Tryptophan In Combination Research Articles

Inhalable ceftazidime-roflumilast powder targeting infection and inflammation: Influence of incorporating roflumilast into ceftazidime-leucine co-amorphous formulation

Co-amorphization of a single drug with amino acid is a technique to improve aerosolization of inhalable spray-dried formulation for inhalation therapy. However, the incorporation of a second drug molecule into drug-amino acid co-amorphous particles to prepare combination formulations has not been explored. Here, we prepared combination powders using two model drugs, ceftazidime and roflumilast, which when concurrently used can potentially improve therapeutic outcome in non-cystic fibrosis bronchiectasis by counteracting both infection and inflammation. The study was performed using a two-step approach. The first step involved the identification of an amino acid and its concentration (% w/w) for the best aerosolization enhancement of ceftazidime by varying the ratios of leucine and tryptophan in combination (0–25 % w/w). In the second step, roflumilast (5–20 % w/w) was incorporated into the formulation containing the selected concentration of the amino acid to understand the impact of introducing a second drug into ceftazidime-amino acid(s) co-amorphous particles. In total, 10 formulations were prepared and characterized in terms of solid-state and aerosol performance. Leucine introduced surface asperity which correlated well with improved aerosolization of the particles. The best fine particle fraction (FPF) (75 %) was achieved with 25 % leucine; hence, leucine was selected as the ideal amino acid at the given concentration to understand the impact of roflumilast inclusion on ceftazidime-leucine system. The ceftazidime-roflumilast powder retained their anti-bacterial and anti-inflammatory properties following formulation. However, inclusion of roflumilast at 5 % dramatically decreased the FPF to 55 % and higher roflumilast concentration did not have much effect on FPF. The decrease in FPF ascribed to the change in particle surface as roflumilast was found to decrease surface asperity. In addition, leucine crystallized with inclusion of roflumilast. This study indicates that inclusion of a second drug into drug-amino acid amorphous matrix particles can affect its solid-state dynamics and aerosol performance; hence, such parameters should be cautiously considered while undertaking similar endeavors of preparing combination formulations.

ФИЗИОЛОГИЧЕСКИЕ ПОКАЗАТЕЛИ И МЯСНАЯ ПРОДУКТИВНОСТЬ ЦЫПЛЯТ-БРОЙЛЕРОВ ПРИ СКАРМЛИВАНИИ ТРИПТОФАНА И КОРМОВОЙ СМЕСИ «ХОНДРОТАН»

The results of studies on the effect of the introduction of the amino acid tryptophan in the amount of 0.04 % in the composition of the combo feed and additionally in the diet of the feed mixture «Chondrotan» (on the physiological parameters and meat productivity of broiler chickens. The greatest effect on the hematological parameters of broilers was provided by tryptophan in combination with the feed mixture «Chondrotan» at the rate of 350 g per 1 ton of mixed feed. It was also revealed that the use of tryptophan and different amounts of «Chondrotan» feed mixture in the feeding of broiler chickens contributes to an increase, in comparison with the control, of the mass of the gutted carcass, respectively, by 2,07 (P<0,05); 5,24 (P<0,001) and 2,99 % (P<0,001), edible parts of the carcass-by 2,11 (P<0,05); 5,72 (P<0,001) and 3,14 % (P<0,001), pectoral muscles – by 2,17 (P<0,05); 5,63 (P<0,001) and 3,20 % (P<0,001). The quality indicators of meat are improving in the young animals of the experimental groups: the content of dry matter in the pectoral muscles – by 0,09; 0,15 (P<0,05) and 0,13 % (P<0,05), protein-by 0,12; 0,40 (P<0,01) and 0,19 % (P<0,05). Of the experimental groups, the highest indicators of meat yield and quality were noted in broilers of the II experimental group.

