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PubMed1986

Rare but serious risks associated with non-narcotic analgesics: clinical experience.

Our data show that 1% of patients who required hospital treatment did so due to severe adverse reactions to analgesics. The most frequent adverse reaction was major gastrointestinal bleeding after aspirin, indomethacin, phenylbutazone or naproxen. Thrombocytopenia, second in frequency, was also mainly a complication of aspirin treatment, as was severe vertigo and tinnitus. Allergic reactions and leucopenia or agranulocytosis occurring in single cases only were associated with the use of pyrazolones. Patients with nephropathy were usually taking phenacetin or one of the close derivatives paracetamol or bucetin. Intensive monitoring for adverse reactions to drugs in 6,000 hospitalised patients in medical wards showed that analgesics, although frequently used, did not lead to life-threatening reactions. Gastrointestinal and neurological side effects were the most commonly observed reactions and these occurred more often after aspirin, indomethacin or pentazocine than after dipyrone or tilidine. Preliminary data of an international case-control-study on agranulocytosis and aplastic anaemia suggest that the incidence of agranulocytosis was in the order of 2 to 3 per million users of analgesics per year. Agranulocytosis occurred predominantly with pyrazolones, with a mortality of 1 to 2 per 10 million users per year. A cohort study on the treatment of colic pain in general practice showed that serious events most likely due to adverse reactions to analgesics were bronchospasm, shock fragments or shock. The incidence of these serious events was about 2 in 1,000 treated cases. The relative risk was not increased by treatment with pyrazolones, opioids or other drugs.

Agranulocytosis↗
PubMed2006

Structure-guided identification of novel VEGFR-2 kinase inhibitors via solution phase parallel synthesis.

Structural analysis of the essential binding elements of the oxindole-based kinase inhibitor (1) led to the identification of a novel class of heterocyclic-substituted pyrazolones. Knoevenagel condensation of a variety of activated methylene nucleophiles with indole or pyrrole carboxaldehydes provided a focused library of molecules, each containing elements of kinase pharmacophore probe. Initial screening for VEGFR-2 kinase inhibition eliminated several of the probes. Identification of an active pyrazolone motif and further optimization resulted in several highly potent VEGFR-2 inhibitors with cellular efficacy, anti-angiogenic activity ex vivo in rat aortic ring explant cultures, and oral anti-tumor efficacy in nude mice.

Administration, Oral↗
PubMed1985

[Skin testing with the components of analgesics in patients with anaphylactoid hypersensitivity reactions to mild analgesics].

In 282 patients presenting with adverse reactions to mild analgesics, prick tests were performed with components of analgesic drugs; in some of them, commercial preparations were also tested. In 19 patients (7%), a total of 40 conclusively positive immediate reactions was found: there were 22 reactions to pyrazolone derivatives, 14 reactions to commercial preparations, and one singular reaction to phenacetin, phenobarbital, carbromal and vitamin B1, respectively. Cross-sensitivity to different pyrazolone derivatives was observed in only 5 of 15 patients with a positive reaction to at least one of these substances. One of the patients with a positive immediate reaction and 2 further individuals developed positive test reactions after 4 to 24 h. Within 117 patients who gave a clear-cut history of anaphylactoid reactions to mild analgesics, there were conclusive immediate prick test results in 15 cases (13%). In these patients, the diagnostic relevance of the prick test increased with the severity of symptoms in the history, and a conclusive immediate reaction was obtained in 25% of those with full shock in the history.

Adolescent↗
PubMedDate not supplied

Human basophil degranulation test in drug allergy.

We have evaluated the usefulness of HBDT as an in vitro method for the diagnosis of drug allergy. Two hundred and thirty six patients with suspected drug sensitization to penicillin, streptomycin, sulfamides, pyrazolones and A.S.A. were analyzed. Seventy-nine of them were allergic; in 43 cases it was confirmed by in vivo methods. Other patients were diagnosed by clinical history only if they had more than two reactions to the same drug. In order to be included in this group patients with reactions to pyrazolones and A.S.A. had to have tolerated other NSAI, therefore these patients were allergic to one compound only. All patients were considered non-allergic were determined by a negative provocation test. In the group of allergic patients we obtained 63 (79%) positive degranulations and 16 (21%) negative. One hundred and thirty two (84%) negative degranulations and 25 (16%) positive were obtained in the group of non-allergic patients. Once having analyzed 10 statistical parameters with each drug, the HBOT appears to be a useful method for these drugs except for streptomycin. In 16 (80%) out of 20 aspirin sensitive asthmatic patients we found that their basophils were degranulated. In 7 patients with urticaria and/or angioedema by A.S.A. and other NSAI the degranulation was negative, confirming the absence of the involvement of basophils in this reactions.

