Acute necrotizing ulcerative gingivitis-periodontitis: a literature review.

Acute necrotizing ulcerative gingivitis-periodontitis (ANUG/NUP) is a relatively uncommon periodontal disease characterized by gingival necrosis and ulceration, pain, and bleeding. The purpose of this paper is to provide a review of current knowledge on ANUG/NUP. Current literature on the epidemiology, pathogenesis, immunology, predisposing factors, and treatment of ANUG/NUP is reviewed.

The long duration response to levodopa in Parkinson's disease.

The duration of effect of levodopa has been reported by some authors to be shorter in fluctuating parkinsonian patients with long standing disease than in stable patients. Other authors report no difference in the two groups of patients. We assessed motor fluctuations and response duration in 15 Parkinson's disease patients. Three patterns of response were observed: deterioration within one day on placebo and marked fluctuations on levodopa; deterioration after one day on placebo and moderate fluctuations on levodopa; no deterioration during 3 days of placebo and no fluctuations on levodopa. One patient who did not deteriorate or fluctuate did both when restudied 12 years later. This study confirms that, in addition to the short duration response to a single dose of levodopa, there is a long duration response to levodopa which is lost as the disease progresses. Loss of this long duration response to levodopa may be a key factor in the emergence of fluctuations in Parkinson's disease.

Hepatic glutathione degradation within the sinusoids of guinea pig livers shows a periportal localization of gamma-glutamyl transferase activity.

In utilizing intact perfused guinea pig livers a probable periportal localization of gamma-glutamyl transferase (GGT) activity was apparent. Untreated livers perfused from the portal to hepatic vein had a significantly greater glutathione efflux than the same livers perfused from the hepatic to portal vein. Switching the perfusion direction also saw a significant rise in the cysteinylglycine efflux. It was apparent from the results that the efflux of glutathione degradation products from the guinea pig livers was significantly greater than those of the intact tripeptide. However, with maximal GGT inhibition glutathione accounted for 90% of the glutathione-related thiols exported from the liver with cysteine accounting for the remaining 10%. Therefore, glutathione exported from hepatocytes may act as a means of transporting its constituent amino acids. The periportal localization of GGT activity ensures that the more susceptible perivenous region faces the greatest concentration of glutathione degradation products.

The pharmacokinetics of albumin conjugates of D-penicillamine in rats.

A protein conjugate that forms during the metabolism of D-penicillamine (D-PEN) in rats is electrophoretically indistinguishable from the (D-PEN-albumin) mixed disulfide that forms during the oxidation of D-PEN in plasma in vitro. Both the conjugate formed in vivo and the mixed disulfide synthesized in vitro are eliminated slowly in rats, with half-lives of 5.33 +/- 0.25 days and 3.48 +/- 0.42 days, respectively. These half-lives approximate or exceed the half-lives of radioiodinated plasma protein in the animals. The stability of the D-PEN-albumin conjugate contrasts with the rapid elimination of D-PEN itself and probably explains delayed elimination of D-PEN-containing disulfides in humans. Stable modification of tissue proteins by D-PEN may also be involved in the mode of action of D-PEN in rheumatoid arthritis.

The effect of concurrent aspirin upon plasma concentrations of tenoxicam.

1. The effect of chronic, high-dose aspirin therapy upon the disposition of a single dose and multiple doses of tenoxicam was examined in normal volunteers. 2. Aspirin caused a 24% drop in the t1/2 (P less than 0.005), a 49% rise in the volume of distribution (P less than 0.0003) and a 98% increase in the clearance (P less than 0.0001) of tenoxicam after a single dose of the tenoxicam. 3. Steady-state concentrations of tenoxicam decreased significantly from 10.4 +/- 1.5 to 4.5 +/- 1.6 micrograms ml-1 in the presence of chronic, high-dose aspirin treatment. 4. Tenoxicam percentage free measured in plasma from a normal volunteer was 0.56 +/- 0.05% over the tenoxicam concentration range 1-20 micrograms ml-1 and rose to 1.24 +/- 0.07% in the presence of aspirin 150 micrograms ml-1. 5. The effect of aspirin upon the disposition of tenoxicam was consistent with a competitive protein binding interaction.

Assay for D-penicillamine-protein conjugate in human plasma utilising chemical reduction followed by high-performance liquid chromatography with gold/mercury electrochemical detection.

