[Herbal medicines alternative to synthetical medicines]. / Phytopharmaka als Alternative zu Synthetika.

Herbal pharmaceuticals in medical practice are similarly used as chemically well defined drugs. Like other synthetical drugs, they are subject to pharmaceutical legislature (AMG) and EU directives. It is to differentiate between phytopharmaceuticals with effectiveness of proven indications and traditional registered herbal medicine. Through the Health Reform Act January 2004 and the policy of the Common Federal Committee (G-BA)on the contractual medical care from March 2009--with four exceptions--Non-prescription Phytopharmaka of the legal Health insurance is no longer (SHI) refundable and must be paid by the patients. The result is that more and more well-established preparations disappear from the market. This article gives an overview of practical relevant indications for herbal medicines, which according to its licensing status, the scientific assessment by the Cochrane Collaboration and the Institute for Quality and Efficiency in Health Care (IQWiG) and evidence-based Medicine (EBM)/ meta-analyzes as an alternative to synthetics can be used.

Investigations on the pharmacokinetic properties of Harpagophytum extracts and their effects on eicosanoid biosynthesis in vitro and ex vivo.

PURPOSE: Harpagophytum extract and its marker substance harpagoside were shown to exert anti- inflammatory effects by interacting with the eicosanoid biosynthesis. In this study, different Harphagophytum extracts were tested with respect to inhibition of leukotriene and thromboxane biosynthesis in vitro and ex vivo. In addition, pharmacokinetic parameters of Harpagophytum extracts were investigated in vivo. METHODS AND SUBJECTS: Different fractions of Harpagophytum extracts were tested in vitro in human whole blood samples for effects on basal and ionophore A23187-stimulated cysteinyl-leukotriene (Cys-LT) and thromboxane synthesis. Furthermore, in 3 independent studies with different numbers of human male volunteers, a Harpagophytum extract was administered orally and tested in whole blood samples for Cys-LT and thromboxane B2 (TXB2) biosynthesis and for the determination of pharmacokinetic parameters of harpagoside. RESULTS: The special Harpagophytum extract WS1531 had a stronger inhibitory effect on ionophore A23187-stimulated Cys-LT levels compared with pure harpagoside or other extract fractions. Fractions without harpagoside had no pronounced inhibitory effect. When Cys-LT levels were measured after oral intake of Harpagophytum extract, a biphasic but dose-independent decrease of 28% and 58%, respectively, in basal Cys-LT formation was observed. Pharmacokinetic studies with the Harpagophytum extract WS1531 showed that the maximum levels of plasma harpagoside were reached after 1.3 to 2.5 hours. A linear relationship between dose and the first maximal concentration (Cmax) or area under the curve (AUC) (0-1)/AUC(0-infinity) was observed. CONCLUSIONS: Our observations strongly indicate a close relation between serum harpagoside levels and the inhibition of leukotriene biosynthesis.

Aah VI, a novel, N-glycosylated anti-insect toxin from Androctonus australis hector scorpion venom: isolation, characterisation, and glycan structure determination.

Aah VI was isolated from the venom of the North African scorpion, Androctonus australis hector. It is the first glycosylated neurotoxin from scorpion venom to be described. It was not toxic to mice, when injected intracerebroventricularly at a dose of 1.2 microg per animal. However, it had typical activity in Blatella germanica cockroaches resulting in gradual paralysis and very low toxicity (LD50 = 8.5 microg/g of animal). It consists of 66 amino acid residues and is heterogeneously N-glycosylated at a single site, on asparagine 9, of the Asn-Gly-Thr sequence. The potential N-glycosylation site was deduced from automatic Edman degradation and amino acid analysis, and glycan heterogeneity was evidenced by ESMS. Determination of the N-glycan structures (dHex, Hex and HexNAc) was assessed by nanoESMS/MS with picomolar amounts of sample. Current knowledge of N-glycan structure and composition suggests that the glycan structures are derived from a common core.

Mood and appetite during minimal-carbohydrate and carbohydrate-supplemented hypocaloric diets.

