Bioequivalence of a new liquid formulation of ursodeoxycholic acid (Ursofalk suspension) and Ursofalk capsules measured by plasma pharmacokinetics and biliary enrichment.

BACKGROUND: Ursodeoxycholic acid is an approved therapy for hepatobiliary disorders but in infants and children compliance is compromised because it is formulated exclusively as capsules, or tablets. AIM: To determine the pharmacokinetics and bioequivalence of a new liquid formulation of ursodeoxycholic acid (Ursofalk suspension) with a standard capsule (Ursofalk) in a randomized, unblinded, crossover designed study of 24 healthy adults. METHODS: Equivalence was based on single bolus oral plasma pharmacokinetics and biliary ursodeoxycholic acid enrichments after repeat doses. Biliary bile acid composition and hydrophobicity index were also compared. Ursodeoxycholic acid was measured in duodenal bile by high-performance liquid chromatography and in plasma by mass spectrometry. RESULTS: The mean percentage biliary ursodeoxycholic acid enrichment after administration of the suspension was not significantly different from that obtained with capsules (44.2 +/- 11.7% vs. 46.9 +/- 10.2%, respectively). The equivalence ratio was 0.94 (95% CI: 0.8-1.1), establishing bioequivalence between suspension and capsules. Both formulations reduced the biliary hydrophobicity index and no differences in bile acid composition were observed between formulations. The plasma pharmacokinetics of both formulations was similar and the tolerability of the suspension was excellent. CONCLUSIONS: A new liquid formulation of ursodeoxycholic acid suitable for paediatric patients is pharmacologically bioequivalent to capsules when given as single, or repeated oral doses.

Both serum receptors of tumor necrosis factor are influenced by mud pack treatment in osteoarthrotic patients.

Several authors have demonstrated the pivotal role of proinflammatory cytokines in inducing progressive cartilage degradation and secondary inflammation of the synovial membrane in osteoarthritis (OA). It has recently been established that tumor necrosis factor (TNF)-alpha plays a well-defined role in the pathophysiology of inflammatory joint diseases and that binding to circulating soluble TNF-alpha receptors can inactivate it. We investigated the influence of mud pack treatment, which is able to diminish TNF-alpha serum values, on specific TNF receptor (sTNF-R) levels. Thirty-six patients with OA were enrolled and randomized into two groups. Group A underwent mud pack treatment and group B underwent thermal bath treatment. A group of 20 healthy untreated subjects was used as a control. Blood samples were collected at baseline and after treatment, and assays of sTNF-R55 and sTNF-R75 were performed in both groups. We found small changes in sTNF-Rs serum values but these were not statistically significant. sTNF-R55 serum values decreased by 0.4% after the therapy in group A, while in group B the decrease was -17.7%. sTNF-R75 was reduced by -21.17% in group A and by -10.6% in group B. In conclusion, through its thermic and ant/inflammatory activity mud pack treatment shows complex interaction with the most common factors of inflammatory and cartilage degradation. Our results suggest that the thermic component of this natural treatment is mainly involved in modulating inflammatory reaction and cartilage damage through binding of the circulating TNF, which controls the activation of the cells responsible for the production of proinflammatory cytokines.

Differences of ropivacaine and bupivacaine relevant to antiinflammatory activity, platelet aggregation and antioxidant activity in vitro.

Ropivacaine and bupivacaine affect the in vitro growth of rat fibroblasts and monkey kidney Vero cells with bupivacaine generally showing the stronger effect. Up to 3 mM concentration the two anesthetics affect the expression of genes differently for CD2, CD3 gamma, CD40L, IL-2, IL-2R alpha, IL-2R beta, IL-2R gamma, IL-4, and IL-4R during activation of human lymphocytes, with bupivacaine showing the higher effect. Human platelet aggregation is inhibited by the two anesthetics which also show an antioxidant effect on lipid peroxidation of rat liver microsomes. In both cases bupivacaine seems more active than ropivacaine.

Enzymatic dopamine peroxidation in substantia nigra of human brain.