Anti-Inflammatory Agents↗
PubMed1995

International renal-cell cancer study. II. Analgesics.

There has been concern about the role of analgesics in the development of renal-cell cancer, although a few studies have reported moderately elevated risks with regular or long-term use. In a large international case-control study of renal-cell cancer we examined, among other hypotheses, the effect of phenacetin-containing and of other types of analgesics: paracetamol (acetaminophen), salicylates (mainly aspirin) and pyrazolones (e.g., antipyrine or phenazone). Relative risks, adjusted for the effects of age, sex, body-mass index, tobacco smoking and study centre, were not significantly increased with intake of phenacetin, either when lifetime consumption was categorized at the level of > or = 0.1 kg or when subjects were subdivided further by amount. Nor were paracetamol, salicylates or pyrazolones linked with renal-cell cancer. No consistently increasing risks with consumption level was found. The lack of association was not altered by restricting analgesic use to that which occurred 5 or 10 years before the defined "cut-off" date or when analysis was restricted to exclusive users of a particular type of analgesic. Neither was the risk influenced by the rate of consumption or whether the consumption had occurred at a young age. Our study provides clear evidence that aspirin is unrelated to renal-cell cancer risk, and our findings do not support the hypothesis that analgesics containing phenacetin or paracetamol increase the risk, although the number of "regular" users and the amount of these types of analgesic consumed were too small to confidently rule out a minor carcinogenic effect of phenacetin and paracetamol.

Acetaminophen↗
PubMedDate not supplied

Aspirin, paracetamol and non-steroidal anti-inflammatory drugs. A comparative review of side effects.

Non-steroidal anti-inflammatory drugs (NSAIDs) effectively control the symptoms of many of the rheumatic diseases although they have little effect on the underlying causes. Their effect is mainly on the mediators of the inflammatory process. Unfortunately, these mediators have important physiological roles in the maintenance of health, particularly in the gastrointestinal tract and the kidney, so that their inhibition results in many unwanted reactions of varying severity. The mechanisms underlying these reactions are described. Their occurrence varies, both qualitatively and quantitatively, and an attempt is made to assess these differences, although it may be that they are related directly to differences in dosage and therapeutic efficacy. In addition, immunologically mediated adverse reactions occur. These mechanisms are outlined and related to the clinical picture. There are considerable differences in frequency of reactions between the compounds: in particular there is a wide variation in the rate of dermatological reactions of this type. Agranulocytosis has been particularly associated with the pyrazolone compounds, although it has been reported with most others. Aplastic anaemia, which may not be an immune-mediated reaction, is also thought of as a pyrazolone reaction, but the incidence with indomethacin approaches a similar level. Although all drugs analysed may cause hepatic reactions, these are rare except with the now withdrawn benoxaprofen. Several types of immunologically mediated renal reactions occur and these rarities are also described. Paracetamol does not have any effect on the inflammatory mediators. Anxieties about this substance relates to the parent compound phenacetin and its necrotic effect on the renal papillae. There is extensive literature on this subject concerning not only paracetamol, but also aspirin and other NSAIDs. This is also assessed and summarised. The danger of paracetamol as a direct hepatic toxin in self-poisoning is discussed. Novel NSAIDs are introduced and others withdrawn with frequent and monotonous regularity. Sometimes the reasons have some medical or scientific plausibility, but often they are over-reactions by registration authorities or pharmaceutical companies in response to uninformed media publicity. The problems of the numerically and scientifically accurate collection and assessment of adverse reaction data are legion and as a result useful agents have been lost. Some of these difficulties are described, and some non-drug 'adverse reactions' are described.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetaminophen↗
PubMed1985

Metabolism of the amino acid beta-pyrazol-1-ylalanine and its parent base pyrazole.

