Inherited pulmonary cylindromas: extending the phenotype of CYLD mutation carriers.

BACKGROUND: Germline mutations in the tumour suppressor gene CYLD are recognized to be associated with the development of multiple cutaneous cylindromas. We encountered such a patient who presented with breathlessness because of multiple pulmonary cylindromas. OBJECTIVES: To search for clinical and radiological features of multiple pulmonary cylindromas in a cohort of 16 patients with CYLD mutations. METHODS: A retrospective case-note review was carried out in a tertiary dermatogenetics clinic where CYLD mutation carriers are reviewed on an annual basis. In-depth investigation was carried out for patients with pulmonary tumours. RESULTS: Four patients had radiological imaging of their lungs, of which two had multiple pulmonary cylindromas that were confirmed histologically. Serial computed tomography monitoring allowed for pre-emptive endobronchial laser ablation, preventing major airway obstruction and pulmonary collapse. CONCLUSIONS: Pulmonary cylindromas are an unrecognized, but infrequently symptomatic, aspect of the phenotype in these patients that can have implications for patient care. They should be considered in patients with a high tumour burden that present with respiratory symptoms, and where appropriate, monitored with serial imaging.

Anxiolytic properties of certain annelated [1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones.

Modification of the benzodiazepine (BZ) receptor binding template 2-aryl[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one by replacement of the annelated benzene ring with various alicyclic and heterocyclic moieties led to novel structures with potent BZ receptor binding affinity. High affinity was found in some cycloalkyl-annelated [1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones and in some 7,8,9,10-tetrahydropyrido[3,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 5(6H)-ones, in which the degree of activity was strongly dependent on the N-substituent in the 9-position. Nine compounds with BZ receptor IC50 binding affinity values equal or superior to diazepam were evaluated in secondary screening. One of these, 9-benzyl-2-phenyl-7,8,9,10-tetrahydropyrido[3,4-e] [1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one, showed good activity in rats as a potential anxiolytic agent without sedative liability. However, it increased the rotorod deficit produced by ethanol at anxiolytic doses, an indication of alcohol interaction. Thus, none of the compounds showed an advantage over CGS 9896 (Yokoyama et al. J. Med. Chem. 1982, 25, 337-339), which is free of sedative and alcohol interaction potential as measured by the test procedures described.

Synthesis and benzodiazepine binding activity of a series of novel [1,2,4]triazolo[1,5-c]quinazolin-5(6H)-ones.

Investigation of tricyclic heterocycles related to the 2-arylpyrazolo[4,3-c]quinolin-3(5H)-ones, structures with high affinity for the benzodiazepine (BZ) receptor, led to the synthesis of 2-phenyl-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one, a compound with 4 nM binding affinity to the BZ receptor. Analogues were prepared to assess the importance of the 2-substituent and ring substitution in modifying activity. Several novel synthetic routes were designed to prepare the target compounds, including a two-step synthesis beginning with an anthranilonitrile and a hydrazide. Of the 34 compounds screened in this series, three compounds were found to be potent BZ antagonists in rat models. The leading compound, 9-chloro-2-(2-fluorophenyl) [1,2,4]triazolo[1,5- c]quinazolin-5(6H)-one (CGS 16228), showed activity comparable to that of CGS 8216 from the pyrazolo[4,3-c]quinoline series.

Tricyclic antidepressants and dextromethorphan bind with higher affinity to the phencyclidine receptor in the absence of magnesium and L-glutamate.

