Generic substitution: the use of medicinal products containing different salts and implications for safety and efficacy.

In their quest to gain early entry of new generic products into the market prior to patent expiration, one of the strategies pursued by generic drug product manufacturers is to incorporate different salts of an approved active pharmaceutical ingredient (API) in a brand company's marketed dosage form and subject such dosage forms to bioequivalence assessment. These initiatives present challenges to regulatory authorities where the decision to approve bioequivalent products containing such pharmaceutical alternatives must be considered in the light of safety and efficacy, and more particularly, with respect to their substitutability. This article describes the various issues and contentions associated with the concept of pharmaceutical alternatives, specifically with respect to the uses of different salts and the implications for safety, efficacy and generic substitution.     

Pharmacological effects and serum levels of orally administered alprenolol in man

Summary The effects of alprenolol on heart rate and systolic blood pressure were studied in healthy subjects during standardized exercise on a bicycle ergometer. In one series of experiments, in which serum concentrations of alprenolol were also measured, the effects of single oral doses of 50, 100 and 200 mg of alprenolol and a placebo were compared by a double blind cross-over technique. In a second series of experiments 100 mg alprenolol was given four times in one day and the effect was followed for up to eighteen hours after the last dose. — Alprenolol diminished the expected increase in heart rate and systolic blood pressure during exercise. The reduction of exercise tachycardia in a given individual was linearly related to the logarithm of the dose or the serum concentration of alprenolol. The serum concentrations required for a given reduction of exercise tachycardia varied almost one hundred-fold amongst the subjects studied. The biological availability of alprenolol was dose-dependent, probably due to a limited capacity biotransformation of the drug before it entered the general circulation. After a single dose the serum level of alprenolol and its chronotropic effect diminished at a rate corresponding to an elimination half life of about two hours. This rate of elimination was consistent with that calculated from the results of the four dose study.     

Inflammation and pharmacokinetics: potential implications for HIV-infection

Introduction: The physiological changes accompanying inflammation may alter the pharmacokinetics (PK) of certain medications. Individuals infected with HIV have chronically elevated inflammatory markers despite viral suppression following effective antiretroviral therapy (ART), as well as age-related inflammation. Understanding the potential clinical implications of inflammation on the PK of medications is important for understanding dose-response relationships and necessitates future research.

Areas covered: An extensive literature search was carried out using PubMed and associated bibliographies to summarize the current state of knowledge regarding altered PK in response to inflammation and its application to the field of HIV.

Expert opinion: Preclinical and clinical studies show that inflammation leads to a downregulation of certain drug metabolizing enzymes and both up and down regulation of transporters depending on the transporter and cell type. Decreased gastric acidity, fluid shifts, and plasma protein alterations also occur with inflammation, leading to potential absorption, distribution, and clearance changes. More research is needed including controlled PK studies to address the clinical relevance of these observations, especially in the aging HIV-infected population. Results from future studies will enable us to better predict drug concentrations in individuals with inflammation, in line with efforts to provide personalized pharmacotherapy in our healthcare system.     

Vitamin A supplementation increases levels of retinoic acid compounds in human plasma: possible implications for teratogenesis

The concentrations of retinoic acid compounds were monitored by a newly developed highly sensitive HPLC procedure in plasma of six volunteers who received 833 IU vitamin A per kg body weight per day during a 20-day period. There was a significant increase of alltrans-retinoic acid (two-fold), 13-cis-retinoic acid (7-fold) and 13-cis-4-oxoretinoic acid (5-fold) over endogenous plasma levels of these retinoids. The same compounds had previously been found after treatment with the teratogenic drug isotretinoin (Roaccutan, Accutane). Our results raise the possibility that high vitamin A intake may carry a teratogenic risk attributable to increased levels of retinoic acid compounds generated from retinol by metabolic processes.The term vitamin A is used for retinol or retinyl esters     

GLC determination of plasma drug levels after oral administration of clorazepate potassium salts.

Plasma nordiazepam levels resulting from the oral administration of clorazepate potassium salts were determined by a sensitive GLC assay. Nordiazepam and the internal standard (diazepam) were selectively extracted into ether at pH 9.2, hydrolyzed to their respective benzophenones, and quantified by electron-capture detection. The assay was used in a comparative bioavailability study of single equimolar oral doses of monopotassium and dipotassium salts of clorazepate in dogs. Both clorazepate salts were rapidly absorbed and exhibited mean peak total drug levels after 1 hr. Clorazepate levels accounted for about 50% of the total drug levels present. No statistical difference in the plasma drug levels of clorazepate mono- and dipotassium salts and the metabolite was found in dogs.     

