Dilevalol

Not only is there a limited number of studies on the effects of vasodilator β-blocker (VBB) therapy on kidney function - specifically, glomerular filtration rate (GFR), serum creatinine (sCr) and proteinuria - but of those that have been reported, the results are mixed. This meta-analysis seeks to assess the efficacy of VBBs on selected renal parameters in hypertensive patients.

We conducted a meta-analysis of any prospective trial that provided both baseline and follow-up of at least 4 weeks of VBB therapy - carvedilol, labetalol, dilevalol, nebivolol and celiprolol in patients with hypertension. We used Ovid MEDLINE, EMBASE and PubMed, all without date restrictions. We included 39 studies totaling 3987 patients.

Although VBBs did not significantly change GFR or sCr levels after at least 4 weeks of therapy, they did significantly decrease protein excretion by -0.12 SD units [95% confidence interval (CI) -0.19 to -0.04; P < 0.01]. VBBs did not alter renal blood or plasma flow, but renal vascular resistance (RVR) decreased by -20.03 mmHg min/l (95% CI -28.92 to -11.15; P < 0.01). In the analysis which compared VBBs with non-VBBs, the only significant difference was the greater decrease in RVR in the VBB group by -38.44 mmHg min/l (95% CI -60.57 to -16.31; P < 0.01).

VBBs do not affect GFR or sCr levels, but decrease protein excretion. This class of β-blockers, however, is not superior to non-VBBs in reducing proteinuria. VBBs decrease RVR significantly more than non-VBBs.

