Slimming Regimen Research Articles

THE APPROACH TO PHYTOTHERAPY APPLICATIONS: A CASE REPORT OF HYPERKALEMIA.

We describe the effects of a phytotherapy application for purpose of weight loss in a case of hyperkalemia. A 59-year-old woman presented with fatigue and weakness for the previous three months. Physical examination was unremarkable, apart from obesity. Her serum potassium level was 5.54 mmol/L. The patient's symptoms were attributed to hyperkalemia. We learned that the patient had been using a mixture of three sticks of cinnamon dissolved in one liter of water and lemon juice every day for three months as a slimming regimen. The hyperkalemia was attributed to phytotherapy applied as a slimming regimen.

Methodologies for the quality assessment of medicinal plants and phytopharmaceuticals

The abundant consumption of herbal medicines is often associated with toxicity problems due to the presence of pesticide residues, bacterial contaminations and confusions between plant species. Thus besides efficacy, safety represents an important issue in phytotherapy, because many plants are used as dietary supplements. In this respect, different cases of intoxication, mostly renal failure, have been reported after consumption of slimming regimens containing nephrotoxic and carcinogenic aristolochic acids [1]. Hepatotoxicity problems have also been reported for different plants containing pyrrolizidine alkaloids such as Petasites hybridus or Tussilago farfara (Asteraceae) [2]. Other toxicity issues have also been reported for edible plants which can be botanically confused and cases are known in which leaves of the autumn crocus (Colchicum autumnale, Liliaceae) have been consumed instead of ramsons (Allium ursinum, Liliaceae). Ginkgo biloba can also present some safety problems related to its content in allergenic alkylphenols [3]. Such hazardous compounds are present only in very low concentrations in phyto-pharmaceutical preparations and European regulation requires that their content do not exceed 5 ppm. In order to solve some of the issues concerning the quality control and standardisation of plant preparations, analytical strategies based on the use of LC-UV-MS, UPLC-TOF-MS and LC-NMR have been developed for a rapid profiling of the extracts [4]. Different examples of analyses in relation with toxicity assessment and quality control will be discussed. The use of these methods for dereplication purposes in the search of new lead compounds from plants will also be treated.

Aristolochic acid induced changes in the metabolic profile of rat urine

Prolonged exposure to aristolochic acid (AA) has shown to pose rapid progressive renal fibrosis in Belgium women in a slimming regimen in the early 90 s. We hypothesize that changes in metabolic profile could have occurred before symptoms were observed, which may allow early treatment. In this study, metabonomics was used for toxicology study of AA in rats. Liquid chromatography coupled with a hybrid quadrupole time-of-flight mass spectrometry (Qq-TOF) was used for the analysis of endogenous metabolites in rat urine samples. The difference in metabolic profiles between the control and the dosed rats was well observed by the principal component analysis (PCA) of the MS data. Significant changes of two metabolite markers, kynurenic acid and hippuric acid, were detected in the rat urine samples. The identification of potential biomarkers was performed by high-resolution mass measurement and MS–MS analyses on a Qq-TOF. We believe that metabolic profiling may act as a preclinical protocol for AA exposure before symptoms are observed.

Weight-reducing regimen associated with polymorphic ventricular tachycardia

Obesity is already a costly problem in developed countries and is significantly becoming one in developing countries, in terms of costs, morbidity, and mortality [1]. Using anorectic drugs as an adjunct in a comprehensive weight-reducing plan has become more common around the world. Among all the anorectic or appetite suppressant drugs available for the treatment of obesity amphetaminelike drugs, phentermine is a sympathomimetic amine with significant anorectic activity in animal models. Its appetite suppressant effect is generally considered to be exerted through the hypothalamus, but it is not certain that this is the only effect related to weight loss [1]. Phentermine has major effects on the dopaminergic and noradrenergic nervous systems. The cardiovascular effects include a pressor response and increase in heart rate and force of contraction. They were withdrawn from the markets. However, many illegally imported slimming regimen (weight-reducing products) may still contain those unsafe drugs. They are possibly being promoted to the general public through the electronic media, print advertisements, and health food stores for which there is no evidence of efficacy. Health professionals too should query their patients about products purchased over the counter and be more vigilant in detecting previously unobserved and/or unreported adverse effects. We report here a case of very dangerous cardiac arrhythmia that was caused by slimming regimen pills containing phentermine and chlorpheniramine.

