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PubMed2001

Calcipotriol ointment. A review of its use in the management of psoriasis.

UNLABELLED: Calcipotriol, a vitamin D3 analog, acts not only to inhibit cell proliferation and enhance cell differentiation in the skin of patients with psoriasis, but also appears to have effects on immunologic markers that are thought to play a role in the etiology of the disease. In several well designed, short term studies in adults, calcipotriol ointment 50 micrograms/g twice daily provided similar or superior efficacy to several other antipsoriatic agents in adult patients with mild to moderate psoriasis. In patients with nonscalp psoriasis, the drug provided superior efficacy to twice daily placebo (vehicle ointment), twice daily fluocinonide 500 micrograms/g, once daily tacalcitol 4 micrograms/g and twice daily coal tar 5% plus allantoin 2% and hydrocortisone 0.5%. Furthermore, calcipotriol therapy generally provided superior efficacy to twice daily betamethasone valerate 1 to 1.2 mg/g or once daily dithranol 1 to 20 mg/g, and similar efficacy to twice daily betamethasone dipropionate plus salicylic acid or once daily maxacalcitol 6 to 50 micrograms/g. Limited data indicated that calcipotriol ointment 50 micrograms/g also improved overall disease severity in children. In combination with other antipsoriatic agents [acitretin, cyclosporine, betamethasone valerate, halobetasol (ulobetasol)], ultraviolet B or psoralen ultraviolet A (PUVA) phototherapy, calcipotriol ointment 50 micrograms/g twice daily improved the beneficial effects of these drugs on overall disease severity in adult patients with moderate to severe psoriasis. Furthermore, in separate trials, calcipotriol combination therapy reduced the dosage of acitretin required to achieve clearance of psoriasis and the duration of PUVA and dosage of UVA phototherapy, potentially improving the benefit/risk ratio for these other antipsoriatic treatments. Calcipotriol was generally well tolerated in short and long term studies in adult patients, with the majority of adverse events being mild to moderate in intensity and transient. The most common adverse events associated with calcipotriol therapy were dermatologic in nature and included lesional or perilesional irritations, face and scalp irritations, worsening of psoriasis and miscellaneous dermatologic events. Notably, there have been very few reports of patients developing hypercalcemia or hypercalciuria during calcipotriol therapy, with most occurring in patients who exceeded the recommended dosage of 100 g/week. Although data in children are limited, the drug was well tolerated with the nature and incidence of adverse effects similar to those observed in adult patients. CONCLUSIONS: Extensive clinical experience, along with several short and long term clinical trials, has shown calcipotriol ointment to be an effective and well tolerated topical agent in adult patients with psoriasis. In addition, calcipotriol ointment proved beneficial in combination with other topical, phototherapy or systemic antipsoriatic treatments, reducing the dosage and/or duration of some of these treatments and potentially improving their benefit/risk ratio. Calcipotriol ointment is valuable as a first- or second-line therapy option for the management of mild to moderate psoriasis and in combination with other antipsoriatic agents for more severe psoriasis.

Administration, Topical↗
PubMed1997

Energy state in HT-29 cells is linked to differentiation.

The relationship between the energy source used by HT-29 cells and their state of differentiation was determined. Short chain fatty acids and acetoacetate were applied to the cells for 9 d, after which the medium was replaced with conventional culture medium for a further 9 d so that the permanence of the changes could be assessed (18 d). Glucose utilization and lactic acid, acetoacetate, and beta-hydroxybutyrate production by the cells were determined. Differentiation was assessed by the presence of the enzymes sucrase-isomaltase and carbonic anhydrase 1, as well as morphological changes of the cells. By tracing carbon from acetate, propionate, and butyrate through the cells, it was found that the carbon from the short-chain fatty acids was fluxed into acetoacetate. Significant amounts of acetoacetate were released by the propionate-treated culture after 9 d and the acetate-, propionate-, valerate-, and caproate-treated cultures after 18 d. A significant positive correlation was found between acetoacetate synthesis and differentiation. Acetoacetate applied to HT-29 cells also induced their differentiation. The acetate-, butyrate-, valerate-, isovalerate-, and caproate-treated cells underwent terminal differentiation, while the propionate- and isocaproate-treated cultures underwent programming events. We, therefore, conclude that HT-29 cells utilize short chain fatty acids in preference to glucose, metabolize these to ketones, thereby raising the energy state and effecting the observed morphological and functional changes in the cells.

Acetoacetates↗
PubMed1997

Oxidation of short and medium chain C2-C8 fatty acids in Sprague-Dawley rat colonocytes.