beta-Pyrazol-1-yl-DL-alanine, an uncommon amino acid from plants of the Cucurbitaceae, was fed to mice. Although pyrazole is known to affect the liver enzymes UDP-glucose dehydrogenase, UDP-glucuronyl transferase and UDP-glucuronic acid pyrophosphatase, and also depresses their liver glycogen concentrations, beta-pyrazol-1-ylalanine had no such effects. beta-Pyrazol-1-ylalanine could not be detected in the liver of the experimental animals but was present in the urine. No other change in urinary amino acid content was observed. Studies with [14C]-beta-pyrazol-1-yl-DL-alanine showed the administered amino acid was excreted over a 4-day period, 93% of the compound supplied was recovered. Similar recoveries were obtained with the L-enantiomer from cucumber seed. The metabolic inertness of beta-pyrazol-1-ylalanine was also apparent in experiments involving subcutaneous injection of this compound. Administration of pyrazole confirmed an earlier report of resultant increased activity of liver UDP-glucose dehydrogenase and UDP-glucuronyl transferase, and of the depression of activity of liver UDP-glucuronic acid pyrophosphatase. A concomitant 40% decrease in liver glycogen content was seen. The urine contained a novel metabolite, identified as a peptide conjugate of a pyrazole derivative. Mass spectrometry and p.m.r. spectroscopy indicate that this derivative is 3,4,4-trimethyl-5-pyrazolone. The amino acid constituents are aspartic acid, threonine, serine, glutamic acid, proline, glycine, alanine, valine and leucine. The urine of mice receiving pyrazole contained less free glycine and alanine than controls. From the results, it is concluded that pyrazole is not a catabolite of dietary beta-pyrazol-1-ylalanine but to the contrary, the amino acid is essentially excreted unchanged. Formation of 3,4,4-trimethyl-5-pyrazolone from pyrazole would imply C-methylation, a process that has not been previously observed in a mammalian detoxication context.

Amino Acids↗
PubMed1993

Determination of combined benzidine in FD & C yellow no. 5 (tartrazine), using a highly sensitive analytical method.

53 samples of FD & C Yellow No. 5 (tartrazine; Colour Index No. 19140) were examined for combined benzidine. These samples, which represent separate lots from 12 dye distributors, were submitted to the US FDA for certification between 28 February 1990 and 27 June 1991. A method was developed to reduce the dye matrix with dithionite so that combined benzidine present in the form of azo or disazo dyes would be converted to free benzidine. Reduction was followed by extraction, diazotization and coupling with pyrazolone T, and the total benzidine present was quantitated as benzidine-pyrazolone T disazo dye (BZPT) by HPLC with detection at 500 nm. The limit of quantitation for benzidine in FD & C Yellow No. 5 by this method is 5 ng/g. 25 samples of FD & C Yellow No. 5 were found to contain 7-83 ng/g of combined benzidine that was released by dithionite reduction. 23 of these samples were from the same manufacturer. The identify of the BZPT from two FD & C Yellow No. 5 samples was confirmed by spectral analysis using HPLC with a photodiode array detector.

Benzidines↗
PubMed1988

Depression by morphine and the non-opioid analgesic agents, metamizol (dipyrone), lysine acetylsalicylate, and paracetamol, of activity in rat thalamus neurones evoked by electrical stimulation of nociceptive afferents.