The main metabolic pathway affected in Parkinson's disease is that of dopamine oxidation and melanin formation in substantia nigra which involves both oxidative and reductive enzymes. The cyclic nature of the biosynthetic pathway from dopamine to melanin implies that a derangement at any of the steps may result in the disappearance of melanin. Possible pathogenetic events such as oxidative stress have therefore no clearcut interpretation since they may be both cause or consequence of the disease. This paper documents the existence of a peroxidase converting dopamine to dopaminochrome in the presence of hydrogen peroxide in the substantia nigra of autopsied human brain. The activatory effect of dopaminochrome on a purified peroxidase is shown, together with the inhibitory effect of dopaminochrome-derived melanin and the activatory effect of melanin/Fe. The toxic effect of dopaminochrome on murine neuroblastoma cells cultured in vitro is demonstrated together with the inhibition of dopaminochrome melanization induced by acetylcholine in vitro.

Isomorphism of quasispecies and percolation models.

Population dynamics of tRNA-like macromolecules and viruses have been interpreted by Eigen (1971, Naturwissenschaften58, 465-526) on the basis of the "quasispecies" model. The present paper contains a qualitative analysis of the similarities between Eigen's quasispecies model and percolation models. In fact, different phenomena characterized by an analogous inner structure can conceivably be described by quite similar mathematical formalisms. The occurrence of a threshold in specific processes predicted by the models is considered first. Secondly, Ising's model of ferromagnetism is taken into account in the last section. An interpretation of the above-mentioned biological theory in terms of percolation, implying a zeroth-order approximation to the real situation, might be a point of departure to a deeper insight obtainable with more refined approaches. A better comprehension of biological phenomena might in any case arise from a percolative approach, even if the description of the systems is simplified. An overview of some quasispecies results and some plausible applications are presented.

Function of the hypothalamic adrenal axis in patients with fibromyalgia syndrome undergoing mud-pack treatment.

Fibromyalgia (FM) is a nonarticular rheumatological syndrome associated with diverse clinical and psychological features. One of the major complaints in FM is reduced pain tolerance, especially in tender points (TP) for which patients derive significant benefit from nonsteroidal antiinflammatory drugs or corticosteroids. Patients with FM also have altered reactivity of the hypothalamic pituitary adrenal (HPA) axis where the predominant feature is reduced containment of the stress response system through diminished adrenocortical output and feedback resistance. Our results show that mud packs together with antidepressant treatment are able to influence the HPA axis, stimulating increased levels of adrenocorticotropic hormone, cortisol and beta-endorphin serum levels. The discharge of corticoids in the blood and the increase in beta-endorphin serum levels are followed by a reduction in pain symptoms, which is closely related to an improvement in disability, depression and quality of life. It seems that the synergic association between a pharmacological treatment (trazodone) and mud packs acts by helping the physiological responses to achieve homeostasis and to rebalance the stress response system. To clarify and optimize the effectiveness of this synergic association, studies involving a larger number of FM patients and a different pharmacological treatment are needed.

A rat brain fraction and different purified peroxidases catalyzing the formation of dopaminochrome from dopamine.

Dopaminochrome formation is catalyzed by commercially available purified peroxidases (EC 1.11.1.7) such as horseradish, lacto- and myelo-peroxidase using dopamine, hydrogen peroxide or promethazine sulfoxide as substrates. A rat brain fraction (RBF) catalyzes a similar reaction and its catalytic power increases after preincubation with hydrogen peroxide/ascorbic acid. The activity of both the purified enzymes and the RBF preparation is inhibited by carnosine and characterized by excess substrate inhibition. The enzymes recognize different substrates but show the highest affinity for dopamine. The RBF fraction is strongly buffered against oxidation by compounds such as glutathione and by bioreductive enzymes such as DT-diaphorase (EC 1.6.99.2) which can use as a substrate menadione or dopaminochrome. The rat brain dopamine peroxidizing activity appeared to be mostly bound to the synaptosomal fraction. The reaction catalyzed by the purified peroxidases was followed by electron spin resonance spectroscopy and, unlike that catalyzed by RBF, was shown to produce the signal of a transient dopamine-o-semiquinone radical.