Effects of spray-dried porcine plasma replacement with tryptophan, pyridoxine, and niacin supplementation on feed intake and growth performance of weaning piglets

The purpose of this experiment was to investigate the effects of feeding a low crude protein diet with supplemental dietary tryptophan in combination with pyridoxine and niacin compared with spray-dried porcine plasma (SDPP) supplementation on the performance and feed intake of weaning pigs. A total of 36 crossbred (Landrace A— Yorkshire A— Duroc) weaned female pigs of 28 days old were reared under three dietary treatments. Treatments were 1) corn-soybean meal diet, 2) 0.30% synthetic tryptophan + pyridoxine + niacin, and 3) 5% SDPP. The experimental results indicated no significant difference (P > 0.05) in feed intake for pigs fed the three experimental diets. However, pigs fed the synthetic tryptophan + pyridoxine + niacin diet tended to have better feed intake than those with other treatments, especially during the first 2 weeks after weaning. At the end of the experimental period, pigs fed synthetic tryptophan + pyridoxine + niacin and a basal control diet tended to have the same weight gain and feed efficiency when compared to pigs fed diets with 5% SDPP (P > 0.05). Therefore, the present study suggests that supplemental tryptophan in combination with pyridoxine and niacin may be used as an alternative for SDPP in weaning piglet diets.

Long-Range Modulation of Chain Motions within the Intrinsically Disordered Transactivation Domain of Tumor Suppressor p53

The tumor suppressor p53 is a hub protein with a multitude of binding partners, many of which target its intrinsically disordered N-terminal domain, p53-TAD. Partners, such as the N-terminal domain of MDM2, induce formation of local structure and leave the remainder of the domain apparently disordered. We investigated segmental chain motions in p53-TAD using fluorescence quenching of an extrinsic label by tryptophan in combination with fluorescence correlation spectroscopy (PET-FCS). We studied the loop closure kinetics of four consecutive segments within p53-TAD and their response to protein binding and phosphorylation. The kinetics was multiexponential, showing that the conformational ensemble of the domain deviates from random coil, in agreement with previous findings from NMR spectroscopy. Phosphorylations or binding of MDM2 changed the pattern of intrachain kinetics. Unexpectedly, we found that upon binding and phosphorylation chain motions were altered not only within the targeted segments but also in remote regions. Long-range interactions can be induced in an intrinsically disordered domain by partner proteins that induce apparently only local structure or by post-translational modification.

Protein source tryptophan versus pharmaceutical grade tryptophan as an efficacious treatment for chronic insomnia

Background : Intact protein rich in tryptophan was not seen as an alternative to pharmaceutical grade tryptophan since protein also contains large neutral amino acids (LNAAs) that compete for transport sites across the blood–brain barrier (BBB). Deoiled gourd seed (an extremely rich source of tryptophan—22?mg tryptophan/1?g protein) was combined with glucose, a carbohydrate that reduces serum levels of competing LNAAs which was then compared to pharmaceutical grade tryptophan with carbohydrate as well as carbohydrate alone. Method : Objective and subjective measures of sleep were employed to measure changes in sleep as part of a double blind placebo controlled study where subjects were randomly assigned to one of three conditions: (1) Protein source tryptophan (deoiled gourd seed) in combination with carbohydrate; (2) pharmaceutical grade tryptophan in combination with carbohydrate; (3) carbohydrate alone. Subjects : Out of 57 subjects 49 of those who began the study completed the three week protocol. Results : Protein source tryptophan with carbohydrate and pharmaceutical grade tryptophan, but not carbohydrate alone, resulted in significant improvement on subjective and objective measures of insomnia. Protein source tryptophan with carbohydrate alone proved effective in significantly reducing time awake during the night. Conclusion : Protein source tryptophan is comparable to pharmaceutical grade tryptophan for the treatment of insomnia.