Age-related endothelial dysfunction : potential implications for pharmacotherapy

Aging per se is associated with abnormalities of the vascular wall linked to both structural and functional changes that can take place at the level of the extracellular matrix, the vascular smooth muscle and the endothelium of blood vessels. Endothelial dysfunction is generally defined as a decrease in the capacity of the endothelium to dilate blood vessels in response to physical and chemical stimuli. It is one of the characteristic changes that occur with age, independently of other known cardiovascular risk factors. This may account in part for the increased incidence of cardiovascular events in elderly people that can be reversed by restoring endothelial function. A better understanding of the mechanisms involved and the aetiopathogenesis of this process will help in the search for new therapeutic agents.Age-dependent alteration of endothelium-dependent relaxation seems to be a widespread phenomenon both in conductance and resistance arteries from several species. In the course of aging, there is an alteration in the equilibrium between relaxing and contracting factors released by the endothelium. Hence, there is a progressive reduction in the participation of nitric oxide and endothelium-derived hyperpolarising factor associated with increased participation of oxygen-derived free radicals and cyclo-oxygenase-derived prostanoids. Also, the endothelin-1 and angiotensin II pathways may play a role in age-related endothelial dysfunction. The use of drugs acting at different levels of these signalling cascades, including antioxidant therapy, lipid-lowering drugs and estrogens, seems to be promising.     

Progesterone pharmacokinetics in the mouse: implications for potential stroke therapy

Objectives Progesterone has been shown to be neuroprotective in a number of preclinical central nervous system injury models including cerebral ischaemia. The aim of this study was to clarify differences in outcomes owing to different dosing regimens and the pharmacokinetic profile of progesterone, particularly in relation to brain levels. Methods Male C57 Bl/6 mice were injected intraperitoneally with progesterone (8 mg/kg in dimethylsulfoxide) or with a bolus injection followed by continuous subcutaneous infusion (1.0 µl/h of a 50 mg/ml progesterone solution) via implanted osmotic minipumps. Plasma and brain samples were collected over 24 h from bolus‐injected mice and 48 h from mice implanted with minipumps. Progesterone concentrations were measured by an enzyme‐linked immunoassay and pharmacokinetic profiles were constructed. Key findings Intraperitoneally injected progesterone had a short half‐life (fast component half‐life of 0.2 h) in both plasma and brain. Minipump delivery resulted in higher concentrations of progesterone in plasma and particularly in brain over a longer period. The volume of distribution with intraperitoneal injection was 172.78 versus 1641.84 ng/h per g via minipump in the first 24 h. Conclusions A bolus intraperitoneal loading dose of progesterone followed by continuous delivery via osmotic minipump is an effective way of delivering progesterone to the brain.     

Doctor to patient transmission of hepatitis B virus: implications of HBV DNA levels and potential new solutions

Hepatitis B virus (HBV)-infected health care workers (HCWs) can infect patients undergoing exposure prone procedures. Until now reviews have focused on the problem of the HBeAg-positive HCWs. After transmission of HBV by HBeAg-negative surgeons, the focus of Public Health Policy in the UK and the Netherlands has changed from HBeAg status to serum HBV DNA level. Viral load and the volume of blood transmitted determine the transmission risk of HBV. We have estimated the number of infectious particles transmitted by needlesticks, in comparison with those attributed in maternal-fetal transfusion. The blood volume transmitted by needlestick is roughly 1-30% of that of delivery. As vertical transmission with maternal HBV DNA levels below 10(7) g Eq./ml is rarely documented, HBV transmission by needlesticks is, according to our assumptions, unlikely to occur with HBV DNA levels below 10(7) g Eq./ml. Sera of transmitting HCWs contained HBV DNA levels between 5.0 x 10(9) and 6.35 x 10(4) g Eq./ml. Interpretation of these levels is hampered as the sera were taken at least 3 months after transmission. To prevent both loss of expertise and nosocomial infection, highly viremic HCWs can be offered antiviral therapy. Lamivudine and alpha-interferon can now be complemented with adefovir, tenofovir and entecavir to provide effective new therapies for chronic HBV-infected HCWs.     