After a baseline period of free-feeding, 20 obese outpatients alternated between four 2-wk periods of minimal-carbohydrate diet (800 kcal; 58% protein and 42% fat by weight) and of a carbohydrate-supplemented diet (1,000 kcal; 42% protein, 30% fat, and 28% carbohydrate). In a comparison of psychological adjustment during the baseline and low-calorie diets, the initial 2 wk of dieting was associated with a decrease in appetite and elevation of psychological well-being, regardless of the composition of the diet. Thereafter, appetite and mood approached basal levels. Further changes in these psychological reactions to dieting did not vary with the type of diet. There was no support for the idea that a minimal-carbohydrate, protein-supplemented fast decreases appetite and elevates mood more in comparison with a similar diet containing enough carbohydrate to minimize ketosis.

Internal mammary arteriovenous malformation with communication to the pulmonary vessels.

A 25 year old asymptomatic man with a past history of pulmonary tuberculosis presented with a continuous murmur. Selective arteriography revealed a left internal mammary arteriovenous malformation in communication with vessels in the left upper pulmonary lobe. No significant hemodynamic abnormalities were detected. This is the 26th reported case of internal mammary arteriovenous fistula and the 6th with a pulmonary communication. Review of the data in previous cases suggests that surgical indications are limited to symptomatic relief, heart failure during infancy or the possible risk of endarteritis, proximal arterial degeneration or rupture.

Stimulant properties of bromocriptine on central dopamine receptors in comparison to apomorphine, (+)-amphetamine and L-DOPA.

1. The activity of bromocriptine has been investigated in tests for the stimulation of central dopaminergic mechanisms. The results obtained have been compared with those of apomorphine, (+)-amphetamine and L-DOPA. 2. Bromocriptine (2.5 to 10 mg/kg) induced stereotyped sniffing and licking in rats. The stereotypy was more intense than that induced by L-DOPA and less intense than that of apomorphine and (+)-amphetamine over the dose ranges studied. 3. In rats lesioned unilaterally in the substantia nigra by local injection of 6-hydroxydopamine, bromocriptine, like apomorphine and L-DOPA, induced turning contralateral to the side of the lesion. The smallest dose of bromocriptine to induce turning was 0.5 mg/kg. 4. Reserpine-induced catalepsy in mice was antagonized by bromocriptine, with an ED50 of 1.8 mg/kg. It was intermediate in potency to apomorphine and L-DOPA. 5. Spontaneous locomotor activity in mice was stimulated by bromocriptine in a dose-dependent manner from 2.5 to 10 mg/kg after an initial suppression of activity. 6. In all experiments, bromocriptine was characterized by a prolonged duration of activity after a delay in the onset of effect. 7. The stereotyped behaviour induced by bromocriptine was inhibited by prior administration of pimozide, reserpine or alpha-methyl-p-tyrosine. 8. Bromocriptine-induced turning behaviour was abolished by pretreatment with pimozide, and reduced after alpha-methyl-p-tyrosine treatment. 9. The results obtained support the conclusion that bromocriptine acts by stimulating dopamine receptors in the central nervous system and that intact catecholamine synthesis and granular amine storage mechanisms are necessary for it to bring about its effects.

Diuretic action of Bay g 2821 in oedema-free volunteers.

The sulphonamide-free diuretic Bay g 2821 was tested under standardized conditions 43 oedema-free volunteers. The threshold dose was 10 mg (0.14 mg/kg). The doseresponse curve was practically linear for doses up to 80 mg. The excretion of sodium and chloride was very high, and that of potassium, magnesium and calcium markedly lower. Itarenal haemodynamic investigations showed that the inulin clearance was unchanged, and the PAH clearance increased slightly. The tubular reabsorption of sodium and chloride was inhibited. Side-effects after a single oral dose did not occur.

The diuretic effect of muzolimine (Bay g 2821) on hepatogenic ascites.