Pyrazolone and salicylic acid derivatives and the aniline derivative, paracetamol, are often classified as peripherally acting analgesic agents, while morphine is a centrally acting analgesic agent. Since indications exist that the non-opioid analgesic agents can also produce central effects, experiments were carried out on rats under urethane anaesthesia in which activity was recorded from single neurones in the dorsomedial part of the ventral nucleus (VDM) of the thalamus that was elicited by supramaximal electrical stimulation of nociceptive afferents in the sural nerve. In addition, activity was recorded in ascending axons of the spinal cord which was evoked by electrical stimulation of nociceptive afferents in the sural nerve. The substances studied were morphine, the pyrazolone derivatives, metamizol (dipyrone) and aminophenazone ('Pyramidon'), lysine acetylsalicylate, and paracetamol. All drugs were found to depress dose-dependently evoked activity in VDM neurones after intravenous (i.v.) injection. The ED50 of morphine in depressing evoked activity in VDM neurones is 0.05 mg/kg. Morphine also dose-dependently reduced activity in ascending axons of the spinal cord, the ED50 being 1.7 mg/kg. The ED50 of metamizol in depressing evoked activity in VDM neurones is 120 mg/kg, and that of aminophenazone is 22.7 mg/kg. The 2 ED50 values differ significantly. It has been found previously that metamizol increased nociceptive activity in some ascending axons and aminophenazone increased this activity in all ascending axons tested. The ED50 of lysine acetylsalicylate in depressing evoked activity in VDM neurones is 74 mg/kg. The drug did not reduce nociceptive activity in ascending axons of the spinal cord. The ED50 of paracetamol in depressing evoked activity in VDM neurones is 19.0 mg/kg. Paracetamol did not depress nociceptive activity in ascending axons of the spinal cord at a dose as high as 150 mg/kg administered by intraperitoneal injection. Naloxone (0.2 mg/kg i.v.) abolished the depressant effects of morphine but failed to reduce those of the non-opioid analgesic agents even at a high dose (1 mg/kg i.v.). Unlike morphine, the non-opioid analgesic agents did not completely block evoked activity in VDM neurones but only partially blocked their activation. The results suggest that the non-opioid analgesic agents tested can produce a central analgesic effect which, however, is weaker than that of morphine.

Acetaminophen↗
PubMed1984

Some new urinary metabolites of famprofazone and morazone in man.

The human urinary metabolism of two pyrazolone derivatives, morazone and famprofazone, has been investigated. After administration of morazone, the metabolites p-hydroxymorazone and phenazone-4-carboxylic acid were excreted in addition to the known metabolite, phenmetrazine, and unchanged morazone. Metabolism of famprofazone led to the formation of methamphetamine; the pyrazolone moiety was excreted as 3-hydroxymethyl-propyphenazone.

Journal Article↗
PubMed2004

Detection and identification of phenazone-type drugs and their microbial metabolites in ground and drinking water applying solid-phase extraction and gas chromatography with mass spectrometric detection.

A new analytical method applying in situ derivatization was developed to enable the extraction of polar drug metabolites from water samples by solid-phase extraction (SPE). An additional derivatization by silylation was used to enhance the sensitivity of analyte detection by gas chromatography-mass spectrometry (GC-MS). Thus, the two metabolites 1,5-di-methyl-1,2-dehydro-3-pyrazolone (DP) and 4-(2-methylethyl)-1,5-dimethyl-1,2-dehydro-3-pyrazolone (PDP), postulated for the degradation of phenazone and propyphenazone, were identified and detected up to the microg/L level in raw and drinking water samples from public water supply.

Acetylation↗
PubMed2000

Heterocyclic derivatives of sugars: the formation of 1-glycosyl-3-methylpyrazol-5-ones from hydrazones.

Conditions to effect the conversion of monosaccharide and disaccharide hydrazones to 1-glycosyl-3-methylpyrazol-5-ones were examined. The sugar pyrazolone derivatives were sensitive to oxidation, but high yields were achieved with 2,2,2-trifluoroethyl acetoacetate in mildly acidic solution. Azo coupling of the pyrazolones produced highly coloured azopyrazolone derivatives that prevented further degradation, and these may prove useful labels for chromatographic analysis of carbohydrates.

Acetoacetates↗
PubMed2001

Quantitative analysis of analgoantipyretics in dosage form using planar chromatography.