Phylogenetic signals and ecotoxicological responses: potential implications for aquatic biomonitoring

Macroinvertebrates can be successfully used as biomonitors of pollutants and environmental health because some groups are sensitive whereas, others are relatively tolerant to pollutants. An issue of ongoing debate is what constitutes an appropriate group for biomonitoring; should the group represent species, genera or higher taxonomic levels? A phylogenetic framework can provide new insights into this issue. By developing phylogenies for chironomids and mayflies, this investigation shows that there is strong phylogenetic signal for pollution responses, and that phylogenetic nodes are common to tolerant and sensitive groups of species. A phylogenetic analysis of biotic indices developed for mayflies based on their response to organic pollution shows that mayfly families varied in pollution tolerance. In contrast, based on sediment zinc concentrations as an indicator of pollution tolerance, Australian chironomids tend to vary in tolerance at lower taxonomic levels. Published data on North American chironomids shows much of the signal for pollution responses is contained within genera rather than sub-families. Tools are now available to distinguish whether this signal reflects historical evolutionary constraints or environmental effects leading to common evolved responses. This suggests that ideally higher taxonomic levels should be used for biomonitoring when there are strong phylogenetic constraints at higher levels. Evolutionary considerations can therefore help to guide the development of macroinvertebrate biomonitors and provide insights into processes that produce sensitive and tolerant taxa.     

T-lymphocytic infiltrate in canine mammary tumours: clinic and prognostic implications

In recent years, considerable progress has been made in understanding the role of the immune system in tumour progression. However, in canine mammary tumours (CMT), the prognostic value of T-lymphocytes is not established. The aims of the present study were to characterize T-lymphocytic infiltrate in 57 canine mammary tumours (21 benign and 36 malign), by immunohistochemical detection of CD3 antigen, and to determine its association with several clinicopathological parameters and overall survival. CD3+ positive cells were counted in 10 high-power fields within the tumour (i.e. The tumour-infiltrating T-lymphocytes, TIL), in the peripheral area of the tumour and in the adnexal non-tumoural mammary gland. CD3(+) TILs were significantly more frequent in benign than in malignant tumours (p<0.001). Conversely, peripheral CD3(+) TILs were significantly more frequent in malignant than in benign neoplasias (p<0.001). For CD3(+) T-lymphocytes in the adnexal non-tumoural mammary gland, there was no statistical difference in their frequency between benign and malignant tumours. On survival analysis, there was a tendency towards an association of a higher number of CD3(+) TILs and a shorter overall survival (p=0.08). Interestingly for CD3(+) T-lymphocytes in the adnexal non-tumoural mammary gland, a statistically significant relationship was observed, with a higher number of lymphocytes conferring a reduced overall survival (p=0.045). Further studies will be required to better understand the biological implications of the current findings.     

Opioid receptor and peptide gene polymorphisms: potential implications for addictions

Addictions to drugs of abuse and alcohol have been shown by studies of genetic epidemiology to have both a heritable and an environmental basis, with these factors influencing addiction to different substances to a different extent. In the search for specific alleles of specific genes that may contribute to the development of the addictions, many researchers have focused on the endogenous opioid system, which mediates a diverse array of neurological, physiological, and behavioral functions. The endogenous opioid system is also centrally important in mediating the effects of drugs of abuse and alcohol. Polymorphisms, including single nucleotide polymorphisms, have been identified in genes of the endogenous opioid receptors and peptides. A number of recent genetic association studies and a few studies of potential function provide clues as to which genes and which alleles may have implications for human physiology and pathophysiology, including the addictions.     