A double-blind study was carried out in 22 patients with hepatogenic ascites to examine the effectiveness of the combination of muzolimine and spironolactone in comparison with combinations of furosemide and spironolactone and placebo and spironolactone. Despite the heterogeneous and variable case material, there was no significant difference between the 3 patient groups prior to treatment. After a diuretic-free preliminary period, all patients received 300 mg spironolactone daily plus 80 mg muzolimine, 80 mg furosemide or placebo for 7 days. Before the start of treatment and at daily intervals, measurements were made of waist size, body weight, and urinary and electrolyte elimination. Blood chemistry was investigated before treatment and on Days 4 and 7. Analysis of the results showed that the combination of muzolimine and spironolactone produced a statistiscally significant stronger saluretic effects than the other two combinations. This can be explained by the different sites of action of muzolimine and spironolactone, resulting in an additive effect. Neither subjective nor objective side-effects were observed during the 7-day treatment period.

The interaction of mofebutazone with furosemide.

A study was carried out in 10 healthy male subjects to investigate whether mofebutazone, a phenylbutazone derivative, influenced furosemide-induced diuresis and PGE2 excretion as has been shown with other non-steroidal anti-inflammatory agents such as aspirin and indomethacin. The subjects received, at random, a single dose of either 40 mg furosemide or 40 mg furosemide plus 600 mg mofebutazone and were then crossed over to the other regimen after 10 days. Urine was collected for 45 minutes before and then for six 45-minute clearance periods after drug administration. Urine volumes and excretion of sodium, potassium, chloride, magnesium, creatinine and the main metabolite of PGE2 were measured at the end of each period, as were blood levels of creatinine and mofebutazone from samples taken before, during and after administration. The results showed no significant differences between the two groups, indicating no interaction between mofebutazone and the diuretic.

Pharmacology of Bay g 2821, a long-acting, high-ceiling diuretic.

Bay g 2821 is a diuretic, from a new class of chemical substances, with both the efficacy of diuretics with a high-ceiling activity, such as furosemide, bumetanide and ethacrynic acid, and the prolonged duration of action of thiazides. Pharmacological investigations showed that Bay g 2821 was more potent than furosemide in dogs but less potent in rats. Bay g 2821 did not differ from furosemide in excretion of electrolytes. Further studies showed that Bay g 2821 had an antihypertensive effect in dogs, spontaneously hpertensive rats, and in rats with artificially-induced renal hypertension. Other pharmacological studies did not reveal any other significant effects.

Bioequivalence between two furosemide-spironolactone formulations: a pharmacokinetic and pharmacodynamic approach.

Two formulations of the drug combination furosemide (20 mg)-spironolactone (100 mg) were tested for bioequivalence in a randomized crossover trial in 12 healthy volunteers. By comparing the AUC values derived from drug serum concentrations, bioequivalence was only achieved for canrenone, the main metabolite of spironolactone, but not for furosemide. A significant difference in the tmax values indicates sustained release of furosemide from one of the formulations. By contrast, bioequivalence was achieved if pharmacodynamic criteria, such as urine volume and Na+ and Cl- excretion over a period of 12 hours, were used. Fractional measurements of urinary volume and electrolyte excretion (0 to 3 h, 3 to 6 h, 6 to 12 h) correlated with the different tmax values for both formulations. These data indicate that bioequivalence is more conclusively verified on the basis of pharmacodynamic parameters than on the basis of pharmacokinetic parameters. These considerations are applicable in particular to drugs displaying large inter-individual variations in serum levels and/or a poor correlation between serum levels and effect.

The effects of a special Agnus castus extract (BP1095E1) on prolactin secretion in healthy male subjects.

The effects of three doses of a special Agnus castus extract (BP1095E1)--extracts from 120 mg, 240 mg and 480 mg of drug per day--were examined within the framework of a placebo-controlled clinical study of tolerance and prolactin secretion in 20 healthy male subjects during a period of 14 days. There was good tolerance during the study as regards the following: adverse effects, the effects on blood pressure and heart rate, blood count, Quick's test, clinical chemistry as well as testosterone, FSH and LH values. During each study phase the 24-hour prolactin secretion profile was measured from the penultimate to the final day, and the amount of prolactin release was monitored an hour after TRH stimulation on the last day. A significant increase in the 24-hour profile was registered with the lowest dose in comparison to placebo, the opposite being the case with the higher doses, i.e. a slight reduction. In contrast to the administration of placebo, the 1-hour AUC after TRH stimulation resulted in a significant increase with the lowest dose and a significant reduction with the highest dose. The results suggest effects of the special Agnus castus extract which are dependent on the dose administered and the initial level of prolactin concentration.

