisuuden näkökulmasta tarkasteltuna. Tutkimuksen tavoitteena on tuottaa esiselvitys Reseptikeskuksen tietosisällön toiminnallisesta laadusta käytettäväksi lähtötietona tiedon laadun arviointiin ja seurantaan. Tutkimuksen empiirinen osuus toteutettiin kvantitatiivisena tutkimuksena analysoimalla Reseptikeskuksen tietosisällöstä poimittua n. 600 potilaan otosta. Tutkitussa tietosisällössä havaittiin joitain poikkeamia tietosisältöä koskeviin määrityksiin verrattuna, mutta merkittäviä eroja terveydenhuollon eri toimijaryhmien apteekeissa, julkisella ja yksityisellä sektorilla kirjaamien reseptien tietosisällön laadussa ei havaittu. Tiedon kontekstisidonnaisuus on keskeinen tekijä tiedon toiminnallisen laadun määrittämisessä, arvioinnissa ja kehittämisessä. Toiminnan kannalta merkityksellinen tieto rakentuu dataan liitettyjen merkitysten, tiedon käyttäjien kokemusten sekä teknisen ja sosiaalisen käyttöympäristön muodostamana kokonaisuutena. Tiedon laadun parantaminen on jatkuva prosessi, jota tulee ylläpitää arvioimalla ja kehittämällä käytettäviä laatumittareita ja analysointimalleja. Reseptikeskuksen tietosisällön laatua voidaan edelleen kehittää ja nyt tehdyn esikartoituksen pohjalta voidaan jatkossa seurata tietosisällön laadun kehittymistä uusien tutkimusten avulla

Human fetal malformations associated with the use of an angiotensin II receptor antagonist: Case Report

Introduction: The potential risks related to drug exposure during pregnancy represent a vast chapter in modern obstetrics and data regarding the safety of antihypertensive drugs during pregnancy are relatively scarce. Case report: A 37-year-old patient discovered her fifth pregnancy at our hospital after 26 weeks and 4 days of gestation. She reported a history of hypertension and was currently being treated with Losartan. Hospitalization was recommended for the patient and further evaluation of fetal vitality was performed. On the fourth day an ultrasound was performed, resulting in a severe oligohydramnios, fetal centralization and abnormal ductus venosus. After 36 hours, the newborn died. Pathologic evaluation: At autopsy, the skullcap had large fontanels and deficient ossification. The kidneys were slightly enlarged. A microscopic examination detected underdevelopment of the tubules and the presence of some dilated lumens. Immunohistochemical detection of epithelial membrane antigen was positive. Immunoreactivity of CD 15 was also assayed to characterize the proximal tubules, and lumen collapse was observed in some regions. Discussion: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor antagonists (ARAs) are among the most widely prescribed drugs for hypertension. They are often used by hypertensive women who are considering become pregnant. While their fetal toxicity in the second or third trimesters has been documented, their teratogenic effect during the first trimester has only recently been demonstrated. Conclusion: Constant awareness by physicians and patients should be encouraged, particularly in regard to the prescription of antihypertensive drugs in women of childbearing age who are or intend to become pregnant.

The effects of fiscal policy after the global recession: assessing the evidences

This paper offers a commented review of the most recent empirical studies of the effects of fiscal contraction on economic growth, which have helped underpin the prescription that fiscal policy should be expansionary in coming years in order to contain economic semi-stagnation in the developed countries. The paper shows that there is ample literature showing that fiscal expansion helps the economy grow, and that fiscal contraction tends to reduce output and employment in the short term.

Cholesterol, cardiovascular disease and statin use in older persons

Older age increases the risk of developing a chronic atherosclerotic cardiovascular disease (CVD), such as coronary heart disease. Complications of CVDs, myocardial infarction or stroke often lead to loss of functional capacity or premature death. Dyslipidemia, high serum levels of total or low-density lipoprotein cholesterol (LDL-c) and low levels of high-density lipoprotein cholesterol (HDL-c), is among the most important modifiable risk factors for CVDs; it can be treated with lifestyle modifications, and with lipid-lowering drugs, primarily statins. In older persons, however, the association of cholesterol levels with cardiovascular and all-cause mortality has been inconsistent in previous studies. Furthermore, the beneficial effects of statins in older persons without previous CVD are still somewhat unclear, and older persons are more prone to adverse effects from statins. This thesis presents a prospective cohort study (TUVA), exploring associations of cholesterol levels with mortality and the changes in cholesterol levels of a 70-year-old population in long-term follow-up. Further, prevalence of CVDs, risk factors and preventive medication use in the TUVA cohort is compared with respective prevalences in another age-matched cohort (UTUVA) 20 years later in order to examine the changes in cardiovascular risk over time. Additionally, to evaluate statin use patterns among older persons, an observational register study was conducted covering the total Finnish population aged 70 and older during 2000-2008. Based on individual-level data retrieved from national health registries, the population was classified into low, moderate and high risk groups according to estimated CVD risk. The prevalence, incidence and persistence of statin use among the risk groups was then evaluated based upon yearly statin purchases tracked from the Prescription Register. The prospective cohort study demonstrated that low total cholesterol, LDL-c and HDL-c were associated with higher mortality in a cohort of home-dwelling 70-year-olds. However, after adjusting for traditional cardiovascular risk factors and cancer this association disappeared. Further, low total cholesterol seemed to be protective, whereas low HDL-c strongly predicted increased risk of CVD death. Cholesterol levels of those elderly who remained available for follow-up and were still home-dwelling at the age of 85 seemed to improve with advancing age. Compared to the TUVA cohort, the later born UTUVA cohort had less CVDs and their risk factors were better controlled, which was reflected in the higher use of preventive medications such as statins and antihypertensives. The register studies confirmed that statin use has increased significantly during 2000-2008 among older persons, especially among the oldest (80+) age groups and among those at high risk for cardiovascular events. Two-thirds of new statin users persisted with their use during the four years of follow-up; the most discontinuations were made during the first year of use. In conclusion, statins are commonly used among older age groups in Finland. Most of the older statin users had a high cardiovascular event risk, indicating that the treatment is well directed towards those who are likely to benefit from it the most. No age-limits should be put on the screening and treatment of dyslipidemia in older persons, but the benefits and adverse effects of statin treatment should be carefully weighed based on an individual assessment of the person’s general health status and functional capacity. Physicians should pay more attention to medication adherence, especially when prescribing preventive medications.