Pharmacotherapy and psychotherapy in the treatment of psychiatric disturbances.

The type of treatment that most psychiatric disturbances receive at present is a mixture of pharmacotherapy and psychotherapy, following the principle that mental functions are the result of the activities of brain machinery subsequent to the interaction between individuals and their external environment. We now know the molecular mechanism of action of several psychoactive drugs but have scant understanding of the correlation between molecular events and mental function. As for psychotherapy, we know that it may have beneficial effects on patients' behavior but ignore the issue of whether this has any correlate at molecular level. A black box still exists between drugs, neurotransmitters, receptors, and the higher brain functions defined as anxiety, emotion, arousal, etc. Yet mental treatments imply a therapeutic method in which the blend of drugs and words administered to patients is determined by the choice of the therapist and by the specific pathology recognized through clinical diagnosis. In this epistemologically confused situation, the pharmaceutical industry is playing a major role in orientating the medical profession towards the use of more and more powerful neurotropic substances with very detailed molecular actions and plenty of side-effects. Nevertheless, the use of psychotropic drugs has allowed the opening of the psychiatric hospitals and the 'liberation' of millions of psychiatric patients. This beneficial effect is counterbalanced by the dependency of millions of individuals on psychotropic drugs. The situation leads to a number of questions relative to the possible links among words, molecules, and behaviors. The present paper illustrates a theoretical model which can be used to compare and contrast psychotherapy and pharmacotherapy.

Colonization by diatoms and antirheumatic activity of thermal mud.

We have identified diatoms among other thermophilic microorganisms as the main agents for the colonization of thermal mud resulting in a 'maturation' which renders the mud suitable to be used for mud-pack treatment of osteoarthrosis patients. The main effects of the diatom growth are the progressive enrichment of mud extracts in chlorophyll a parallel to the building up of a sulfoglycolipid endowed with an anti-inflammatory action. The sulfoglycolipid was also produced by diatoms isolated from the mud and cultivated in vitro.

Toxicity of dopamine and dopaminochrome on cultured cells.

Cultured rat fibroblasts, monkey kidney tumor cells (line Vero) and murine neuroblastoma cells were exposed to dopamine or dopaminochrome in the presence and absence of ascorbic acid. Ascorbic acid is able to potentiate the toxicity of both dopamine and dopaminochrome for all the tested cells. The toxicity of dopaminochrome was higher than that of dopamine. There is a correlation between toxicity and levels of bioreductive defenses of the cells, e.g. DT-diaphorase (NAD(P)H:quinone oxidoreductase EC 1.6.99.2) and glutathione. In general, tumor cells have lower defenses and seem to be more sensitive to the toxic action.

A synthetic calcium-chelating L-glutamyl-L-serine phosphate (Glu-Ser.P) enhances calcium absorption in the rat.

A new synthetic procedure was used to prepare L-glutamyl-L-serine phosphate (Glu-Ser.P) with a good yield. The phosphopeptide is able to chelate calcium ion as shown by conductimetric titration and through the use of a calcium-specific electrode. Intestinal absorption of radioactive calcium is enhanced in rats fed 45Ca and Glu-Ser.P.

Serum levels of a prostaglandin and a leukotriene after thermal mud pack therapy.

BACKGROUND: Mud pack therapy (MPT) influences the serum levels of several cytokines involved in chondrocyte metabolism and in the pathogenesis of osteoarthrosis. In fact, we have observed decreases of IL-1 and TNF-alpha, involved in cartilage inflammation and destruction, and increases of IGF-1 that have a protective influence on the cartilage. It is known that in osteoarthrosis MPT is also able to decrease pain, largely attributable to the inflammatory response. METHODS: We enrolled 31 subjects undergoing MPT and collected blood samples before and after the therapy to assay serum levels of prostaglandin (PGE2) and leukotriene (LTB4) compounds with potent inflammatory and algesic properties. RESULTS: The study shows a decrease in PGE2 and LTB4 serum levels in all the samples after MPT with no correlation between the PGE2 and LTB4 decreases. CONCLUSIONS: Mud pack therapy exerts a protective effect on the cartilage and is able to induce pain relief by reducing the inflammatory reaction.