Toxicity in Kidney and Urinary Tract induced by Chinese Herb Medicine

Toxicity in kidney and urinary tract after using Chinese herb medicine in general people could be a problem in Korea. However, reported cases of Chinese herb toxicity in the literature are unexpectedly rare compared to the actual clinical experiences. It is assumed that this low incidence is due to the difficulty of the user to know the prescription or exact name of herb medicine. Ignorance about the nature of Chinese herb medicine might result in fatal effect for the health of general people. To prevent the possible organ toxicity of Chinese herb medicine, we need to consider three requirements. First, enough cases showing toxicity of herb medicine should be collected. Second, comparative analysis of the collected cases should be carried out. Third, public relations (P.R.) to the general people and the governmental regulation should be performed. That is, Information collection Data analysis P.R. and Regulation. I have been personally experienced some cases of typical Chinese herb induced nephropathy in the patients with past history using chines herb medicine. All of them showed clinical progression to chronic renal failure. The common problem in these patients were the ignorance about the prescribed herb medicine. These are actual reality in Korea and it means that the resolution of the problem and further prevention for the other people is impossible in this country. Rapidly progressive renal fibrosis after a slimming regimen including Chinese herbs containing aristolochic acid has been identified as Chinese-herb nephropathy. Chinese herb nephropathy have been reported in the literature world-widely (Toxicology 2002; 181-2: 577-80; Clin Nephrol 2000; 53(4): 301-6; Intern Med 2001; 40(4): 296-300; Am J Nephrol 2001; 21(6): 441-8; Nephrology 2004; 9(3): 126-9) since an outbreak of rapidly progressive renal failure observed in Belgium in 1992~1993, related to a slimming regimen involving Chinese herbs (Bull Mem Acad R Med Belg 1994; 149: 128-35). Seventy one cases were registered and renal failure has been progressed in most cases despite the withdrawal of the Chinese herbs. Renal biopsies showed an extensive interstitial fibrosis with loss of tubules. Chinese herb nephropathy contains a variety of clinical features of progressive renal failure to Fanconi's syndrome. Fanconi's syndrome has mostly been reported in Asian countries, and is characterized by proximal tubular dysfunction and slower progression to end-stage renal disease. It has been reported that Aristolochic acid componant in chinese herb induce the toxicity in kiney and urinary tract in humans and animals (J Pharm Belg 1997; 52(1): 7-27; J Am Soc Nephrol 2002; 13: 431-6). It has also been reported that the prevalence of urothelial carcinoma among patients with end-stage Chinese-herb nephropathy (caused by aristolochia species) is high (N Engl J Med 2000; 342(23): 1686-92). Chinese herb, Aristolochia Fang-chi, has been proved nephrotoxic and does not provide enough safety for common health care. The overview shows that attention is caught to the danger of Chinese herbs of unknown origin and these observations indicate the need of intensive search of nephrotoxins in cases of interstitial nephritis of unknown origin.

Aristolochic acid and 'Chinese herbs nephropathy': a review of the evidence to date.

