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Enterobius vermicularis infection in a children's ward.

Following the discovery that two patients on a children's orthopaedic ward were excreting Enterobius, all patients and staff on the ward were screened for the presence of pinworms. None of the staff was infected but 11 (55%) of 20 patients either had Enterobius ova on the anal margin or excreted worms following piperazine treatment. Epidemiological investigations indicated that this was unlikely to be a ward outbreak because four of the infected children had been on the ward for under 3 days, i.e., less than the prepatent period for Enterobius. Although none of the children was symptomatic, all children and staff on the ward were treated with piperazine. Faecal samples were collected from nine children and the majority of their worm load was shed within 32 h of starting therapy. Microscopic examination of the adult male worms showed that each patient was excreting both Enterobius vermicularis and E. gregorii.

Animals↗

Phenothiazine in the origin of benzimidazole resistance in population-B equine strongyles.

Clinical trials on a central Kentucky Thoroughbred Farm (B) during 1960-1961 involved nine test treatments of mares, yearlings and weanlings (n = 124), and compared efficacies of phenothiazine (PTZ), piperazine (PPZ), mixtures of PTZ + PPZ and thiabendazole (TBZ) for (1) percent reduction and (2) complete clearance or graded reduction of strongyle egg per gram (epg) counts. Three grades of PTZ (N.F. green, micronized purified and 2-3 microns purified) at the dose rate of 55 mg kg-1 were ineffective in six tests; reduction of strongyle epg count were low grade (26%) and complete clearance was found in only 1 of 32 horses. Piperazine alone at 88 mg base kg-1 was efficacious in two tests; epg counts were effectively reduced (98%), but complete clearance was found in only 2 of 10 horses. Several mixtures of PTZ + PPZ with various dosages of PTZ (27.5-55 mg kg-1) plus PPZ base (88 mg kg-1) were quite effective in six tests, as epg counts were reduced by 96% and complete clearance occurred in 25 of 38 horses. Four trials with TBZ at dose rates between 13 and 44 mg kg-1 in 1961 reduced epg counts by 98%, but cleared only 15 of 36 horses. These data indicated: (1) a large segment of the Farm B small strongyle population was resistant to PTZ at the outset of these observations in 1960; (2) TBZ-resistant individuals were also present in this population when TBZ was first used in 1961. During the ensuing 4-year study (1962-1965) on Farm B mares (n = 15 per year) and yearlings (n = 15-17 per year), biweekly epg and larvae per gram (lpg) counts were carried out to compare the efficacy of three treatment programs: (1) monthly doses of TBZ at 26 mg kg-1; (2) monthly doses of TBZ at 13 mg kg-1; (3) bimonthly doses of a mixture of PTZ + PPZ and carbon disulfide (CS2) at dose rates of 27.5 + 88 and 78 mg kg-1, respectively, or a mixture of PTZ + PPZ + trichlorfon (TCF) at dose rates of 27.5 + 88 + 40 mg kg-1, respectively. Emergence of a TBZ-resistant segment of the small strongyle infections was evaluated by three criteria: (1) annual mean strongyle epg counts; (2) efficacy of individual treatments for epg reductions (%); (3) complete clearance or graded reductions of strongyle epg counts.4+ PTZ-resistant small strongyles. Initial use of TBZ in 1961 produced effective epg reductions, but complete clearance data revealed the presence of TBZ-resistant small strongyles at the outset...

Animals↗

Novel fluoroquinolones: design, synthesis, and in vivo activity in mice against Mycobacterium tuberculosis H37Rv.

Novel 6,8-difluoro-1-alkyl-5-amino-1,4-dihydro-4-oxo-7-{4-substituted piperazin-1-yl}-quinoline-3-carboxylic acids, with the substituents at 4th position of piperazine being -[2(pyridine-4-carbonyl) hydrazono]propyl and -2 [(pyrazine-2-carbonyl) amino] ethyl, were synthesized and evaluated in vivo against Mycobacterium tuberculosis H(37)Rv in Swiss albino mice. Test compounds exhibited activity comparable to that of sparfloxacin (survival rate, reduction of splenomegaly and reduced tubercular lesions) at a dose of 200 mg/kg.

Animals↗

A method for recording the effects of anthelmintics on the movements of Ascaris lumbricoides.