Effects of acute and short-term administration of tryptophan plus ethanol on noradrenaline and serotonin metabolites in the locus coeruleus

The effects of acute and short-term administration of tryptophan or tryptophan plus ethanol on serotonin [5-hydroxytryptamine (5-HT)] and two of its metabolites, 5-hydroxyindoleacetic acid (5-HIAA) and 5-hydroxytryptophol (5-HTPL), in the locus coeruleus were investigated in rats by using the microdialysis method. In addition, the acute effects of these drugs on noradrenaline and its metabolite 4-hydroxy-3-methoxymandelic acid (HMMA) were addressed. A single co-administration of tryptophan (50 mg/kg, i.p.) and ethanol (1.25 g/kg, i.p.) did not change the concentrations of either noradrenaline or its metabolite in the locus coeruleus. In contrast, administration of tryptophan (50 mg/kg, i.p.) for three consecutive days caused an increase in the concentration of 5-HIAA, but not that of 5-HT, in the locus coeruleus. Combined administration of tryptophan plus ethanol for 3 days resulted in marked increases in 5-HIAA concentrations in the locus coeruleus, but not in 5-HTPL concentrations. However, administration of ethanol (1.25 g/kg) for 3 days had no effect on the concentrations of 5-HT and its metabolites. The increased 5-HIAA concentration that resulted with combined tryptophan plus ethanol administration was remarkably suppressed by disulfiram. Moreover, in comparison with tryptophan-treated rats, the behavioral sign of teeth-chattering was significantly detected in tryptophan plus ethanol–treated rats, but the enhancement of behavioral signs with combined treatment was markedly suppressed by disulfiram. Results of the current study seem to indicate that the stimulation of 5-HT metabolism in locus coeruleus serotonergic neurons by tryptophan was strengthened by the simultaneous administration of ethanol in short-term experiments, and that the increased 5-HIAA concentrations in the locus coeruleus are responsible for behavioral activation.

Novel tryptophan dioxygenase inhibitors and combined tryptophan dioxygenase/5-HT reuptake inhibitors

Tryptophan dioxygenase (TDO) is a liver enzyme that is responsible for the majority of the metabolism of tryptophan. A series of novel 3-(2-pyridylethenyl)indoles are shown to be potent inhibitors of TDO with selected members of the series also having 5-hydroxy tryptamine (5-HT) reuptake inhibitory activity. These compounds are shown to provide significant increases in the levels of tryptophan and 5-HT in the cerebrospinal fluid and are thus of interest for antidepressant therapy.

Acute tryptophan depletion in bulimia: Effects on large neutral amino acids

Acute tryptophan depletion, which may reduce brain serotonin synthesis in humans, was evaluated in bulimic and normal subjects assessing its effects on the plasma ratio of tryptophan to the sum of the other large, neutral amino acids (TRP/ΣLNAA). Thirteen bulimic and 9 control women ingested an amino acid mixture containing either 2.3 g (control mixture) or 0 g of tryptophan (active mixture), in combination with 100 g of the other amino acids. Six healthy male volunteers were also studied, using a similar mixture containing 4.6 g of tryptophan. Bulimic and control women both experienced sizable reductions in the plasma TRP/ΣLNAA ratio, compared to baseline values, for both the active mixture (10% of baseline) of the control mixture (45% of baseline). For bulimic women, the active mixture produced a significant increase in fatigue and a trend toward increased anxiety and indecisiveness. The control mixture did not maintain baseline TRP/ΣLNAA ratios so we identified a control amino acid mixture that does not cause a drop in the plasma TRP/ΣLNAA ratio when ingested (4.6 g tryptophan in combination with 100 g of other amino acids). An oral, tryptophan-deficient amino acid mixture produced acute, substantial reductions in the plasma TRP/ΣLNAA ratio in all subjects, suggesting that the treatment should reduce brain tryptophan uptake and serotonin synthesis. A control mixture containing tryptophan was also identified that maintains the plasma TRP/ΣLNAA ratio at pretreatment values.

Mechanism of serotonin effects on prolactin and growth hormone secretion in domestic fowl.