Lack of changes in beta-endorphin plasma levels after repeated treatment with fluoxetine: possible implications for the treatment of alcoholism--a pilot study

Clinical and animal studies indicate that selective serotonin-reuptake inhibitors (SSRIs) may help to reduce alcohol intake but investigations led to conflicting results. A few studies indicated that serotonin (5-HT) may modulate the brain beta-endorphin level, which plays an important role in the development of alcohol craving. Our study examined the influence of fluoxetine on the endogenous opioid system. We investigated plasma levels of beta-endorphin in rats with either high alcohol preference (Warsaw High-Preferring; WHP) or low alcohol preference (Warsaw Low-Preferring; WLP) after repeated treatment with fluoxetine (5 mg/kg i.p. for 21 days). We examined the rats 24 hours after fluoxetine treatment in order to determine whether chronic fluoxetine produces a long-term change in the beta-endorphin levels. The animals received either a single dose of ethanol (2 g/kg) or an identical single dose of saline one hour before blood collection. While a few studies observed an increase in the level of beta-endorphin after a single fluoxetine injection, we did not observe any increase in beta-endorphin plasma levels after repeated fluoxetine treatment. We also did not observe any changes in beta-endorphin levels of rats treated with fluoxetine and injected with ethanol. A lack of increase of beta-endorphin levels may explain why fluoxetine has a limited value in the prevention of craving for alcohol.     

Gene therapy for ulcerations of the gastrointestinal tract

Ulcer healing requires cell proliferation, migration (re-epithelialization) and angiogenesis - all ultimately leading to scar formation. All these processes are controlled by growth factors. Gene therapy has shown only limited promise for effective treatment of congenital diseases. This is due to time-limited gene expression, adverse immune responses and/or complications related to viral vectors. However, short- term expression of genes encoding angiogenic growth factors appears to be ideal for treatment of chronic ulcers and wounds, which require only limited temporal gene overexpression. Since angiogenesis is essential for wound and ulcer healing, the genes encoding proangiogenic growth factors have been utilized for treatment of experimental esophageal, gastric and duodenal ulcers. These studies demonstrated that a single local injection of plasmids expressing vascular endothelial growth factor and angiopoietin-1 dramatically accelerates the healing of duodenal, gastric and esophageal gastric ulcers. Preliminary data indicate that such treatment can also be effective for the healing of experimental colitis.     

Measurement of mycophenolate mofetil plasma levels after heart transplantation and a potential side effect of high levels.

Mycophenolate mofetil (MMF) is gaining momentum in its use as an immunosuppressant and in the field of heart transplantation because of its efficacy and ease of use without a reported need to monitor plasma levels. We describe a case in which standard dosage of MMF (initially 1.5 g twice daily) produced elevated trough levels of mycophenolic acid (MPA). Although organ rejection was eradicated by the use of MMF, the patient developed severe anemia, which required repeated blood transfusions while the patient was on therapy. This case illustrates the potential value of monitoring MPA concentrations.     

Beta-blocking effect and serum levels of alprenolol in man after administration of ordinary and sustained release tablets

Summary The effect of alprenolol administered as ordinary and as sustained release tablets was compared by studies on the inhibition of the haemodynamic response to physical work. Serum levels of alprenolol were also determined. Two types of double-blind cross-over studies were performed in healthy volunteers. In one the effects of ordinary tablets, sustained release tablets and a placebo were followed for 12 h. In two other studies each preparation was given for five days. The sustained release tablets were given b.i.d., and were compared with ordinary tablets administered q.i.d., or with a placebo. A dose of 200 mg alprenolol in sustained release tablets had almost the same initial peak effect as 100 mg in ordinary tablets. The duration of the effect was longer after the sustained release tablets, and 200 mg b.i.d. gave approximately the same degree of beta-blockade during the day as 100 mg in ordinary tablets given q.i.d. The results indicated that both dosage regimens had an effect for 24 h, and that more constantive effect levels were obtained by the use of sustained release tablets. No accumulation was found in the five day study, neither in terms of the pharmacological effects nor of serum levels of alprenolol. The concentration of alprenolol in serum rarely exceeded 10 ng per ml, and approximately the same steady state level was obtained after sustained release tablets as after ordinary tablets.     