The oxidative metabolism of catecholamines in the brain: a review.

This paper summarizes the strong evidence that we now have that the oxidative pathway of metabolism of the catecholamines, dopamine and norepinephrine via their respective quinones occurs in vivo in the brain. This fact is not yet widely appreciated. The evidence is based on the chemical structure of neuromelanin, advanced mass spectrometry techniques and the identification of intermediates of this system, such as 5-cysteinyl dopamine, in the brain. Supportive evidence is presented from a number of sources including enzymology. A suggestion as to the possible normal function of this system is made.

[Changes in the intrabronchial microflora of patients with chronic bronchitis after inhaling mineral water]. / Izmeneniia intrabronkhial'noi mikroflory u bol'nykh khronicheskim bronkhitom posle ingaliatsii s mineral'noi vodoi.

The authors' investigations show that inhalations of sodium chloride bromine-iodine water given in spray modify intrabronchial microflora of patients with chronic bronchitis reducing the number of the pathogenic bacteria and elevating the number of bacteria typical for physiological composition of the bronchial mucus.

A peroxidase-catalyzed sulfoxidation of promethazine.

Lactoperoxidase, when incubated with increasing amounts of promethazine (P) and promethazine sulfoxide (PO) catalyzes the formation of promethazine sulfoxide accompanied by oxygen consumption. An intermediate radical of PO can be detected by electron spin resonance (ESR). Catalase or superoxide dismutase do not inhibit the reaction while dopamine does. The lactoperoxidase-catalyzed formation of dopaminochrome in the presence of hydrogen peroxide is inhibited by P. Both P and PO inhibit acetyl- and butyrylcholinesterase. Purified enzymes were used throughout the study and horseradish peroxidase but not myeloperoxidase had an activity similar to that of lactoperoxidase.

Mud pack therapy in osteoarthrosis. Changes in serum levels of chondrocyte markers.

We have previously shown that thermal mud therapy is able to influence chondrocyte activity of osteoarthrosic patients by modulating the production of serum cytokines, such as interleukin 1, and this was related to the presence of an anti-inflammatory principle in mature thermal mud. Mud therapy influences many biochemical processes of the body, independently of the thermic stimulation alone and the present paper documents specific increases of insulin growth factor 1 and decreases of tumor necrosis factor alpha in serum of osteoarthrosic patients after 12 days of mud pack application.

Physical and biochemical changes of thermal mud after maturation.

Thermal mud is a therapeutic agent whose antirheumatic effectiveness is optimized by a process of maturation. The maturation of thermal mud was followed at 48 degrees C under controlled conditions by measuring physical and biochemical changes due to the growth of colonizing thermophilic microorganisms. Thermogravimetric measurements allowed us to identify the building up of an organic component including phospholipids and in particular a previously recognized sulfoglycolipid, which was further purified. The compound may be responsible for the antirheumatic effect of the mud and is produced by the colonizing species which develop in a period of maturation subsequent to that of production of photosynthetic pigments.

Horseradish peroxidase-catalyzed sulfoxidation of promethazine and properties of promethazine sulfoxide.

Promethazine sulfoxide was obtained with a quantitative yield in a horse radish peroxidase-catalyzed reaction of promethazine and hydrogen peroxide and was also prepared by direct chemical synthesis. The enzymatic sulfoxidation of promethazine was studied in vitro as a function of pH, promethazine, and hydrogen peroxide concentration. Promethazine sulfoxide inhibits with an apparent K(i) of 59.7 microM at pH 5.5 the enzymatic reaction, followed spectrophotometrically, polarographically, potentiometrically, and luminometrically. The reaction was also inhibited by ascorbic acid (K(i) 26.8 microM) and glutathione (K(i) 41.8 microM). The spectrophotometric techniques employed, together with ESR spectrometry, allowed the identification of at least three radical species formed in the course of the reaction. Promethazine sulfoxide is devoid of the antioxidant effect exhibited by promethazine on rat brain synaptosomes. The sulfoxide also lacks photosensitizing action, while retaining the neuroleptic effect of the parent compound.