Adult roundworms (Ascaris lumbricoides) obtained from pigs were suspended in modified Tyrode solution at 37 degrees in fine nylon stockings, and the movements of the stockings were recorded. This method of suspension avoided damage to the cuticle or occlusion of the alimentary tract of the worm.Piperazine salts caused gradual narcosis, the time of onset of which was related linearly to the logarithm of the concentration of drug in the bath. The method is suitable for the assay of preparations of piperazine. Tetrachlorethylene, hexylresorcinol, and oil of chenopodium all caused stimulation of movement before the worm was immobilized. Santonin caused incoordination of the movements of the anterior end of the worm; the movements of the body were apparently unaffected. Piperazine is the safest preparation available for the treatment of ascariasis.

Animals↗

Unusual cerebellar ataxia: "worm wobble" revisited.

We present an unusual case of cerebellar ataxia in a 2 year old girl several days after treatment with piperazine citrate for suspected worm infestation. This is the first reported case of delayed onset neurotoxicity following the therapeutic administration of piperazine in a previously well child.

Antinematodal Agents↗

Effect of heterocyclic based organoclays on the properties of polyimide-clay nanocomposites.

Polyimide-clay nanocomposites were prepared from their precursor, namely, polyamic acid, by the solution-casting method. Organomodified montmorillonite (MMT) clay was prepared by treating Na+MMT (Kunipia F) with three different intercalating agents, namely, piperazine dihydrochloride, 1,3-bis(4-piperidinylpropane) dihydrochloride and 4,4'-bipiperidine dihydrochloride at 80 degrees C. Polyamic acid solutions containing various weight percentages of organomodified MMT were prepared by reacting 4,4'-(1,1'-biphenyl-4,4'-diyldioxy)dianiline with bicyclo[2.2.2]oct-7-ene-2,3,5,6-tetracarboxylic dianhydride in N-methyl-2-pyrrolidinone containing dispersed particles of organomodified MMT at 20 degrees C. Nanocomposite films were prepared from these solutions by solution casting and heated subsequently at a programmed heating rate. These films were transparent and brown in color. The extent of layer separation in nanocomposite films depends upon the chemical structure of the organoclay. These films were characterized by inherent viscosity, FT-IR, DSC, TMA, WAXD, TEM, UV, and TGA. The tensile behavior and surface energy studies were also investigated. The nanocomposite films had superior tensile properties, thermal behavior, and solvent resistance. Among the three organoclays, piperazine dihydrochloride was the best modifier.

Aluminum Silicates↗

Effect of selected anthelmintics on three common helminths in the brown pelican (Pelecanus occidentalis).

The effect of selected anthelmintics (albendazole, fenbendazole, piperazine dihydrochloride and clorsulon) against three major helminths (Contracaecum multipapillatum, Mesostephanus appendiculatoides, and Phagicola longus) were studied in 29 brown pelicans (Pelecanus occidentalis). Albendazole and fenbendazole were highly effective against all three parasites. Clorsulon had moderate effect against M. appendiculatoides and poor effect against C. multipapillatum and P. longus. Piperazine dihydrochloride had no effect against these helminths.

Albendazole↗

A possible role of the redox interactions in the dual, activatory and inhibitory, action of DPI 201-106 on the potential-dependent Na+ channels.

Dual, activatory and inhibitory, effects of a cardiotonic drug DPI 201-106 on Na+ channels were compared with the redox properties of the DPI itself and of the constituents of its molecule, indole and piperazine. The indole component accepted electrons from radical intermediates of the light excited dye; the piperazine part of DPI acted as an electron donor in the same radical reactions. These data extend the previously obtained results which characterized organic blockers of Na+ and Ca2+ channels as electron donors, whereas activators of these channels were shown to be electron acceptors in test radical reactions. The whole DPI 201-106 molecule revealed both the electron-donor and electron-acceptor activity. The described electrophysiological effects of this compound (G. Wang et al., 1989) are discussed within the framework of the Na+ channel redox model (B. Marinov, 1991).

Allosteric Regulation↗

Investigating the reaction of a novel silica capillary coating compound with proteins/peptides by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry.

Quaternized piperazine ((N-methyl-N-omega-iodobutyl-N'-methyl)piperazine; QPzl) is a novel compound described as an ideal coating material for the silica capillaries that are commonly used for capillary zone electrophoresis. In the course of such analysis, contact between such coatings and biomolecules may result in certain modifications of the latter. To gain specific information on such potential modifications, solutions at pH 10.0 containing both QPzl and standard proteins/peptides were incubated for various periods and examined by matrix-assisted laser desorption/ionisation mass spectrometry. The reduction of the S-S bridges, denaturation in 8 M urea, the isoelectric point of the protein and the duration of the incubation had a profound influence on the investigated reaction. Analysis in reflectron mode and post source decay identified Cys as the likely site of interaction. The implications of the present measurements for proteome analysis using capillary and gel electrophoresis are discussed.