Chinese herbs nephropathy (CHN) is a rapidly progressive interstitial nephropathy reported after the introduction of Chinese herbs in a slimming regimen followed by young Belgian women. It is characterised by early, severe anaemia, mild tubular proteinuria and initially normal arterial blood pressure in half of the patients. Renal histology shows unusual extensive, virtually hypocellular cortical interstitial fibrosis associated with tubular atrophy and global sclerosis of glomeruli decreasing from the outer to the inner cortex. Urothelial malignancy of the upper urinary tract develops subsequently in almost half of the patients. Suspicion that the disease was due to the recent introduction of Chinese herbs in the slimming regimen was reinforced by identification in the slimming pills of the nephrotoxic and carcinogenic aristolochic acid (AA) extracted from species of Aristolochia. This hypothesis was substantiated by the identification of premutagenic AA-DNA adducts in the kidney and ureteric tissues of CHN patients. Finally, induction of the clinical features (interstitial fibrosis and upper urothelial malignancy) typical of CHN in rodents given AA alone removed any doubt on the causal role of this phytotoxin in CHN, now better called aristolochic acid nephropathy (AAN). AAN is not restricted to the Belgian cases. Similar cases have been observed throughout the world, but AA is sometimes incriminated on the basis of the known content of AA in the herbs. The possibility remains that in some individuals in whom AA has not been demonstrated, other phytotoxins might be implicated. Biological and morphological features of AAN are strikingly similar to those reported in another fibrosing interstitial nephropathy of still unknown aetiology, Balkan endemic nephropathy (BEN). Interestingly, AA was incriminated as the cause of BEN many years ago, a hypothesis yet to be fully explored. The intake of AA and the presence of tissular AA-DNA adducts in patients with an unequivocal diagnosis of BEN remains to be demonstrated. The tragic phenomenon of CHN, recognised only 10 years ago, has been at the root of significant research and progress both in nephrology and oncology. It has provided a fascinating opportunity to understand the link between a fibrosing interstitial nephropathy and urothelial carcinoma. It allows the categorisation of interstitial nephritis on the basis of histological findings, of initiating toxic substances and of associated clinical features. Finally, it has led to the withdrawal in several countries of a previously unsuspected carcinogenic and nephrotoxic substance.

Chinese herbal nephropathy and urothelial malignancy.

In Belgium, between 1991 and 1992, seven women under the age of 50 years were admitted to a regional renal dialysis unit with progressive renal failure. All seven had been following the same slimming regimen, prescribed by the same clinic. They had an identical pattern of interstitial fibrosis on renal biopsy. Subsequently it became evident that all were at risk of developing urothelial malignant change. Could there possibly be a link to the prescribed drugs, which included Chinese herbs?

Detection of aristolochic acid in Chinese phytomedicines and dietary supplements used as slimming regimens

Over the last 10 years, numerous cases of intoxications, leading for the most part to end-stage renal failure, have been reported after consumption of slimming regimens made of Chinese herbal preparations. These intoxications were associated with species of the Aristolochia genus, such as Aristolochia fangchi (Aristolochiaceae), known to contain very nephrotoxic and carcinogenic metabolites named aristolochic acids. Several commercial dietary supplements, teas and phytomedicines used as slimming regimens were analysed for their aristolochic acid I content. A preliminary detection of this toxic compound was made by thin-layer chromatography. The presence of aristolochic acid I in these preparations was confirmed by a HPLC/UV-DAD/MS analysis. A quantitative determination of aristolochic acid I was also achieved in the incriminated preparations using both UV and MS detection. Out of 42 analysed preparations, four were found to contain aristolochic acid I and two were suspected to contain aristolochic acid derivatives. Immediate removal of these products from the Swiss market was called for.

Analyses of DNA adducts formed by ochratoxin A and aristolochic acid in patients with Chinese herbs nephropathy

Chinese herbs nephropathy (CHN), a unique type of nephropathy has been associated with the intake of weight-reducing pills containing the Chinese herb Aristolochia fangchi. Moreover, an association between the use of A. fangchi and urothelial cancer in CHN patients has been reported indicating that aristolochic acid (AA) the major alkaloid of A. fangchi might be the causal agent. Similarities of CHN to the Balkan endemic nephropathy (BEN) have led to the hypothesis of a common etiological agent for both diseases. Evidence has accumulated that BEN is an environmentally-induced disease strongly associated with the fungal mycotoxin ochratoxin A (OTA). Both, AA and OTA are nephrotoxic and carcinogenic and induce the formation of DNA adducts. As OTA has been suspected as fungal contaminant in the herbal batches used for the preparation of the weight-reducing pills we analysed tissues from CHN patients by the 32 P -postlabeling procedure for the presence of DNA adducts related to both OTA and AA exposure. Whereas, AA-specific DNA adducts were detected in all five urinary tract tissues from five patients (total RAL: 32–251 adducts per 10 9 nucleotides), OTA-related DNA adducts were detectable in two kidneys and one ureter only (total RAL: 1.5–3.7 adducts per 10 9 nucleotides). Thus, OTA-related DNA adduct levels were about 50 times lower than AA-DNA adduct levels. In female and male rats that were treated with the slimming regimen in the same way like the CHN patients except that the amount of Chinese herbs was 10 times higher, AA-DNA adducts were found in kidney tissues (total RAL ranging from 51 to 83 adducts per 10 9 nucleotides) but adducts derived from OTA were not observed. These results demonstrate that OTA-related DNA adducts do not play a key role in CHN or CHN-associated urothelial cancer.