Sirtuin modulators: mechanisms and potential clinical implications

In the last years, studies about longevity have highlighted that caloric restriction can be linked with a less normal agingassociated damage, and in the same way, with the activity of the Silent Information Regulator 2 (SIR2) gene. Sir2-like genes, known as sirtuins (SIRTs), have been found in organisms ranging from bacteria to mammals promoting health and survival. At the moment, it has been identified seven classes of SIRTs in mammalian and the understanding of many of them remains still rudimentary. However, they are in the spotlight by their potential protection against aging-associated diseases and have emerged as key mediators of longevity in evolutionarily distant organisms models. SIRTs are proteins found in numerous compartments within the cell, which are NAD(+)-dependent protein deacetylases and adenosine diphosphate (ADP)-ribosyltransferases. They catalyse a reaction in which NAD(+) and an acetylated substrate are converted into a deacetylated substrate, nicotinamide and a novel metabolite O-acetyl ADP ribose. Therefore, its enzymatic activity requires NAD(+), which is a crucial molecule intermediary of many metabolic reactions in cells. Basically, SIRTs are mediators of aging process, they have the potential of ameliorating and taking part in important cellular processes associated, such as metabolic homeostasis, tumorigenesis and cancer cell proliferation, inflammatory disorders, cardiovascular diseases and neurodegeneration. This background opens up new lines of investigation into the modulation of SIRTs activity in order to develop novel therapeutic targets to these age-related diseases. Current experiments using molecule activators or inhibitors and genetically engineered animals have facilitated new insights into the role of these enzymes and contributed to highlight some of the potentially relevant targets. This review is intended to provide an appreciation of the possible protection against aging-associated diseases by these enzymes, summarize novel underlying mechanisms and evaluate potential clinical applications.     

Decreased plasma concentrations and clinical effects of alprenolol during combined treatment with pentobarbitone in hypertension.

The antihypertensive effect of alprenolol has been studied before, during and after additional pentobarbitone treatment. The combined alprenolol-pentobarbitone treatment significantly decreased alprenolol levels by 59% and 4-hydroxyalprenolol by 24%. The effect was significant after three doses and declined over 4-5 days after pentobarbitone withdrawal. The decreased alprenolol plasma levels were associated with increased pulse rate (6%), and systolic (8%) and diastolic (9%) blood pressure. The inhibition of exercise tachycardia by alprenolol was reduced by 18% at the end of pentobarbitone treatment compared to initial monotherapy with alprenolol. The interaction is probably clinically important in those patients with hypertension and angina pectoris that are treated with barbiturates and alprenolol.     

不同血浆靶浓度瑞芬太尼对压力感受反射敏感性的影响

目的观察不同血浆靶浓度瑞芬太尼对压力感受反射敏感性（baroreflex sensitivity,BRS）的影响,以了解瑞芬太尼通过对自主神经系统的作用而影响血流动力学调节的某种机制。方法30例女性患者,ASAⅠ或Ⅱ级。随机分成三组（n=10）：R2组（瑞芬太尼血浆靶浓度2ng/mL）、R4组（瑞芬太尼血浆靶浓度4ng/mL）、R6组（瑞芬太尼血浆靶浓度6ng/mL）。予血浆靶浓度为3μg/mL异丙酚、不同血浆靶浓度瑞芬太尼、维库溴胺0.1mg/kg快速诱导。用药物升压法测定BRS,分别于诱导前（T0点）、气管插管后5min且瑞芬太尼达到设定血浆靶浓度平衡（T1点）测定BRS。结果R2组、R4组、R6组T1时点BRS较T0时点均显著降低（P〈0.01）,且T1时点R6组BRS低于R2组（P〈0.05）。结论瑞芬太尼抑制BRS,使血压下降,心率减慢。血浆靶浓度为6ng/mL的瑞芬太尼对BRS的抑制作用增加。     

不同肿瘤患者血浆纤维蛋白原水平的相关性研究

目的　研究血浆纤维蛋白原 (FIB)水平与恶性肿瘤的关系 ,为临床诊断、治疗提供参考指标。方法　应用ACL— 70 0 0血凝分析仪检测其健康人组、良性肿瘤组、恶性肿瘤未转移组、恶性肿瘤转移组血浆中FIB的含量 ,并对部分患者进行手术前后的跟踪监测 ,进行FIB变化与疾病的相关性分析。结果　血浆FIB水平健康人组和良性肿瘤组差异无统计学意义 (P >0 0 5 ) ,恶性肿瘤组较前两组差异有统计学意义 (P <0 0 1) ,转移组较未转移组差异有统计学意义 (P <0 0 1)。各癌种间则无特异性改变。复发的病人FIB升值更高。结论　血浆FIB水平升高与恶性肿瘤的发生及转移呈正相关 ,与预后呈负相关。监测FIB有助于良、恶性肿瘤的鉴别诊断和疗效观察。