Animals↗

Synthesis and antibacterial activity of new 7-piperazinyl-quinolones containing a functionalized 2-(furan-3-yl)ethyl moiety.

A number of 7-piperazinylquinolones carrying a functionalized 2-(furan-3-yl)ethyl moiety attached to the piperazine ring have been synthesized and evaluated as antibacterial agents against a panel of Gram-positive and Gram-negative bacteria. Most of the synthesized compounds exhibited significant antibacterial activity, and this activity can be modulated through the nature of the functionality on ethyl spacer attached to piperazine ring and the type of side chain present at the N-1 position of quinolone ring.

Anti-Bacterial Agents↗

CB694, a novel antimitotic with antitumor activities.

During the course of a mechanism-based screening program aimed at identifying new antimitotic agents, a novel microtubule depolymerizing piperazine derivative, 1-(5-chloro-2-methoxybenzoyl)-4-(3-chlorophenyl) piperazine, was identified. The compound, designated CB694, caused inhibition of proliferation of a wide range of cancer cell lines, with an average IC50 of 85 nM. A multidrug-resistant cell line was sensitive to inhibition by CB694, suggesting that this compound is a poor substrate for transport by P-glycoprotein. CB694 caused formation of abnormal mitotic structures in HeLa cells. Specifically, CB694 caused a concentration-dependent increase in bipolar spindles with lagging chromosomes and, with slightly higher concentrations, formation of multipolar mitotic spindles. These mitotic abnormalities occurred at concentrations that did not cause significant changes in the appearance or quantity of interphase microtubules. Coincident with the formation of abnormal mitotic spindles, CB694 caused G2/M arrest. CB694 inhibited the assembly of purified tubulin with an IC50 of 2.3 microM. Colchicine binding was strongly inhibited by CB694, suggesting that it binds to tubulin at the colchicine site. Bcl-2 phosphorylation and activation of ERK and JNK and caspase 3-dependent cleavage of PARP were observed in MDA-MB-435 cells treated with CB694. CB694 caused phosphorylation of Aurora A within 8 hr of treatment, and increases in Aurora A protein levels were coincident with mitotic accumulation. The efficacy of CB694 against a syngeneic murine transplantable solid tumor, Mammary 16/C, was also evaluated. CB694 was well tolerated and showed antitumor activity.

Animals↗

The characterization of the metabolites of ranolazine in man by liquid chromatography mass spectrometry.

The metabolism of ranolazine (RS-43285) or (+)N-(2,6-dimethylphenyl)-4[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1- piperazine acetamide dihydrochloride was investigated in man using plasma samples obtained from four different clinical studies. The metabolite profiles following single and multiple doses of 342 mg instant release (IR) ranolazine, following multiple doses of 1000 mg sustained release (SR) ranolazine and following dosing with both ranolazine (IR) and a potentially co-administered drug, diltiazem, were compared. Metabolism of ranolazine in man was shown by LC/MS analysis to be extensive with up to seven primary routes of metabolism identified. N-dealkylation by hydrolysis at the piperazine ring produced three metabolites whilst O-demethylation and O-dearylation at the methoxyphenoxy moiety produced a further two compounds. Additionally, hydrolysis of the amide group formed one other species. Oxygenation at various points in the molecule produced a further four metabolites. Direct conjugation of ranolazine with glucuronic acid and with an uncharacterized adduct were also identified as a route of elimination. Ten other biotransformation products were formed as a result of multiple metabolic steps. Conjugation was also associated with the desmethyl metabolite (glucuronide and unidentified conjugates) of hydroxylated ranolazine. In a previous publication (Journal of Chromatography, 1995, accepted for publication) semi-quantitative analyses of pooled plasma from the study where ranolazine was dosed at 1000 mg twice daily showed that of the twelve metabolites studied only four accounted for AUC's in excess of 10% of the ranolazine AUC.

Acetanilides↗

Effects of tryptophan and of 5-hydroxytryptamine receptor subtype agonists on feeding.