BACKGROUND: The predominant colonic short chain fatty acids, acetate, propionate, and butyrate, are oxidised into CO2 in colonocytes from rat and humans in the preferred order of butyrate (C4) > propionate (C3) > acetate (C2)- hence butyrate is considered to be the principal oxidative substrate for colonocytes. AIMS: To compare colonocyte oxidation of valerate (C5), hexanoate (C6), and octanoate (C8) with that of butyrate. METHODS: Isolated rat colonocytes were incubated in the presence of a concentration range of 1-14C labelled C2-C8 fatty acids. Oxidation rates were obtained by quantifying the production of 14CO2, and Vmax (maximum velocity) and K(m) (Michaelis-Menten constant) were calculated by computer fitting of the data to a Michaelis-Menten plot. RESULTS: The K(m) value of acetate (0.56 (SEM 0.02) mmol/l) was about fourfold higher than the K(m) of butyrate (0.13 (0.01) mmol/l), whereas the K(m) values of valerate (0.19 (0.01) mmol/l), hexanoate (0.19 (0.01) mmol/l), and octanoate (0.16 (0.01) mmol/l) were of the same order of magnitude as the K(m) of butyrate. Acetate did not influence butyrate oxidation, whereas butyrate strongly inhibited the oxidation of acetate. By contrast, valerate, hexanoate, and octanoate inhibited colonocyte oxidation of butyrate equally or more than the reverse inhibitory effect of butyrate on valerate, hexanoate, and octanoate oxidation. The maximum rates of ATP production were in the order of valerate > octanoate = hexanoate > butyrate > acetate (28.47 (0.70), 21.78 (0.75), 21.33 (0.78), 16.12 (0.49), 9.09 (0.34) (mumol/min/g) respectively). CONCLUSIONS: Valerate, hexanoate, and octanoate seem to be excellent substrates for colonocyte oxidation, similar to butyrate. These results may influence the choice of fatty acid composition in enemas used for treatment of patients in whom deficient colonocyte oxidation is suspected-for example, patients with ulcerative colitis and diversion colitis.

Acetates↗
PubMed1981

Two forms of biotin-responsive multiple carboxylase deficiency.

Biotin-responsive multiple carboxylase deficiencies are classified into early and late forms. The early form showed higher urinary excretion of 3-hydroxyisovalerate and 3-hydroxypropionate than the late form and was associated with normal plasma biotin concentrations. It is proposed that holocarboxylase synthetase and intestinal biotin absorption are defective in the early and late forms respectively.

Acute Disease↗
PubMed1996

Sequential production of two different polyesters in the inclusion bodies of Pseudomonas oleovorans.

When Pseudomonas oleovorans was grown on a mixture of 5-phenylvaleric acid, PVA, and nonanoic acid, NA, the reserve polyester produced included both a homopolymer and a copolymer. The homopolymer poly-3-hydroxy-5-phenylvalerate, PHPV, contained only 3-hydroxy-5-phenylvalerate units, while the copolymer contained the same long chain 3-hydroxyalkanoates as those present in the copolymer poly-3-hydroxynonanoate, PHN, which is produced from acid alone. The intracellular location of each of these polymers was determined by selective staining of the inclusion body granules with ruthenium tetraoxide and examination by transmission electron microscopy showed that both types of polyesters occurred in the same granule. PHN was present in the center of the granule, while PHPV accumulated around the PHN in the inclusion body. The proteins associated with the inclusion bodies were separated using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). In all cases, two different polymerase enzymes of molecular weight 59 and 55 KDa were present, indicating that the same polymerase enzyme system was responsible for the production of both PHN and PHPV. Attempts were made to produce a random copolymer containing both alkyl and phenylalkyl repeat units by varying the growth conditions, but a mixture of PHN and PHPV was always produced instead.

Electrophoresis, Polyacrylamide Gel↗
PubMed1987

Experimental studies on reproduction with the lipid-regulating agent gemfibrozil.

Gemfibrozil, a new lipid-regulating agent, was evaluated in rats and rabbits for effects on various phases of the reproduction process. In teratology studies groups of pregnant rats and rabbits received gemfibrozil at doses up to 200 mg/kg during organogenesis (rat, Days 6-15; rabbit, days 6-18). For peri- and postnatal studies, groups of pregnant rats were given 92 or 331 mg/kg from Day 15 of gestation through weaning. In fertility studies groups of sexually mature male rats were given 93 or 326 mg/kg of gemfibrozil for 61 days and females were given 94 or 318 mg/kg for 15 days prior to mating within treatment groups. Drug administration continued in females through gestation and weaning of the F1 offspring. In subsequent fertility experiments, treated male rats were mated with untreated females and treated females were cohabitated with untreated males. Gemfibrozil did not elicit a teratogenic response in either rats or rabbits up to doses that resulted in maternal toxicity. Reduced pup weights during the neonatal and weaning periods in the female fertility study as well as in the perinatal-postnatal study were the only apparent drug effect. Treatment of female rats prior to mating had no significant effects on general reproductive parameters. Male rats given doses of about 300 mg/kg/day showed inconsistent and equivocal lower rates of fertility relative to the concurrent controls. No adverse effects were seen in the reproductive performance of offspring of gemfibrozil-treated male rats.