In the therapy of pain of weaker genesis, frequently used drugs usually represent a mix of analgoantipyretics of different chemical structures, mostly derivatives of salicylic acid, pyrazolone and p-aminophenol as well as derivatives of propionic and acetylsalicylic acid. For the determination of these drugs, different chromatographic methods have been applied, mostly HPLC, due to the the lower polarity (pyrazolones derivatives) and thermolability, as well as nonvolatility of compounds investigated. TLC method, considering advantages which include simplicity, reasonable sensitivity, rapidity, excellent resolving power and low cost has been successfully explored for the determination of analgoantipyretic compounds. The aim of this work was to develop a simple and rapid HPTLC method for the determination of acetylsalicylic acid, paracetamol, caffeine and phenobarbitone in dosage form. The determination of analgoantipyretics were performed on pre-coated HPTLC silica gel plates (10 x 20 cm(2)) by development in the mobile phase dichlormethane-ethyl acetate-cyclohexane-isopropanol-0.1 M HCL-formic acid (9:8:3:1.5:0.2:0.2 v/v/v/v/v/v). Migration distances (68.6+0.2 mm, 54.1+0.1 mm, 36.4+0.14 mm and 85.9+0.11 mm for acetylsalicylic acid, paracetamol, caffeine and phenobarbitone, respectively) with low RSD values (0.13--0.39%) showed a satisfactory reproductivity of the chromatographic system. TLC scanner was used for direct evaluation of the chromatograms in the reflectance/absorbance mode. Established calibration curves (r>0.999), precision (0.3--1.02%) and detection limits, as well as recovery values (96.51--98.1%) were validated and found to be satisfactory. The method was found to be reproducible and convenient for the quantitative analysis of compounds investigated in their dosage forms.

Analgesics↗
PubMed1999

Risk factors for acetaminophen and nimesulide intolerance in patients with NSAID-induced skin disorders.

BACKGROUND: Previous studies show skin reactions after exposure to acetaminophen and/or nimesulide to occur in about 10% of patients with a history of urticaria induced by aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). This fact is surprising since cross-reactivity among different NSAIDs should not occur among subjects without a history of chronic urticaria. OBJECTIVE: To detect risk factors for intolerance to alternative drugs such as acetaminophen and nimesulide in different groups of patients with a history of adverse skin reactions (urticaria/angioedema, or anaphylaxis) after the ingestion of aspirin and other NSAIDs. METHODS: Two hundred fifty-six patients with a history of recent pseudoallergic skin reactions caused by NSAIDs underwent elective oral challenges with increasing doses of both acetaminophen and nimesulide. Patients were divided into three groups: A = 69 subjects with chronic urticaria, B = 163 otherwise normal subjects with a history of urticaria after the ingestion of aspirin, and C = 24 otherwise normal subjects with a history of urticaria after the ingestion of pyrazolones but aspirin-tolerant. RESULTS: Forty-eight (19%) patients reacted to acetaminophen and/or nimesulide. Similar numbers of patients with chronic urticaria (23%) and of normal subjects with a history of aspirin-induced urticaria (19%) did not tolerate one of the alternative drugs challenged. Pyrazolones-intolerant patients showed the lowest number of reactors (4%). Aspirin intolerance represented a risk factor for acetaminophen- and/or nimesulide-induced urticaria (RR = 5.4). A history of anaphylactoid reactions induced by NSAID represented a risk factor for urticaria after the ingestion of the alternative study drugs (RR = 5.7). Atopic status was associated with a higher risk of reactivity to nimesulide: this drug induced urticaria in 11/47 (23%) atopics versus 18/209 (9%) non-atopics (P < .005; RR = 3.2). A history of intolerance to antibacterial drugs was not associated with a higher prevalence of reactivity against acetaminophen and/or nimesulide. CONCLUSIONS: In at least 20% of patients with a history of urticaria/angioedema or anaphylaxis induced by aspirin or other NSAIDs, but without a history of chronic urticaria, cross-reactivity with other NSAIDs occurs. Atopy as well as a history of aspirin-induced anapylactoid reactions seem to represent relevant risk factors for intolerance to alternative NSAIDs. In view of these findings, aspirin-intolerant patients with such clinical features should be submitted to peroral tolerance tests with at least two alternative substances in order to avoid potentially severe reactions.

Acetaminophen↗
PubMed2002

First structurally characterized silver(I) derivatives with nonfluorinated beta-diketones.