D-Penicillamine (D-pen), a thiol with antirheumatic activity, forms a mixed disulphide with albumin in vivo. This conjugate is important in the pharmacokinetics and possibly the mode of action of D-pen. An assay was devised for D-pen-albumin disulphide, based on separation from plasma by acid precipitation followed by quantitative reduction with sodium borohydride in an anoxic environment. The liberated D-pen was then assayed by high-performance liquid chromatography with gold/mercury electrochemical detection. The assay was sensitive to 1.2-microM D-pen-albumin disulphide (signal-to-noise ratio greater than 2), absolute recovery was 92.7% and intra-assay coefficient of variation was 4.6% in human plasma. This technique also may be useful for quantitating protein conjugates of other thiols.

Flumazenil in the management of acute drug overdosage with benzodiazepines and other agents.

A double-blind, randomized, placebo-controlled trial was employed to evaluate the place of flumazenil, a benzodiazepine antagonist, in the early management of 60 patients who went to an accident and emergency center with overdosage of sedatives. The level of consciousness was monitored by a modified Glasgow Coma Scale, and the response to the intravenous administration of up to 1 mg flumazenil or placebo was followed for periods between 1 and 24 hours. The increases in the glasgow coma scale at 5 minutes in the flumazenil-treated group were significant in the group as a whole (+4.9; P less than 0.005), in those who had taken benzodiazepines only (+5.3; P = 0.005), and in those with mixed overdosages (+5.6; P less than 0.005). There were no significant changes in the placebo-treated group. Some patients with overdosage with ethanol also responded to flumazenil, but there was no effect in patients with overdosage of barbiturates alone or tricyclic antidepressants. Flumazenil was well tolerated although three patients had mild withdrawal reactions. The need for intensive physiologic support was avoided in several cases, and the differential diagnosis of the unconscious patient was facilitated.

Modulation of dopamine receptors in the Tapes clam by dextroamphetamine and phenylethanolamine.

The mechanism underlying the modulation, by dextroamphetamine and compounds related to phenylethanolamine, of responses to dopamine and serotonin has been studied in the isolated ventricle and aortic bulb of the clam Tapes watlingi. Dextroamphetamine and phenylethanolamine but not cocaine and benztropine have the ability to unmask inhibitory responses to both dopamine and serotonin in the ventricle. Chlordimeform but not clozapine attenuates the inhibitory response to both dextroamphetamine and phenylethanolamine in concentrations which have little or no effect on the inhibitory response to dopamine in the ventricle. Phenylethanolamine, dextroamphetamine, phenylpropylolamine and p-chloro-phenylethanolamine but not octopamine or noradrenaline attenuate the contractile responses to both dopamine and serotonin in preparations of the quiescent aortic bulb. These data show that there are specific receptors for phenylethanolamine in the Tapes heart capable of modulating responses to dopamine and serotonin, and suggests that this biogenic phenethylamine can act as an environmental and physiological factor which may determine how the mollusc heart responds to dopamine.

The concentration in brain of octopamine and tyramine after portal-systemic bypass in rats: neuroamine concentrations determined simultaneously by methane chemical ionization gas chromatography mass spectrometry.

The concentration in brain of both octopamine (OCT) and tyramine (TYR) was significantly increased in rats 8 weeks after portal-systemic bypass. This suggests that the increase in OCT is secondary to increased decarboxylation of tyrosine to TYR. However, the role these neuroamines, particularly OCT, play in the development of hepatic encephalopathy remains controversial.

Stereoselective accumulation of hydroxylated metabolites of amphetamine in rat striatum and hypothalamus.

The stereoselective accumulation of alpha-methyl-p-tyramine (AMPT) and alpha-methyl-p-octopamine (AMPO) in rat striatum and hypothalamus after acute and chronic administration of the (+)- and (-)-isomers of amphetamine (Amphet) and the acute administration of (+)- and (-)-AMPT has been investigated by chemical ionization gas chromatography mass spectrometry (c.i.g.c.m.s.). Two h after the administration of (+)- or (-)-AMPT (5 mg kg-1 i.p.), the concentrations of the isomers in striatal tissue were approximately equal; 18 h later, the concentration of the (+)-isomer was 10 times that of the (-)-isomer. The concentrations of AMPO in the striatum and hypothalamus 20 h after administration of (+)-AMPT were 68 ng g-1 and 484 ng g-1 respectively. After the administration of the (-)-isomer of AMPT, small quantities of AMPO were detected in both brain areas. Twenty h after the last of 7 daily injections of (+)-Amphet (5 mg kg-1, i.p.), the concentration of AMPO in the hypothalamus was 5.4 times the concentration at 20 h after one injection. In the striatum, the corresponding ratio for AMPO was 3.5 and for AMPT was 2.5. These data indicate that, although both isomers of AMPT formed from Amphet administered systemically, cross the blood brain barrier, the (+)-isomers AMPT and AMPO are preferentially stored in striatal and hypothalamic aminergic nerve terminals. The accumulations of AMPT and AMPO in rat striatum and hypothalamus after chronic administration of Amphet demonstrates that these metabolites persist in neuronal storage in these brain areas for days after administration. The half-lives of (+)-AMPT and (+)-AMPO in striatal neuronal storage, calculated from this data, were 1.5 days and 2.5 days, respectively. The corresponding half-life for hypothalamic (+)-AMPO was 7 days. 7. These findings suggest the involvement of accumulated AMPT and AMPO in the development of behavioural augmentation to repeated injections of Amphet (Randrup & Munkvad, 1970).