Rapidly progressive fibrosing interstitial nephritis associated with Chinese herbal drugs

Rapidly progressive fibrosing interstitial nephritis after a slimming regimen containing aristolochic acid has been identified as Chinese herbs nephropathy (CHNP). From 1995 to 1998, we observed 12 Chinese people from different areas of Taiwan who underwent renal biopsy for unexplained renal failure. Medical history gave no clue to the causes of impaired renal function except for the ingestion of traditional Chinese herbs. Although these patients ingested herbal drugs from various sources for different purposes, their renal biopsy samples showed amazingly similar histological findings, with extensive hypocellular interstitial fibrosis and atrophy and loss of tubules in all cases. Glomeruli were apparently intact. They also had similar clinical features, such as normal or mildly elevated blood pressure, early and severe anemia, low-grade proteinuria, glycosuria, and insignificant urinary sediments. Renal function deteriorated rapidly in most patients despite discontinuation of the herbal medicines. Seven patients underwent dialysis, and the remainder experienced slowly progressive renal failure. Bladder carcinoma was found in one patient. Morphologically and clinically, the nephropathy in our patients was similar to CHNP, reported in Belgium. Because of the complexity and unknown types of herbs used in different clinical situations, unidentified phytotoxins other than aristolochic acid might be responsible for this unique disease entity. We conclude that the relation of this nephropathy to the consumption of Chinese herbs is striking. Using uncontrolled herbal remedies carries a high risk for developing interstitial renal fibrosis and urothelial malignancy.

Urothelial lesions in Chinese-herb nephropathy

Rapidly progressive renal fibrosis after a slimming regimen including Chinese herbs containing aristolochic acid (AA) has been identified as Chinese-herb nephropathy (CHN). We reported urothelial atypia in three patients with CHN, with the subsequent development in one patient of overt transitional cell carcinoma (TCC). Therefore, it was decided to remove the native kidneys, as well as the ureters, in all patients with CHN. Nineteen kidneys and ureters removed during and/or after renal transplantation from 10 patients were studied to assess critically urothelial lesions and to characterize the cellular expression of p53, a tumor-suppressor gene overexpressed in several types of malignancies. Multifocal high-grade flat TCC in situ (carcinoma in situ; CiS) was observed, mainly in the upper urinary tract, in four patients, a prevalence of 40%. In one of those patients, a superficially invasive flat TCC of the right upper ureter, as well as two additional foci of noninvasive papillary TCC, were found in the right pelvis and left lower ureter, respectively. This patient also presented recurrent noninvasive papillary TCC of the bladder. Furthermore, in all cases, multifocal, overall moderate atypia was found in the medullary collecting ducts, pelvis, and ureter. All CiS and papillary TCC, as well as urothelial atypia, overexpressed p53. These results show that the intake of Chinese herbs containing AA has a dramatic carcinogenic effect. Carcinogenesis is associated with the overexpression of p53, which suggests a role for a p53 gene mutation. The relationship of this mutation with the reported presence of AA DNA adducts in the kidney remains to be explored.

Chinese herbs nephropathy-associated slimming regimen induces tumours in the forestomach but no interstitial nephropathy in rats.