Recent studies from our laboratory have provided evidence that multiple states of the phencyclidine (PCP) receptor exist. In addition, several compounds such as PCP and the novel anticonvulsant MK-801 were found to inhibit binding more potently in the presence of Mg2+ and L-glutamate (L-GLU) than when these agents were excluded from the binding assay. In the present study, a number of pharmacological compounds that have been suggested to interact within the N-methyl-D-aspartate (NMDA) receptor complex, including tricyclic antidepressants (TCAs), were examined for their ability to inhibit the binding of [3H]1-[1-(2-thienyl)cyclohexyl]piperidine [( 3H]TCP) in the absence or presence of Mg2+ and L-GLU. The TCAs imipramine, amitriptyline, and opipramol produced shallow inhibition curves in the absence of Mg2+ and L-GLU. Computer analysis of the binding data indicated that a two-component binding model described the data significantly better than a one-component model. In the presence of Mg2+ and L-GLU, the inhibition curves became steeper and were shifted to the right, and computer analysis of the binding data indicated that a one-component model adequately described the binding data. A series of other centrally active compounds, including several antipsychotics and antihistamines, the antiparkinsonian anticholinergic trihexyphenidyl and the antitussive dextromethorphan, were also found to be affected similarly by the inclusion of Mg2+ and L-GLU in the binding assay. Dextrorphan, in contrast to dextromethorphan, inhibited [3H]TCP binding more potently in the presence of Mg2+ and L-GLU. The present results suggest that the compounds that inhibit binding more potently in the absence of Mg2+ and L-GLU are interacting with the PCP receptor in a different manner from that of PCP and MK-801, because these open-channel blockers inhibit [3H]TCP binding more potently in the presence of Mg2+ and L-GLU. The data support previous findings that TCAs interact with the NMDA receptor complex and suggest that the compounds trihexyphenidyl and dextromethorphan, which have been shown to block NMDA-mediated neurotoxicity, may produce their effects through an interaction with the PCP receptor, albeit by a different mechanism from that of open-channel blockers.

CGS 20625, a novel pyrazolopyridine anxiolytic.

CGS 20625 (2-(4-methoxyphenyl)2,3,5,6,7,8,9,10-octa hydrocyclohepta[b]pyrazolo-[3,4-d]pyridin-3-one) is a potent and selective ligand for the central benzodiazepine receptor (IC50 = 1.3 nM), with little or no affinity to several other neurotransmitter receptor binding sites in vitro. CGS 20625 had a gamma-aminobutyric acid ratio of 0.9 and increased t-[35S]butylbicyclophosphorothionate binding by 20% in vitro, a profile indicative of a partial agonist or mixed agonist/antagonist. In vivo, CGS 20625 blocked a pentylenetetrazol discriminative cue with an ED50 = 1.7 mg/kg p.o. The compound selectively increased conflict responding in the Cook-Davidson paradigm with a minimal effective dose of 0.3 mg/kg p.o., as compared with 3.0 mg/kg p.o. for diazepam. At doses as high as 100 mg/kg p.o., CGS 20625 had no effect on variable interval responding, suggesting minimal sedation. Unlike diazepam, CGS 20625 had no effect on rotorod performance at doses up to 100 mg/kg p.o. indicating no overt muscle relaxation, and did not potentiate the action of ethanol in this behavioral paradigm. Also, CGS 20625 had no marked effect on locomotor behavior, did not potentiate hexobarbital sleep time and had no sedative activity at doses up to 300 mg/kg p.o. CGS 20625 was efficacious in preventing pentylenetetrazol-induced seizures (ED50 = 0.7 mg/kg p.o.), had less efficacy with no clear dose-response relationship against picrotoxin-induced seizures and had no effect on either strychnine or electroshock-induced convulsions at doses up to 300 mg/kg p.o.(ABSTRACT TRUNCATED AT 250 WORDS)

The NMDA antagonists, CPP and CGS 19755, lack affinity for central benzodiazepine receptors.

CPP (3-(2-carboxypiperazin-4-yl-propyl-1-phosphonic acid), a rigid analog of AP7 (2-amino-7-phosphonoheptanoate), previously shown to be a selective antagonist of the NMDA (N-methyl-D-aspartate) receptor (IC50 = 209 nM) has been reported to be exceptionally active (IC50 = 430 pM) at benzodiazepine binding sites. Re-examination of CPP, and the rigid AP5 analog, CGS 19755 (cis-4-phosphonomethyl-2-piperidine carboxylic acid; 0.001-10,000 nM), showed that, as previously reported, neither compound affected the binding of [3H]flunitrazepam. These compounds are thus selective NMDA receptor antagonists.