Effect of chlordimeform and clonidine on the turnover of P-octopamine in rat hypothalamus and striatum.

The effect of the invertebrate octopamine agonists chlordimeform and clonidine on the concentration and turnover of p-octopamine and m- and p-tyramine was determined in rat hypothalamus and striatum. Clonidine (0.25 mg/Kg, s.c.) did not alter the concentration of p-octopamine in the hypothalamus or p-tyramine in the striatum. Administration of chlordimeform (50 mg/Kg, i.p.) resulted in an increase in p- and m-tyramine concentrations in the striatum but not that of p-octopamine in the hypothalamus. This increase in the tyramine isomers is consistent with the ability of chlordimeform and its metabolite, demethylchlordimeform, to inhibit monoamine oxidase (MAO). The concurrent administration of chlordimeform (50 mg/Kg, i.p.) and pargyline (75 mg/Kg, i.p.) produced a significant decrease in the accumulation of octopamine in the hypothalamus but not in the striatum. In contrast, the concurrent administration of clonidine (0.25 mg/Kg, s.c.) and pargyline (75 mg/Kg, i.p.) caused a significant decrease in the accumulation of octopamine in the striatum but not hypothalamus. These results show that the turnover of octopamine in the hypothalamus and striatum is decreased by chlordimeform and clonidine, respectively. Further, clonidine is known to modulate the turnover of amines in mammalian noradrenergic nerve terminals by an action at presynaptic adrenergic receptors. These data suggest that two mechanisms, one involving presynaptic adrenergic receptors in the striatum, and the other involving as yet unidentified receptors in the hypothalamus, modulate the turnover of octopamine in the mammalian brain.

Evidence that alpha-methyl-p-tyramine is implicated in behavioural augmentation to amphetamine.

Behavioural studies showed that administration of alpha-methyl-p-tyramine (AMT; 10 mg/kg i.p.) to rats 24 hr before treatment with d-amphetamine (AMPHET; 4 mg/kg i.p.) resulted in augmentation of AMPHET-induced stereotype activity. Parallel experiments involving electro-chemical estimation of dopamine metabolites in the striatum showed that the decrease in the concentration of homovanillic acid (HVA) produced by AMPHET (4 mg/kg) was enhanced in AMT (10 mg/kg) pretreated animals. These findings suggest that AMT derived from previous doses of AMPHET may play a role in the phenomena of behavioural augmentation observed after chronic administration of AMPHET.

Octopamine receptors in the molluscan aortic bulb: effects of clozapine and chlordimeform.

The presence of specific, stereo-selective octopamine receptors has been demonstrated in the non-spontaneously beating accessory ventricle (aortic bulb) of the clam Tapes watlingi. Analogues of octopamine with a single chloro group in either the para or meta positions of the benzene ring were 10 times less potent than octopamine in their agonist activity. In low concentrations (less than 200 microM), phentolamine, chlordimeform and clozapine were octopamine antagonists. In high concentrations (greater than 200 microM), clozapine, clonidine and chlordimeform induced changes in aortic tone similar to that produced by p-octopamine. This activity may result from the chloro-substituted phenamidine skeleton in both clozapine and chlordimeform.

The effects of (+)-amphetamine, alpha-methyltyrosine, and alpha-methylphenylalanine on the concentrations of m-tyramine and alpha-methyl-m-tyramine in rat striatum.