Animals↗
PubMed1981

Effects of repeated administration of rat 2-diethylaminoethyl-2-2-diphenylvalerate-HCI (SKF 525 A) on liver.

Repetitive administration to male rats of 2-diethylaminoethyl-2-2-diphenyl-valerate-HCI (SKF 525 A) (50 mg/kg, i.p.), decreases the intensity of [14C]-orotic acid incorporation/mg of RNA but not the 14C-incorporation/g liver. The RNA content/g liver is significantly higher in SKF-treated animals than in controls. Decay of label in liver RNA from [14C] orotic acid pretreated animals, is not significantly different in SKF 525 A treated animals than in controls. SKF 525 A repetitive administration, does not modify the rate of incorporation of 32P in liver microsomal lipid when results are expressed per microgram of inorganic phosphorus but it does when expressed in terms of per gram liver. There is a significant decrease in the decay rate of label from 32P-prelabeled liver microsomal phospholipids when animals are treated with SKF 525 A. There is a significant increase in the protein and phospholipid content in the smooth endoplasmic reticulum fraction. The electron microscopy of liver from SKF 525 A-treated animals, shows the presence of large areas of round vesicles of swollen endoplasmic reticulum, partly due to smooth component and part due to rough component, having detached the ribosomes from their membranes. Results suggest an inhibitory effect of SKF 525 A on RNA and phospholipid degradative processes.

Animals↗
PubMed1976

Beta-methylcrotonic aciduria associated with lactic acidosis.

A patient is described in whom lactic acidosis of very severe degree was found to coincide with the presence of beta-methylcrotonic acid and rho-hydroxyphenyllactic acid in urine in large amounts, while beta-hydroxyisovaleric acid was found to be a relatively minor excretion product. Beta-methylcrotonic acid is demonstrated, for the first time, to be present in blood and CSF. These findings are discussed in relation to the patients previously reported to have beta-methylcrotonylglycinuria and raise the possibility that our patient's organic aciduria may be secondary to acquired disease rather than to an inborn error of metabolism.

Amino Acids↗
PubMed1985

Biotin deficiency complicating parenteral alimentation: diagnosis, metabolic repercussions, and treatment.

Biotin deficiency associated with total parenteral nutrition is an emerging clinical problem; criteria for diagnosis and dosage for treatment are unclear. We have diagnosed and successfully treated biotin deficiency in three patients. Each patient had alopecia totalis, hypotonia, and developmental delay. Two developed the characteristic scaly periorificial dermatitis; one had only an intermittent scaly rash on the cheeks and occipital scalp. Zinc and essential fatty acid supplements were adequate; serum zinc levels and triene/tetraene ratios confirmed sufficiency of these nutrients. None of the patients received biotin prior to diagnosis, and each had decreased excretion of urinary biotin and increased urinary excretion of organic acids diagnostic of deficiency of two biotin-dependent enzymes (methylcrotonyl-coenzyme A carboxylase and priopionyl-coenzyme A carboxylase). Only one patient had a plasma biotin concentration below the normal range (Ochromonicas danica assay). The rash, alopecia, and neurologic findings responded dramatically to biotin therapy (100 micrograms/day in all patients; an initial larger dose of 1 mg/day for 1 week plus 10 mg/day for 7 weeks in one patient), and did not recur. However, abnormal organic acid excretion persisted in one patient who did not receive the larger dose. We conclude that plasma biotin concentration does not reflect biotin status in all cases and speculate that the biotin supplement currently recommended for pediatric patients (20 micrograms/day) may not be adequate therapy for biotin deficiency and might not even be adequate to maintain normal biotin status during TPN.

Alopecia↗
PubMed1986

Mechanism of inactivation of gamma-aminobutyrate aminotransferase by 4-amino-5-fluoropentanoic acid. First example of an enamine mechanism for a gamma-amino acid with a partition ratio of 0.