Chinese herbs nephropathy (CHN), a rapidly progressive interstitial fibrosis of the kidney, has been described in approximately 100 young Belgian women who had followed a slimming regimen containing some Chinese herbs. In 4 patients multifocal transitional cell carcinomas (TCC) were observed. Aristolochic acid (AA), suspected as the causal factor of CHN, is a well known carcinogen but its ability to induce fibrosis has never been demonstrated. The objective of this study was to evaluate the latter using doses of AA, durations of intoxication and delays of sacrifice known to yield tumours in rats. We also tested the hypothesis that a possible fibrogenic role of AA was enhanced by the other components of the slimming regimen. Male and female rats were treated orally with 10 mg isolated AA/kg per day for 5 days/week, or with approximately 0.15 mg AA/ kg per day 5 days/week contained in the herbal powder together with the other components prescribed in the slimming pills for 3 months. The animals were killed respectively 3 and 11 months later. At sacrifice, animals in both groups had developed the expected tumours but not fibrosis of the renal interstitium. Whether the fibrotic response observed in man is due to species and/or strain related differences in the response to AA or to other factors, remains to be determined. Interestingly, despite the addition of fenfluramine and diethylpropion, two drugs incriminated in the development of valvular heart disease, no cardiac abnormalities were observed.

Slimming Diet and the Development of Acute Leukemia: A Possible Relationship? Report of Three Cases

Diet may play a key role in the pathogenesis of cancer and evidence for the role of a reduced intake of micronutrients with antioxidant properties have been increasingly reported. Until now, epidemiologic research in humans has focused on the negative effect of different diets containing excessive caloric intake and relatively little is known on the possible correlation between slimming diets and the incidence of acute leukemia. In this report we describe the temporal association of umbalanced slimming regimens and the subsequent diagnosis of acute leukemia in three cases. This association may be coincidental or perhaps suggests a possible relationship of the diet with the development or progression of acute leukemia.

関西地方におけるChinese herbs nephropathyの多発状況について

In 1993, Vanherweghem and his associates reported cases of rapidly progressive renal interstitial fibrosis in young women who were administered a slimming regimen including Chinese herbs. Subsequently, similar cases have been reported. In Japan, especially in the Kansai area, several cases of Chinese herbs nephropathy have already been reported. We experienced a patient suffering from Chinese herbs nephropathy (CHN), and further detected aristolochic acids from the Chinese herbs taken by the patient. Aristolochic acids are known to be causative agents of CHN. The danger of CHN should be noted as soon as possible and drugs containing aristolochic acids should be prohibited.

Chinese herbs nephropathy presentation, natural history and fate after transplantation.

Chinese herbs nephropathy is a new type of subacute interstitial nephropathy reported in women who had followed a slimming regimen including Chinese herbs. We report the clinical presentation and follow-up of 15 cases and compare them with a control group of 15 women with interstitial nephropathies of other origins, matched for age, sex, and initial serum creatinine (mean 3 mg/dl). At presentation the Chinese herbs nephropathy group differed from the control group by a lower proteinuria (P = 0.009), a more severe anaemia (P = 0.002), and a higher prevalence of aortic insufficiency (42% vs 0%, P < 0.05). It was further characterized by mild hypertension in 80%, glycosuria and leukocyturia in 40% and asymmetric kidneys in 54% of the cases. During follow-up, deterioration of renal function was faster in the Chinese herbs nephropathy than in the control group (P < 0.05). It was influenced by the duration of Chinese herbs treatment (P = 0.037) and the delay between the end of Chinese herbs ingestion and diagnosis of the disease (P = 0.013). In three cases, renal failure developed 3 years after Chinese herbs ingestion. Complications included severe aortic regurgitation requiring surgery (n = 1), urothelial carcinoma (n = 2), bilateral ureterohydronephrosis due to periureteral fibrosis (n = 1). Five patients with Chinese herbs nephropathy were successfully transplanted, without evidence of recurrence of the disease. Chinese herbs nephropathy is characterized by a lower proteinuria, more severe anaemia, and a faster progression to renal failure than other interstitial nephropathies. The duration of Chinese herbs treatment and interval between withdrawal of Chinese herbs and diagnosis are correlated with the rate of progression. Severe, unusual extrarenal complications may affect Chinese herbs nephropathy patients.