Kava (Piper methysticum) was prohibited in unlicensed medicines in the United Kingdom 4 years ago, following an extensive evaluation of the potential for kava products to produce toxic effects on the liver. This article provides a commentary on the justification for the prohibition from a regulatory perspective. Kava is a herbal product derived from the root of Piper methysticum, a plant belonging to the pepper family, which is native to the islands of the South Pacific. Kava has been in use in the South Pacific for thousands of years, where it is employed in rituals, and recreationally as a mild inebriant, as well as for medicinal purposes as an anxiolytic, a hypnotic, and a sedative, and as a local anaesthetic, antiseptic, aphrodisiac, diuretic, and an expectorant [1]. The biggest consumer of kava products in Europe has been Germany, where they were authorized for the treatment predominantly of anxiety, tension and restlessness. Three kava products were also licensed in the United Kingdom for more than 30 years for the treatment of bladder discomfort, and for abdominal discomfort following meals. In the late 1990s there was a massive increase in the global demand for kava. Kava is a slow-growing crop. The root is normally only harvested after 4 to 5 years. In order to increase supply to meet the demand, it is believed that faster growing varieties of kava were cultivated and that there was an increase in the use of parts of the plant other than the traditional kava root, such as stem peelings. A signal suggesting an association between kava products and liver damage was first reported by the Swiss regulatory authority in 2000. The number of cases was small at that time and no cases had been reported from UK sources. By October 2001, 30 case reports of hepatotoxicity in association with kava had accumulated. A significant proportion of these cases was severe; four patients had required a liver transplant and one patient had died. In December 2001, all kava containing products were voluntarily withdrawn from the UK market pending the outcome of the investigation of the association between kava and liver damage. An Expert Working Group (EWG) was established to examine the available data. This group included experts in toxicology, hepatotoxicity, pharmacognosy and clinical pharmacology. In July 2002 the EWG reported its findings to the UK Committee on Safety of Medicines (CSM), and recommended that the marketing authorizations for the three licensed kava products in the UK should be revoked and that the sale and supply of kava in unlicensed medicines should be prohibited. The CSM concurred with these recommendations. A public consultation followed, and the UK herbal sector appealed to the Medicines Commission against the decision of the CSM. The Medicines Commission concluded in November 2002 that there was evidence, in rare cases, of a risk of hepatotoxicity associated with unlicensed kava products (at that time 68 spontaneous case reports had been received worldwide). The term ‘rare’ is taken to mean between 1/1000 and 1/10 000 according to regulatory convention. The Medicines Commission also found the hepatotoxic effect of kava to be unpredictable as there were no identifiable factors relating to an increased risk with specific preparations, doses, or groups of susceptible patients. Thus a prohibition order covering kava in unlicensed medicinal products came into force on 13January 2003 [2], and equivalent regulatory action was taken to prohibit kava in foods. The prohibition was challenged in the House of Commons [3, 4] and in the High Court and the Court of Appeal. All challenges to date have failed to provide convincing evidence that the return of kava products in the UK might serve the public interests. At the time of prohibition in the UK, Ministers committed to a review of the data relevant to the hepatotoxicity of kava after 2 years. In October 2005 the EWG on the Safety of Kava met again to consider the data. The Group published a report summarizing the evidence leading to its conclusions and recommendations [5]. By October 2005, 110 spontaneous cases of hepatotoxicity had been reported worldwide. Eleven had required liver transplantation, and nine cases had a fatal outcome, including two patients who had received liver transplants. The case reports, in which the time to onset following the start of intake of kava was stated, indicate that the peak incidence of liver reactions occurs at 3 months. The EWG concluded on the basis of its review that the prohibition order in the UK remained justified and proportional. The mechanism of hepatotoxicity of kava remains obscure. A number of hypotheses have been advanced, each of which was considered by the EWG, which concluded that none could satisfactorily explain all of the plausible case reports implicating kava products as the causal factor [5]. These include inhibition of enzymes in the cytochrome P450 system by concomitant medications; the existence of one or more unidentified toxic constituents, possibly associated with particular production methods, or the inclusion of stem peelings or aerial parts of the plant; an unidentified toxic metabolite; CYP 2D6 deficiency; cyclo-oxygenase inhibition; and depletion of glutathione. Kava has been withdrawn from many markets including those of the European Union. Severe hepatic reactions continue to be reported following regulatory action in those countries in which kava has not been withdrawn, particularly in the USA and Australia. Hepatotoxicity is the single most common adverse reaction responsible for major drug problems, including withdrawals of drugs from the market. Kava has joined the ranks of a long list of mainstream pharmaceuticals that have suffered a similar fate; nefazadone, trovafloxacin, bromfenac, tolcapone, troglitazone, pemoline, dilevalol, and perhexiline are a few notable examples. As was the case with kava, hepatotoxicity associated with these products was rare, too rare to be detected in clinical trials designed to investigate efficacy. When examining the association between drugs and rare adverse reactions one hardly ever deals with data sets large enough to provide a reliable statistical estimate of the comparative incidence of the reaction in prospective trials. Some doubts about the presumption of an association may remain when this is based predominantly on data of lesser inferential strength, such as spontaneous adverse reaction reports. The cumulated evidence, however, strongly indicates that there is something about kava products that is doing some livers no good whatsoever [5]. Furthermore, there is no evidence that the source of the problem has yet been identified or that effective remedial steps have been taken in those jurisdictions in which kava remains freely available [5]. Unlike the mainstream pharmaceuticals mentioned above, kava is a heterogeneous collection of herbal products. The possibility therefore exists that something of kava may be salvageable. It would take only a small fraction of the profits generated by the kava industry to investigate any legitimate hypothesis concerning kava's toxicity in order to attempt either to exonerate some forms of kava, or to provide recommendations that will assure their safe use. While the kava story may not yet have reached its final conclusion, what can we learn from what has transpired to date? The most important lesson is that herbal medicines must be treated with the same degree of respect as any other medicine. The experience with kava, and the mortality and morbidity associated in recent years with Aristolochia [6], and drug interactions with St John's Wort [7], demonstrate that herbal remedies should never be assumed to be intrinsically harmless. Safety issues associated with herbal remedies can undermine consumer confidence, and do not reflect a good image of the herbal industry. The balance might be redressed somewhat if herbal practitioners and others involved in the sale and supply of herbal remedies, as well as consumers and health professionals, were to report suspected adverse reactions to herbal medicines through the Yellow Card reporting scheme in the UK, to allow the early detection of potential problems. Finally, in order to make informed choices, consumers have a right to unambiguous information on the safety and quality of herbal medicines. The herbal industry should be moved to take advantage of the opportunity presented by the Traditional Herbal Medicines Registration Scheme, which requires that herbal products meet specific standards of safety and quality, and that they are accompanied by clear information for consumers regarding their safe use. This scheme was launched in the UK in October 2005 and the first products are now beginning to be registered.