Feeding or food withdrawal can affect the supply of tryptophan to the brain and hence (in some circumstances) 5-HT synthesis therein. Also fenfluramine which releases 5-HT to postsynaptic receptors suppresses appetite and there are reports that tryptophan can have a similar effect. Furthermore, feeding is reported to release hypothalamic 5-HT. Therefore 5-HT could have a role in the normal termination of feeding and perhaps also in disorders of appetite. The recognition of various 5-HT receptor subtypes has stimulated research in this area. We have now investigated the involvement of the subtypes in the pharmacological control of feeding. Thus, 5-HT1A agonists (8-OH-DPAT, buspirone, gepirone etc.) stimulate intake in freely feeding rats, probably by activating autoreceptors on the cell bodies of 5-HT neurons so that 5-HT release at terminals is decreased. The hyperphagia is not explicable by increased activity or gnawing and is strikingly manifest against carbohydrate in carbohydrate vs. protein choice experiments. Feeding in previously food deprived rats is decreased by the 5-HT agonists RU 24969, 1-(3-chlorophenyl)piperazine (mCPP) and 1-[3-(trifluoromethyl) phenyl]piperazine (TFMPP). Effects of antagonists suggest that RU 24969-induced hypophagia depends on 5-HT1B receptors only while mCPP and TFMPP induce hypophagia at 5-HT1C sites, though this effect also requires 5-HT1B receptors for its expression. Responsible sites occur in the paraventricular nucleus of the hypothalamus as infusing either RU 24969 or TFMPP therein causes hypophagia. On systemic injection, the hypophagic drugs are particularly active in female rats, an effect of conceivable relevance to human anorexic illness.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

BIMT 17, a 5-HT1A receptor agonist/5-HT2A receptor antagonist, directly activates postsynaptic 5-HT inhibitory responses in the rat cerebral cortex.

BIMT 17 (1-[2-[4-(3-trifluoromethyl phenyl) piperazin-1-yl] ethyl] benzimidazol- [1H]-2-one), a 5-HT1A receptor agonist/5-HT2A receptor antagonist (see Borsini et al., accompanying paper), in a dose range of 1-10 mg/kg i.v., dose-dependently inhibited the electrical activity of rat medial prefronto-cortical neurons, whereas buspirone, in a dose range of 0.1-1000 micrograms/kg, increased it. 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and 1-[2-(2-thenoylamino)ethyl]-4-[1-(7-methoxynaphthyl)] piperazine (S 14671) presented biphasic patterns of response; they increased electrical activity at doses in the range of 0.1-10 micrograms/kg and 0.1-3 micrograms/kg i.v. respectively, and reduced it at high doses, 30-300 micrograms/kg and 10-30 micrograms/kg i.v., respectively. The inhibitory effect of BIMT 17 on the firing rate of neurons in the frontal cortex was antagonized by the 5-HT1A antagonists tertatolol and WAY 100135, and was still present after destruction of serotonin (5-HT) containing neuronal endings by the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT; 150 micrograms/rat, given intraventricularly), which reduced the cortical 5-HT content by 85%. This destruction of 5-HT neurons, while suppressing the ability of 8-OH-DPAT to inhibit the firing rate at high doses, did not change the excitatory action of this compound at low doses. The addition of ritanserin, a 5-HT2A receptor antagonist, potentiated both the excitatory and inhibitory effects of 8-OH-DPAT on neuronal electrical activity. Direct microiontophoretic application (100 nA/20 s) of 5-HT and BIMT 17, but not that of 8-OH-DPAT, onto medial prefronto-cortical neurons, decreased the firing rate of these neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗

Role of nitric oxide in penile erection and yawning induced by 5-HT1c receptor agonists in male rats.

The effect of the intracerebroventricular (i.c.v.) administration of NG-nitro-L-arginine methyl ester and NG-monomethyl-L-arginine, two inhibitors of nitric oxide (NO) synthase, on penile erection and yawning induced by 1-(3-chlorophenyl)-piperazine (m-CPP)- and N-(3-trifluoromethylphenyl)-piperazine (TFMPP), two selective 5HT1c receptor agonists, was studied in male rats. Both NO synthase inhibitors (50-500 micrograms i.c.v.) prevented dose-dependently the behavioural responses induced by m-CPP (0.5 mg/kg s.c.) or by TFMPP (1 mg/kg s.c.), but NG-nitro-L-arginine methyl ester was about 4-5 times more potent than NG-monomethyl-L-arginine. The D-isomer of NG-monomethyl-L-arginine, which does not inhibit nitric oxide synthase, was ineffective. The inhibitory effect of NG-nitro-L-arginine methyl ester on m-CPP- and TFMPP-induced responses was prevented by the administration of L-arginine (1 mg i.c.v.). In contrast, NG-nitro-L-arginine methyl ester (20 micrograms) was ineffective when injected in the paraventricular nucleus of the hypothalamus, a brain area that plays a key role in the expression of these behavioural responses. m-CPP- and TFMPP-induced penile erection and yawning was prevented also by the i.c.v. administration of LY 83583 (50-200 micrograms) or methylene blue (50-400 micrograms), two inhibitors of guanylate cyclase but not by reduced hemoglobin (50-400 micrograms), a NO scavenger. The results suggest that central nitric oxide is involved in the expression of penile erection and yawning induced by 5-HT1c receptor agonists.