Vulnerability to adverse consequences of drinking and problem drinker status as predicted by risky drinking behaviours, drug use, sex differences and affect : a test of multiple models /

Although alcohol problems and alcohol consumption are related, consumption does not fully account for differences in vulnerability to alcohol problems. Therefore, other factors should account for these differences. Based on previous research, it was hypothesized that risky drinking behaviours, illicit and prescription drug use, affect and sex differences would account for differences in vulnerability to alcohol problems while statistically controlling for overall alcohol consumption. Four models were developed that were intended to test the predictive ability of these factors, three of which tested the predictor sets separately and a fourth which tested them in a combined model. In addition, two distinct criterion variables were regressed on the predictors. One was a measure of the frequency that participants experienced negative consequences that they attributed to their drinking and the other was a measure of the extent to which participants perceived themselves to be problem drinkers. Each of the models was tested on four samples from different populations, including fIrst year university students, university students in their graduating year, a clinical sample of people in treatment for addiction, and a community sample of young adults randomly selected from the general population. Overall, support was found for each of the models and each of the predictors in accounting for differences in vulnerability to alcohol problems. In particular, the frequency with which people become intoxicated, frequency of illicit drug use and high levels of negative affect were strong and consistent predictors of vulnerability to alcohol problems across samples and criterion variables. With the exception of the clinical sample, the combined models predicted vulnerability to negative consequences better than vulnerability to problem drinker status. Among the clinical and community samples the combined model predicted problem drinker status better than in the student samples.

On affirmation and becoming : a Deleuzian reading of Nietzsche's critique of nihilism

The main thrust of this thesis is the re-exploration of Friedrich Nietzsche's "critique of nihilism" through the lenses of Gilles Deleuze. A Deleuzian reading of Nietzsche is motivated by a post-deconstrnctive style of interpretation, inasmuch as Deleuze goes beyond, or in between, henneneutics and deconstrnction. Deleuze's post-deconstrnctive reading of Nietzsche is, however, only secondary to the main aim of this thesis. The primary thrust of this study is the critique of a way of thinking characterized by Nietzsche as nihilistic. Therefore, it should be noted that this study is not about Deleuze's reading per se; rather, it is an appraisal of Nietzsche's "critique of nihilism" using Deleuze's experimental reading. We will accrue Nietzsche's critique and Deleuze's post-deconstrnctive reading in order to appraise Nietzsche's critique itself. Insofar as we have underscored Deleuze's purported experimentation of Nietzschean themes, this study is also an experiment in itself. Through this experimentation, we will find out whether it is possible to partly gloss Nietzsche's critique of nihilism through Deleuzian phraseology. Far from presenting a mere exposition of Nietzsche's text, we are, rather, re-reading, that is, re-evaluating Nietzsche's critique of nihilism through Deleuze's experimentation. This is our way of thinking with Nietzsche. Nihilism is the central problem upon which Nietzsche's philosophical musings are directed; he deems nihilism as a cultural experience and, as such, a phenomenon to be reckoned with. In our reconstruction of Nietzsche's critique of nihilism, we locate two related elements which constitute the structure of the prescription of a cure, Le., the ethics of affirmation and the ontology of becoming. Appraising Nietzsche's ethics and ontology amounts to clarifying what Deleuze thinks as the movement from the "dogmatic image of thought" to the "new image of thought." Through this new image of thought, Deleuze makes sense of a Nietzschean counterculture which is a perspective that resists traditional or representational metaphysics. Deleuze takes the reversal of Platonism or the transmutation of values to be the point of departure. We have to, according to Deleuze, abandon our old image of the world in order to free ourselves from the obscurantism of foundationalist or essentialist thinking. It is only through the transmutation of values that we can make sense of Nietzsche's ethics of affirmation and ontology of becoming. We have to think of Nietzsche's ethics as an "ethics" and not a moral philosophy, and we have to think of his ontology as 1/ ontology" and not as metaphysics. Through Deleuze, we are able to avoid reading Nietzsche as a moral philosopher and metaphysician. Rather, we are able to read Nietzsche as one espousing an ethical imperative through the thought of the eternal return and one advocating a theory of existence based on an immanent, as opposed to transcendent, image of the world.

Deviance of syntax in oral languages and oral reading behavior

The major hypothesis of this paper is that any deviance in syntax present in oral language will be evident in oral r eading behaviour. Using Lee and Canter's Developmental i 1 Sentence Scoring technique (1971) and Y. Goodman and Burke's Reading Miscue Inventory (1972) linguistic competence was established in t hree male children. ages 10 to 11. patterns of strengths and weaknesses in reading were determined. and the relationships t hat were established, were examined. Results of the study i ndicate that oral language behaviour is closely tied to oral r eading behaviour. This type of approach can be used as a basis for a diagnosis of a reading difficulty and then a prescription for language and reading skills.