The concentration in rat striatum of the meta and para isomers of tyramine and alpha-methyltyramine, after the administration of (+)-amphetamine, alpha-methyl-p-tyrosine (AMPT) and alpha-methylphenylalanine (AMPA) has been determined using chemical ionization gas chromatography mass spectrometry (c.i.g.c.m.s.). Twenty hours after the last of 7 daily injections of (+)-amphetamine (5 mg kg-1 i.p.) the concentration of alpha-methyl-p-tyramine in striatal tissue increased twofold compared to the concentration 20 h after a single injection. In contrast the concentration of alpha-methyl-m-tyramine did not change. alpha-Methyl-m-tyramine and alpha-methyldopamine were found in the striatum at concentrations of 42 ng g-1 and 13.5 ng g-1 respectively after treatment of rats 20 h before with AMPA (100 mg kg-1 i.p.). After treatment with AMPT (100 mg kg-1, 20 h before decapitation) only the para isomer of alpha-methyltyramine could be detected (13.7 ng g-1) although the striatal concentration of alpha-methyldopamine was 274 ng g-1, a level 20 times greater than that observed after AMPA treatment. The combined administration of both AMPT and AMPA (100 mg kg-1 each, 20 h) resulted in a reduction of the striatal concentration of alpha-methyl-m-tyramine but not alpha-methyl-p-tyramine. These data suggest that alpha-methyl-m-tyramine in rat striatum is formed by the enzyme tyrosine hydroxylase on substrate AMPA, rather than by ring dehydroxylation of alpha-methyldopa and alpha-methyldopamine. Significant reductions in the striatal concentrations of m-tyramine 2 h after the administration of AMPT, suggest that tyrosine hydroxylase is involved similarly in the production of m-tyramine.

The pharmacokinetics of chlorbutol in man.

The pharmacokinetics of chlorbutol were studied after oral administration in 4 healthy subjects on two occasions. Following the rapid attainment of peak concentrations, plasma concentrations fell by approximately 50 per cent in 24 h. After the first dose of chlorbutol, the terminal elimination half-life was 10.3 +/-1.3 days (mean +/- S.E.M), the volume of distribution was 233 +/- 141 and the plasma clearance was 11.6 +/- 1.0 ml min-1. The binding to plasma proteins was 57 +/- 3 per cent. In 3 of the 4 subjects, there was a small but significant decrease in the terminal half-life of chlorbutol after the second dose. The mean urinary recovery over 17 days in two of the subjects accounted for only 9.6 per cent of the dose, 7.4 per cent of the total as the glucuronide and sulphate conjugates and 2.2 per cent as unchanged chlorbutol. A significant factor in the elimination of chlorbutol may be its instability under physiological conditions. Its half-life in vitro is 37 days at pH 7.4. The long terminal half-life of chlorbutol makes it unsuitable as a sedative drug because of the considerable accumulation which will occur when the drug is taken in multiple doses.

Enhanced metabolism of mexiletine after phenytoin administration.

1 Unexpectedly low plasma concentrations of mexiletine were observed in three patients treated with mexiletine and concurrently taking phenytoin. 2 Six healthy volunteers were given a single oral dose of mexiletine (400 mg), before and after 1 week of phenytoin administration (300 mg/day). 3 The mean +/- s.d. area under the plasma mexiletine concentration-time curve decreased from 17.67 +/- 6.21 to 8.01 +/- 3.64 micrograms ml-1 h (P less than 0.003). 4 The mean +/- s.d. half-life of elimination of mexiletine decreased from 17.2 +/- 5.26 to 8.4 +/- 4.17 h (P less than 0.02) 5 The suggested mechanism of the interaction is hepatic mixed-function oxidase enzyme induction by phenytoin. 6 The interaction is likely to be clinically significant.

Absence of alpha-methyldopamine in rat striatum after chronic administration of d-amphetamine.

Direct measurement by gas chromatography methane chemical ionization mass spectrometry of alpha-methyldopamine and alpha-methylnorepinephrine in rat striatum has shown the failure of these compounds to be accumulated in vivo after chronic administration of d-amphetamine despite the accumulation of alpha-methyltyramine, an immediate in vitro precursor. Further, both alpha-methyldopamine and alpha-methyltyramine accumulate in rat striatum after administration of alpha-methyltyrosine. These data suggest that, after administration of alpha-methyltyrosine, alpha-methyldopamine is formed via decarboxylation of alpha-methyldopa and not from hydroxylation of alpha-methyltyramine. Finally, our results indicate that alpha-methyldopamine does not play a role in the development of tolerance to d-amphetamine.