25 The cytotoxicity of aristolochic acid in the MDCK and LLC-PK1 renal cell lines

Rapidly progressive fibrosing interstitial nephritis in young women following a slimming regimen including Chinese herbs was ascribed to the administration of Aristolochiafangchi instead of Stephania tetrandra. This was concluded from the presence of aristolochic acid (AA) in the capsules used (Vanhaelen et al., Lancet 343, 174, 1994). Here we report the in vitro cytotoxicity of AA in the MDCK (canine distal) and LLC-PK1 (porcine proximal) renal cell lines of tubular origin. A commercially available mixture of 52% AAI and 41% AAII was used to measure the neutral red uptake inhibition. The results were quantifed by the NI50, i.e. the concentration (in mg/l) of AA inducing a 50% inhibition in neutral red uptake. The NI50 values are given in the table. The cyto-

Multiple tubular dysfunction induced by mixed Chinese herbal medicines containing cadmium

Traditional Chinese herbal medicine remains very popular in Taiwan. Here, Western medicine is readily available at affordable price, yet many local population choose Chinese herbal medicine as an alternative or complementary source of health-care even at a higher cost. The preference of Chinese herbal medicine comes from the generalized belief that herbs are natural, more gentle, and less toxic than synthetic Western medicine. Incidents of herbal poisoning are rare, mild, and obviously underestimated in literature [1]. Recently, Professor Vanherweghem and colleagues [2] reported rapidly progressive interstitial renal fibrosis in nine young women who had followed a slimming regimen including Chinese herbs. The report raised concern about nephrotoxicity of a cocktail of Chinese herbs. Several components were suspected to respond to the interstitial fibrosis, although no one was certain [3]. In addition, any herbal products can be contaminated during production and processing, especially by heavy metals or mycotoxin [3]. We report on a young woman who took a cocktail of Chinese herbs contaminated by cadmium and developed a unique syndrome of multiple renal tubular dysfunction not fully explained by cadmium-induced tubulopathy [4].

The usefulness of dietary medium-chain triglycerides in body weight control: fact or fancy?

Compared to long-chain triglycerides (LCT), medium-chain triglycerides (MCT) display some specific physico-chemical, and biological characteristics. Thus, MCT are currently used in clinical nutrition as energy-yielding substrates, and have been advocated for three decades as a useful mean for body weight reduction. This review encompasses most aspects of MCT metabolism arguing this slimming hypothesis pro and con. Findings in support of the opinion (lower energy density, control of satiety, rapid intrahepatic delivery and oxidation rates, poor adipose tissue incorporation) may be invalidated by counteracting data (stimulation of insulin secretion and of anabolic-related processes, increased de novo fatty acid synthesis, induced hypertriglyceridemia). The balance between these two opposing influences depends on the composition (energy intake, nature of ingredients, MCT/LCT ratio, octanoate/decanoate ratio) and duration of the regimen. Due to the high energy level (around 50%) of MCT necessary to achieve body weight loss, long-term compliance to such slimming regimens is unlikely in human nutrition.

Alternative and complementary cancer therapies

Alternative and complementary cancer therapies

Drugs of abuse and renal disease.

The complications of drug abuse encompass a spectrum of glomerular, interstitial, and vascular diseases. They comprise the heroin-associated nephropathy seen in African-American intravenous drug addicts, which, however, has given way in the 1990s to HIV-associated nephropathy. Infections with methicillin-resistant Staphylococcus aureus may cause acute glomerulonephritis by releasing bacterial superantigens. Hepatitis C has supplanted hepatitis B and may give rise to membranoproliferative glomerulonephritis and cryoglobulinemia. Addicts who inject drugs subcutaneously ('skin popping') may develop amyloidosis. Cocaine causes rhabdomyolysis, severe hypertension, occasionally renal failure in the absence of rhabdomyolysis, and may hasten progression to uremia in patients with underlying renal insufficiency. 'Ecstasy', an amphetamine-like recreational drug, has caused acute renal failure, electrolyte disturbances, and malignant hypertension. In Belgium and some other European countries, women taking Chinese herbs in a slimming regimen have developed a severe and irreversible interstitial fibrosis that is assuming epidemic proportions.