Synthetic, spectroscopic, and single-crystal X-ray structural studies of diverse complexes of silver(I) acylpyrazolonate salts AgQ(R') (QH = 1-phenyl-3-methyl-4-R'(C=O)-pyrazol-5-one; Q(1), R = Ph; Q(2), R' = CF(3); Q(3), R' = Me) with neutral ligands L = unidentate PR(3) (R = Ph, o-tolyl, cyclohexyl) and Hmimt (1-methyl-2-mercaptoimidazole) and bidentate dppe (Ph(2)P(CH(2))(2)PPh(2)) and trimen (N,N,N'-trimethylethylenediamine) define the donor capability of the anionic Q(R') ligand in a variety of roles. In the free ligand Q(3)H (which crystallizes in the monoclinic space group C2/c (no. 15), Z = 8, unit cell parameters a = 17.981(6) A, b = 5.0641(4) A, c = 24.271(6) A, and beta = 99.67(2)), the acidic OH group hydrogen-bonds intramolecularly to the adjacent pyrazolone oxygen, i.e., the two oxygen atoms are cis, true of the other Q(R') species structurally characterized here in their anionic complexed forms, in which they chelate the silver in the usual beta-diketonate manner, but not of the free anion, found in the array [Ag(Ph(3)P)(Hmimt)(2)](Q(1)) (triclinic space group P(-)1(no. 2), Z = 2, unit cell parameters a = 11.553(1) A, b = 11.943(1) A, c = 15.479(2) A, alpha = 74.829(2), beta = 76.094(2), and gamma = 78.185(2)), or [Ag(trimen)Q(1)] (monoclinic space group P2(1)/c (no. 14), Z = 4, unit cell parameters a = 7.982(1) A, b = 12.299(2) A, c = 21.507(3) A, and beta = 95.119(3)), which forms an infinite one-dimensional polymer string, Q(1) linking successive silver(I) atoms by coordination by way of the unsubstituted nitrogen and the pyrazolonate oxygen. In all [Ag(R(3)P)(2)(chelate-Q(1))] (R = Ph, Cy) complexes, P(2)Ag(O,O') arrays are found (R = Ph, monoclinic space group C2/c (no. 15), Z = 8, unit cell parameters a = 16.193(8) A, b = 13.859(7) A, c = 39.306(7) A, and beta = 100.02(3); R = Cy, triclinic space group P(-)1(no. 2), Z = 2, unit cell parameters a = 10.4655(9) A, b = 12.079(1) A, c = 22.804(2) A, alpha = 104.872(2), beta = 95.180(2), and gamma = 104.144(2)), also true of [Ag(Ph(3)P)(2)(O,O'-Q(2))] (triclinic space group P(-)1(no. 2), Z = 2, unit cell parameters a = 10.672(2) A, b = 10.710(2) A, c = 18.713(3) A, alpha = 87.573(2), beta = 80.972(2), and gamma = 81.734(2)), whereas [Ag(o-tol(3)P)Q(1)] (monoclinic space group P2(1)/c (no. 14), Z = 2 dimers, unit cell parameters a = 11.8221(6) A, b = 13.2601(6) A, c = 20.5141(10) A, and beta = 91.758(1)) exists as a dinuclear species containing two AgO(2)NP units where the acylpyrazolonate is coordinated in a bridging O,O'-Q-Nfashion. Silver atoms are four-coordinate in all except the Hmimt complex.

Journal Article↗
PubMed2002

Metal-induced cyclization of thiosemicarbazones derived from beta-keto amides and beta-keto esters: open-chain and cyclized ligands in zinc(II) complexes.

The reactions of Zn(OAc)(2) with acetoacetanilide, methyl acetoacetate, o-acetoacetanisidide, and ethyl 2-methylacetoacetate thiosemicarbazones (HTSC(1), HTSC(2), HTSC(3), and HTSC(4), respectively) were explored in methanol. With HTSC(1), HTSC(2), and HTSC(3), following isolation of the corresponding zinc(II) thiosemicarbazonates [Zn(TSC(x))(2)] (x = 1, 2, 3), the mother liquors afforded pyrazolonate complexes [ZnL(1)(2)(H(2)O)] (HL(1) = 2,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-carbothioamide) that had been formed by cyclization of the corresponding TSC(-). The reaction of HTSC(4) with zinc(II) acetate gave only the pyrazolonate complex [ZnL(2)(2)(H(2)O)] (HL(2) = 2,5-dihydro-3,4-dimethyl-5-oxo-1H-pyrazole-1-carbothioamide). All compounds were studied by IR and NMR spectroscopy, and HTSC(3), [Zn(TSC(3))(2)] x DMSO, [ZnL(1)(2)(H(2)O)] x 2DMSO, and [ZnL(2)(2)(H(2)O)] x 2DMSO were also studied by X-ray diffractometry, giving a thorough picture of the cyclization process. In preliminary tests of the effects of HL(1) and [ZnL(1)(2)(H(2)O)] on rat paw inflammatory edema induced by carrageenan, HL(1) showed antiinflammatory activity.