Interaction of L-glutamate and magnesium with phencyclidine recognition sites in rat brain: evidence for multiple affinity states of the phencyclidine/N-methyl-D-aspartate receptor complex.

Biochemical and electrophysiological studies have provided evidence that a complex comprising the N-methyl-D-aspartate (NMDA)-type excitatory amino acid (EAA) receptor and the phencyclidine (PCP) recognition site exists in mammalian brain. This complex, which has been compared to that established for the inhibitory amino acid, gamma-aminobutyric acid, and the benzodiazepine anxiolytic, diazepam, is sensitive to the effects of the divalent cation Mg2+, which has suggested the presence of a third, ion channel component. Using a radioreceptor assay for the PCP receptor, L-glutamate (L-Glu) produced a concentration-dependent increase in the binding of [3H]thienyl cyclohexylpiperazine ([3H]TCP) in well washed membranes from rat forebrain. The EAA produced a maximal increase in specific binding of 400%, with an EC50 value of 340 nM. The ability of L-Glu to enhance [3H]TCP binding was 10-fold more potent in the presence of 30 microM Mg2+, which inhibits NMDA-evoked responses in intact tissue preparations and produces a 50% increase in [3H]TCP binding on its own. Analysis of saturation curves indicated that the effect of both L-Glu and Mg2+ could be attributed to an increase in receptor affinity as well as increases in the proportion of a high affinity state of the PCP-binding site. Assessment of the effect of a number of EAAs on basal [3H]TCP binding (well washed membranes in the absence of either L-Glu or Mg2+) showed that the EAA recognition site involved in the effects of L-Glu was the NMDA subtype. Further studies examined a series of compounds thought to interact with either the NMDA or PCP components of the receptor complex under four binding conditions: basal, +Mg2+; +L-Glu; and +Mg2+/L-Glu. These results showed that dissociative anesthetics, such as dexoxadrol and PCP, as well as the novel anticonvulsant MK-801, selectively interact with the high affinity state of the PCP receptor. NMDA antagonists, such as CPP, were also found to inhibit binding to the high affinity state of the PCP receptor, although not as potently as the dissociative anesthetics. Interestingly, the NMDA antagonists did not inhibit any of the binding to the low affinity state of the receptor. The sigma ligands (+/-)-SKF 10,047 and haloperidol recognized two components of [3H]TCP binding only in the presence of L-Glu. The results of the present study are consistent with the finding that agonists of the NMDA receptor induce a high affinity state of the PCP receptor.

Single dose ciprofloxacin for treating gonococcal infections in men.

A single oral dose of ciprofloxacin 500 mg was used to treat five men with gonococcal urethritis and five men with gonococcal proctitis, and all were cured. In a subsequent study the dose of ciprofloxacin was reduced to 250 mg, and 54 men with 57 gonococcal infections (47 urethral, seven rectal, and three pharyngeal) were treated; of the isolates of Neisseria gonorrhoeae, four were penicillinase producing strains. All the patients were cured of gonococcal infection. Urethral specimens from nine of the men with gonococcal urethritis yielded Chlamydia trachomatis before treatment. These organisms were isolated again from all these patients seven days after treatment, and from a further seven men who had been chlamydia negative before treatment. It is concluded that a single oral dose of ciprofloxacin is an effective treatment for uncomplicated gonorrhoea, but is ineffective against C trachomatis. Of the 54 men given 250 mg ciprofloxacin, six (11%) showed minor abnormalities of liver function tests after treatment.

Treatment of uncomplicated gonorrhoea in women with a combination of rifampicin and erythromycin.

One hundred women with uncomplicated gonorrhoea (in five cases due to penicillinase producing strains of Neisseria gonorrhoeae (PPNG)) were treated with a single oral dose of rifampicin 900 mg and erythromycin stearate 1 g. N gonorrhoeae was reisolated from the oropharynx of one patient, who was infected with a PPNG strain, but was eradicated from the genital tract in 100% of cases. The combination eradicated Chlamydia trachomatis from only 10 (28%) of the 36 patients infected. Side effects were predominantly mild and consisted of transient nausea. The treatment merits evaluation in areas with a high incidence of PPNG strains.