Brain serotonin levels were increased in immature chickens by ip injection of pargyline (75 mg/kg) and clorgyline (5 mg/kg) and by L-tryptophan (100 mg/kg) and imipramine (10 mg/kg) treatment. These treatments increased the circulating prolactin level and reduced the concentration of plasma growth hormone (GH). Treatment with para-chlorophenylalanine (PCPA, 100 mg/kg) reduced the brain serotonin content and the level of plasma prolactin. Treatment with these drugs in vivo similarly affected the basal level of prolactin release from pituitary glands in vitro, although it did not affect the basal level of GH release. The in vitro responsiveness of the pituitary gland to hypothalamic stimuli eliciting prolactin secretion was increased by in vivo pargyline and combined tryptophan: imipramine treatment but reduced by PCPA administration. The in vitro GH response to hypothalamic stimulation was reduced after the in vivo injection of pargyline, clorgyline and tryptophan: imipramine. The hypothalami from clorgyline and tryptophan: imipramine treated birds induced a greater stimulation of in vitro prolactin secretion from control pituitary glands than hypothalami from controls birds, whereas the GH releasing activity was reduced. These results suggest that serotonin stimulates prolactin secretion in chickens by increasing pituitary responsiveness to hypothalamic releasing factors and by increasing the prolactin releasing activity of the hypothalamus. Serotonin appears to suppress GH secretion by reducing pituitary sensitivity to releasing factors and by reducing hypothalamic GH releasing activity.

5‐HT reuptake inhibitors plus tryptophan in endogenous depression

In a previous double-blind, 3-week study we compared the effect of clomipramine + placebo with clomipramine + tryptophan in 24 patients with endogenous depression. The patients in the latter group showed a significantly more rapid improvement than those in the former group, especially with regard to the depression-anxiety cluster of symptoms. These results prompted us to perform a similar study in which zimelidine, a more specific inhibitor of 5-HT reuptake, was used instead of clomipramine. In other respects the design was practically identical to that used in the previous study. Unexpectedly, tryptophan in combination with zimelidine, was not superior to placebo + zimelidine with respect to antidepressant activity. In comparison with the previous study, the antidepressant action of zimelidine showed no statistically significant difference from clomipramine. However, the patients tended to show a more prompt response after zimelidine + placebo than after clomipramine + placebo. The changes in CSF metabolites were likewise different in the two studies. In the two studies taken together 12 out of 49 patients showed prompt improvement within one week. This raises the question whether the therapeutic response to antidepressant drugs necessarily involves a delay as is generally assumed. Side effects were remarkably few and mild in the second study.

CLINICAL, BIOCHEMICAL, AND PHYSIOLOGICAL FEATURES DISTINGUISHING MYOCLONUS RESPONSIVE TO 5-HYDROXYTRYPTOPHAN, TRYPTOPHAN WITH A MONOAMINE OXIDASE INHIBITOR, AND CLONAZEPAM

Fifteen patients with a variety of myoclonic syndromes were studied clinically, pharmacologically, and physiologically. CSF tryptophan, 5HIAA, and HVA were also measured. Of these patients, 8 were improved to varying degrees by therapy with 5HTP, tryptophan in combination with MAOI (but not tryptophan alone), and clonazepam. This group included 6 cases of post-anoxic myoclonus, one case of post-traumatic myoclonus and one undiagnosed case of non-progressive focal myoclonus and epilepsy. In this group low levels of CSF 5HIAA were found compared to non-responsive cases and controls. Two cases of dysynergia cerebellaris myoclonica, 2 cases of undiagnosed aetiology, 2 cases of essential myoclonus, and one case of palatal myoclonus failed to respond to drug therapy. However, even amongst the responsive group the improvement varied. The most dramatic responses were seen in those patients in whom physiological study suggested that myoclonus was mediated by brain-stem structures. Less dramatic responses were seen in patients in whom the myoclonus appeared to originate from cortical structures. The neurochemical basis of myoclonus responding to 5HT precursors and clonazepam is discussed. It is suggested that such myoclonus arises from a relative hypoactivity of the 5HT neuronal system which results in a release of abnormal responses to sensory stimuli which characterize this type of myoclonus.