The mechanism of inactivation of pig brain gamma-aminobutyric acid aminotransferase (GABA-T) by (S)-4-amino-5-fluoropentanoic acid (1, R = CH2CH2COOH, X = F) previously proposed [Silverman, R. B., & Levy, M. A. (1981) Biochemistry 20, 1197-1203] is revised. apo-GABA-T is reconstituted with [4-3H]pyridoxal 5'-phosphate and inactivated with 1 (R = CH2CH2COOH, X = F). Treatment of inactivated enzyme with base followed by acid denaturation leads to the complete release of radioactivity as 6-[2-hydroxy-3-methyl-6-(phosphonoxymethyl)-4-pyridinyl]-4-oxo-5-+ ++hexenoic acid (4, R = CH2CH2COOH). Alkaline phosphatase treatment of this compound produces dephosphorylated 4 (R = CH2CH2COOH). These results support a mechanism that was suggested by Metzler and co-workers [Likos, J. J., Ueno, H., Feldhaus, R. W., & Metzler, D. E. (1982) Biochemistry 21, 4377-4386] for the inactivation of glutamate decarboxylase by serine O-sulfate (Scheme I, pathway b, R = COOH, X = OSO3-).

4-Aminobutyrate Transaminase↗
PubMed2001

Development of a process for the biotechnological large-scale production of 4-hydroxyvalerate-containing polyesters and characterization of their physical and mechanical properties.

A process for the large-scale production of 4-hydroxyvalerate (4HV)-containing biopolyesters with a new monomer composition was developed by means of high-cell-density cultivation applying recombinant strains of Pseudomonas putida and Ralstonia eutropha, harboring the PHA-biosynthesis genes phaC and phaE of Thiocapsa pfennigii. Cell densities of about 20 g/L revealing a PHA content of 52% (w/w) and a molar fraction of 4HV of up to 15.4 mol % were obtained by a two-stage fed-batch cultivation process at a 25-L scale using octanoic acid during the growth phase and levulinic acid for the accumulation of 4HV-containing polyesters. Besides 4HV the polyester contained significant amounts of both 3-hydroxybutyric acid (3HB) and 3-hydroxyvaleric acid (3HV) and traces of 3-hydroxyhexanoic acid (3HHx) and 3-hydroxyoctanoic acid (3HO). With glucose or gluconic acid as the growth substrate, the components of the polyester could be reduced to mainly 3HV and 4HV with only a negligible fraction of 3HB, resulting in a polyester with a new composition. Scale-up of the cultivation process to a 500-L scale was successfully performed, resulting in the production of these polyesters at a pilot plant scale. Short-term shifts in temperature and pH resulted in the formation of cell agglomerates of about 50-100 microm by which the effectiveness of the semicontinuous centrifugation process was drastically increased. Washing of the freeze-dried cells with boiling methanol significantly shortened the extraction process and resulted in a polyester of higher purity. The physical and mechanical properties of these copolyesters were characterized by means of size exclusion chromatography, dynamic mechanical analysis, differential scanning calorimetry, stress-strain measurements, and measurements of the viscosity of the solution. The copolyesters were cast into films, spun to fibers, or processed into test bars by melt spinning and injection molding, respectively. They revealed an almost entirely amorphous structure and consequently were sticky and lacked strength. However they showed high thermal stability and an unusually high elongation at break of about 200%; the molecular weights (M(w)) were between 2.0 x 10(5) and 3.3 x 10(5) g/mol. It was shown that 4HV-containing polyesters belong to the class of thermoplastic elastomeres.

Aerobiosis↗
PubMed1988

Gemfibrozil decreases platelet reactivity in patients with hypercholesterolemia during physical stress.

The effects of the lipid-lowering drug gemfibrozil on platelet reactivity at rest and during submaximal exercise were investigated in 10 patients with serum cholesterol levels greater than 270 mg/dl. No significant changes were observed in platelet reactivity at rest after gemfibrozil treatment. However, a marked decrease in platelet reactivity was seen in almost all patients treated with gemfibrozil during exercise. The adrenaline concentration necessary to induce secondary aggregation increased in eight patients during exercise after gemfibrozil and in two after placebo treatment. When adenosine diphosphatase (2 to 4 mumol/L) was used to induce aggregation, 5-hydroxytryptamine (serotonin) and thromboxane B2 secretion by platelets decreased by 35% and 67%, respectively, during exercise in patients treated with gemfibrozil. The area under the aggregation curve decreased by 28% during exercise after gemfibrozil. No significant changes occurred in these variables during exercise after placebo. Thus, gemfibrozil seems to have antiplatelet effects that might have importance in the prevention of acute complications of atherosclerosis in patients with hypercholesterolemia.

Adult↗