Amino Acid Oxidoreductases↗

Selective reduction by serotonergic agents of hypertonic saline consumption in rats: evidence for possible 5-HT1C receptor mediation.

Previously, it has been shown that, in small doses, putative 5-HT1A receptor agonists selectively increase ingestion of hypertonic saline without affecting either water or isotonic saline intake. Evidence was obtained in the present series of experiments for selective reduction in hypertonic saline following the administration of a variety of serotonergic directly- and indirectly-acting agonists. Water, isotonic saline (0.9%), or hypertonic saline (1.8%) were made available to separate groups of water-deprived rats. The results indicated some selectivity with the 5-HT-uptake inhibitor and releaser d-fenfluramine and the 5-HT uptake inhibitor fluoxetine, and with the 5-HT agonists mCPP [1-3-chlorophenyl)piperazine] and MK 212 [6-chloro-2-(1-piperazinyl)pyrazine]. In each case, hypertonic intake was significantly suppressed. Distinct from these compounds were TFMPP [1-(3-(trifluoromethyl)phenyl)piperazine], RU 24969 [5-methoxy-3-(1,2,3,6-tetrahydropyridinyl)1H-indole], and quipazine. This second group either reduced fluid intake indiscriminately or reduced water and isotonic saline drinking. Selective reduction in the intake of hypertonic saline did not occur. Finally, peripheral-administration of 5-HT or the 5-HT1B agonist CGS 12066B [7-trifluoromethyl-4(4-methyl-1-piperazinyl-pyrolo) (1,2-a) 1:2 maleate], had no significant effect on fluid intake in any fluid condition. The results are discussed in terms of a possible serotonergic mechanism which may underlie inhibition of hypertonic salt drinking, and which involves mediation through a subtype of the 5-HT1 receptor.

Animals↗

Translocation, distribution and metabolism of triforine in plants.

After short-ter root-treatment of plants with 3H-triforine (labelled in the piperazine ring) or 14C-triforine (labelled in the side chain), the label was translocated primarily to the leaves present at the time of treatment, without any redistribution of the label taking place after termination of the treatment. Autoradiography showed the radioactivity to be very evenly distributed over the leaf blades, without any appreciable accumulation in leaf margins. In infected leaves, however, there was a tendency for increased accumulation at the infection sites. In dilute aqueous solution triforine was decomposed rather rapidly, the chemical half-life being three days only. From these solutions several non-fungitoxic degradtion products have been isolated and their chemical structures determined. In plants, decomposition of triforine was considerably slower than in aqueous solutions, the half-life of the compound varying depending on plant species. In plants, at least four conversion products could be demonstrated, one of which is piperazine. Whether the other three compounds are identical with or structurally related to the breakdown products found in aqueous solution is not yet known. Its low persistence and low animal toxicity suggest that triforine does not offer serious hazards to the environment.

Age Factors↗

An examination of the behavioural specificity of hypophagia induced by 5-HT1B, 5-HT1C and 5-HT2 receptor agonists using the post-prandial satiety sequence in rats.

Previous studies have shown that administration of 5-HT1B, 5-HT1C or 5-HT2 agonists decreases food intake in rats. However, it has not been established whether these drugs induce satiety or decrease feeding by a non-specific mechanism. In the present study the post-prandial satiety sequence was used to characterise the actions of the 5-HT2 receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), the 5-HT1B/5-HT1C receptor agonists, 1-(3-chorophenyl) piperazine (mCPP) and 1-[3-(trifluoromethyl)phenyl] piperazine (TFMPP), and the 5-HT1B agonist, 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)H-indole (RU 24969), on feeding in rats. All four compounds reduced food intake in rats that had been food deprived overnight. The 5-HT1B/5-HT1C agonists, TFMPP (at a dose of 1.0 mg/kg) and mCPP (at a dose of 3.0 mg/kg), appeared to produce satiety as their effects on the satiety sequence were similar to those induced by a food pre-load. In contrast, the 5-HT1B agonist RU 24969 and the 5-HT2 agonist DOI did not produce behavioural profiles that resembled satiety. Thus, RU 24969 elevated active behaviours and did not accelerate resting whereas DOI appeared to induce hypophagia by a non-specific fragmentation of behaviour. The results suggest that simultaneous activation of 5-HT1B and 5-HT1C receptors may be sufficient to elicit behaviourally specific satiety in the rat. In contrast, selective activation of 5-HT2 receptors does not induce satiety but elicits active behaviours and decreases feeding by response competition.

Amphetamines↗