Is the biopharmaceutical quality of extracts adequate for clinical pharmacology?

According to definition, an extract is a multi-substance mixture from a medicinal plant obtained by extraction of specific parts of the plant. Corresponding to the active ingredients in each case, each extract exhibits, qualitatively and quantitatively, a specific content spectrum, so that an extract is not just any extract. With an increasing demand for demonstrating the clinical efficacy of plant-based substances, extracts or extract fractions, we necessarily confront the problem of phytogenerics, i.e. extract-identical preparations for exchange versus the innovator. Up to now, pharmacognosic experts, phytochemists, and pharmacists have dealt with the problem as to the bioequivalence of phytopharmaceuticals within the context of pharmaceutical and biopharmaceutical/technological equivalence. In the meantime, however, from a number of plant extracts, the active ingredients determining their efficacy are known and analytical methods have been established, so that bioavailability/bioequivalence studies similar to those for chemical/synthetic substances are now possible.

Pharmacokinetics of thiamine derivatives especially of benfotiamine.

Pharmacokinetic data of orally administered lipid-soluble thiamine analogues like benfotiamine are reviewed and assessed. It is quite clear that benfotiamine is absorbed much more better than water-soluble thiamine salts: maximum plasma levels of thiamine are about 5 times higher after benfotiamine, the bioavailability is at maximum about 3.6 times as high as that of thiamine hydrochloride and better than other lipophilic thiamine derivates. The physiological activity (alphaETK) increased only after benfotiamine was given. Due to its excellent pharmacokinetic profile benfotiamine should be preferred in treatment of relevant indications.

Differential therapy of constipation--a review.

Constipation is a common condition occurring with increasing frequency in advanced age. As a symptom, it is not always dealt with directly by the physician, but is often left to the care of nurses. Many patients rely on self-medication. Constipation not only interferes with the quality of life, but often has the rank of a syndrome requiring competent medical intervention. This is of clinical importance, because a thorough understanding of the pathophysiology of constipation enables the clinician to identify the potential causes and, if necessary, initiate a differentiated therapy with the aid of only simple additional investigations. This review outlines a clinical approach including medical history, spectrum of causes, radiopaque pellets method to differentiate between slow transit constipation and defecation disturbances for the differential diagnosis of constipation. The mechanisms of action of laxatives (anti-absorptive, secretagogue, osmotic, filling and swelling agents) are further components and important for the individual therapy. Based on this fundamental information, a differentiated therapy is possible in each specific case such as coprostasis. Chronic symptomatic constipation reduces the quality of life and should be evaluated by physicians. If situations such as drug-induced constipation or hypothyroidism which have to be treated causally can be ruled out, laxative treatment according to the clinical picture, mode of action of drug used and side effects of the laxative can be initiated. Laxative abuse due to chronic constipation is rare and almost always associated with psychosomatic-psychiatric disorders.

Absorption behavior of sulpiride described using Weibull functions.

Deconvolution absorption profiles of oral sulpiride formulations were calculated from plasma concentration-time data obtained in an open, 3-period study with a crossover of the 2 oral formulations in 12 healthy volunteers following single intravenous (100 mg) and oral (2 x 50 mg capsules, 200 mg tablets) application of sulpiride. A model based on 2 Weibull-functions, and applied using NONMEM, described the complex absorption profiles more satisfactorily than a first order absorption model or a model based on a single Weibull-function.

A radiopharmacological study without human radiation exposure.

The development, study and control of new drugs today is hardly conceivable without nuclear medicine studies. Nuclear physicians on ethical commissions bear great responsibility in the planning and execution of such studies. In order to protect subjects and patients those nuclear techniques are therefore to be welcome which do not include exposure to radiation. Nuclear techniques used in in-vitro diagnostics (RIA) and the determination of naturally occurring nuclides incorporated in the human body belong to this category. With the aid of a clinico-pharmacological study of a new combination of diuretics it is shown that both methods supply valuable pharmacodynamic evidence.