Amides↗
PubMed2003

Rhenium(I)-induced cyclization of thiosemicarbazones derived from beta-keto esters.

The reactions of methylacetoacetate and ethyl 2-methylacetoacetate thiosemicarbazones (H(2)L(A) and H(2)L(B), respectively) with [ReX(CO)(5)] and [ReX(CO)(3)(CH(3)CN)(2)] (X = Cl, Br) were explored under various experimental conditions. Besides the adducts fac-[ReX(CO)(3)(H(2)L)], in which the rhenium is coordinated to three carbonyl groups, the X anion, and the N,S-bidentate thiosemicarbazone ligand, the following complexes were also isolated: fac-[ReBr(CO)(3)(Hpyz(B))], the tetrameric complexes fac-[Re(pyz(A))(CO)(3)](4) and fac-[Re(pyz(B))(CO)(3)](4), and fac-[Re(pyz(B))(CO)(3)(H(2)O)] (where Hpyz(A) and Hpyz(B) are pyrazolones derived by cyclization of H(2)L(A) and H(2)L(B), respectively). The cyclization reactions were monitored by (1)H NMR spectroscopy and the complexes isolated were identified by elemental analysis, mass spectrometry, IR and (1)H NMR spectroscopy, and in some cases by X-ray diffractometry. The isolation and the full structural identification of the rather unusual fac-[ReBr(CO)(3)(Hpyz(B))], which contains the enol form of the pyrazolone ligand, affords new insight into the cyclization of thiosemicarbazones derived from beta-keto esters.

Journal Article↗
PubMed1999

Urothelial cancer at different tumour sites: role of smoking and habitual intake of analgesics and laxatives. Results of the Berlin Urothelial Cancer Study.

BACKGROUND: In Germany about 20000 new cases of urothelial cancer (UC) and about 7500 deaths from bladder cancer alone occur each year. Among the manifold risk factors, little research has been done on the role of smoking and the habitual intake of analgesics and laxatives-practices that are common in parts of the German population. The aim of this study is to define the proportion of risk derived from these preventable habits for the development of UC at its different sites. Subjects and methods. A case-control study in the area of the former West Berlin was performed from 1990 to 1995 including all newly diagnosed incident cases of UC from the eight hospitals of the study area. Study subjects and population-based controls individually matched by age (+/-2 years) and sex were evaluated by a standardized face-to-face interview about the lifelong exposure to cigarette smoking, analgesics, and laxatives. Adjusted risk analysis was carried out for the main exposure variables in relation to the different sites of UC in the bladder, ureter, and renal pelvis. RESULTS: Six hundred and forty-seven cases of UC (571 bladder, 25 ureter, and 51 renal pelvis) and an identical number of controls were included in the analysis (response rate in cases, 84.6%; in controls, 70.2%). Smoking increased the risk of bladder cancer (BC) by an odds ratio (OR) of 3.22 (95% confidence interval (CI) 2.29-4.52), that of ureter (URC) or renal pelvis cancer (RPC) together by OR 6.20 (95% CI 2.04-18.81), and that of RPC alone by OR 5.91 (95% CI 1.47-23.66). Ex-smoking was associated with an increased risk for BC (OR 1.55, 95% CI 1.10-2.19). Intake of more than 1 kg of phenacetin in analgesic mixtures was associated with an OR of 5.28 for RPC (intake of > or = 1 kg paracetamol, OR 3.27; > or = 1 kg pyrazolones, 1.12) and 0.75 for BC (not significant). Laxatives significantly increased the risk of BC (OR 2.14, 95% CI 1.26-3.63) and RPC/URC (OR 9.62, 95% CI 1. 01-91.24) in both sexes. CONCLUSION: Habitual risks from smoking and intake of laxatives significantly contribute to the development of UC, especially of the renal pelvis and ureter cancer. Intake of at least 1 kg of analgesic substances (anilides, pyrazolones) as calculated from this study base is associated with increased but not significant risks for RPC. These data underline that restrictive and educational measurements focusing on common habits would have a strong impact on preventing UC in Germany.

Aged↗