Measurement of the bioavailability of aescin-containing extracts.

OBJECTIVE: In horse chestnut seed extracts (HCSE), the triterpene saponin mixture aescin is considered the active principle. The bioavailability and pharmacokinetics of different HCSE preparations have been studied under single and repeated applications using a radioimmunological method (RIA) developed to identify beta-aescin, one of the pharmacologically active fractions of the saponin mixture. In this paper, the available pharmacokinetic data are reviewed and the observed heterogenicity between comparable studies is discussed. DATA SOURCES: Pharmacokinetic data from 5 single- and 4 multiple-dose bioequivalence studies with HCSE-containing products, were measured by the same analytical laboratory using the same RIA. EVALUATION: In studies where procedures were identical the pharmacokinetic data of beta-aescin show high variations. Even under steady-state conditions a considerable variability for the same HCSE product is obtained. CONCLUSION: Formal reasons like study design and medications can be ruled out as a source of pharmacokinetic variation. In extracts of herbal drugs like HCS, the relative concentration of the individual saponin fractions can considerably differ from batch to batch. For immunological methods, identification of such antigens with intermolecular variability, e.g., the structural aescin analogs, is of unknown validity. Therefore the shape of the concentration-time curve would only show an approximation of the time course but not for the absolute concentrations. A specific validation procedure for the RIA must be developed, otherwise a LC-MS/MS-method of sufficient sensitivity should be elaborated.

Studies on vitamin B12 status in the elderly--prophylactic and therapeutic consequences.

Because of the large liver stores (about 5 mg), low turnover rate (0.143%) and small daily requirement (3 micrograms), vitamin B12 deficiency does not occur under normal circumstances. This is not the case in individuals with chronic inflammatory or trophic changes at vitamin B12 absorption sites. Without supplementation, vitamin B12 deficiency can be expected within 5 years of gastrectomy. Characteristic features of type A gastritis are hyposecretion and mucosal atrophy in the fundus and body of the stomach, with absent intrinsic factor. In the small intestine, active and/or passive absorption is impaired by extensive ileal resection, exocrine pancreatic insufficiency and chronic inflammatory disorders such as Crohn's disease. Definitive plasma concentrations cannot be quoted for vitamin B12 deficiency. Dietary habits, subjective symptoms, hematological laboratory results, function tests and gastrointestinal endoscopic and histological findings must all be taken into account in the diagnosis. Modern diagnostic parameters, such as methylmalonic acid and homocysteine serum assays, are useful for achieving early diagnosis and hence optimal treatment. With their assured availability, parenteral vitamin B12 preparations remain the treatment of choice. Results from vitamin B12 bioavailability studies in healthy subjects suggest that > 300 micrograms probably suffices as an oral maintenance dose after parenteral loading. Further well-documented cases are needed in order to establish whether these doses are adequate in malabsorption syndromes and gastrointestinal diseases. Various case reports indicate the value of prophylactic and therapeutic oral vitamin B12 administration, especially in disorders of homocysteine metabolism, a substance postulated as a further important risk factor for atherosclerosis.

Pharmacodynamics and pharmacokinetics of furosemide-retard and furosemide-retard/triamterene.

In a randomized cross-over study the saluretic effect of furosemide-retard was compared with the combination of furosemide-retard/triamterene in 10 healthy male volunteers. The combination led to a significantly stronger excretion of sodium and a significantly lower excretion of potassium than furosemide-retard. The interaction of the saluretic with the antikaliuretic was even more distinctly expressed regarding sodium related quotients. The combination furosemide-retard/triamterene differs significantly from furosemide-retard in the main considering Na+/Cl-, Na+/K+ and Na+/Mg2+ quotients. The concentration time curves for furosemide and OH-TA-sulphate in the plasma are nearly similar. Maximal plasma levels for furosemide are reached after 3.9h and for OH-TA-sulphate after 2.2h. The 'apparent' elimination half-life time for furosemide is 2.1h and the elimination half-life time for OH-TA-sulphate is 2.0h.