Pharmacological properties of fluphenazine-mustard, an irreversible calmodulin antagonist

We describe an improved synthesis and properties of fluphenazine-mustard, a potent phenothiazine having an alkylating chlorethylamine chain in its structure. The drug possesses anticalmodulin activity equivalent to the parent compound, but unlike fluphenazine dihydrochloride, the mustard derivative irreversibly antagonizes the ability of calmodulin to activate cyclic nucleotide phosphodiesterase. This property is partially calcium-dependent and can be overcome by coincubation with excess fluphenazine dihydrochloride. The compound irreversibly inactivated calmodulin when incubated with intact cells and caused single-stranded breakage of DNA. Fluphenazine-mustard possesses potent antiproliferative and cytotoxic properties against malignant cell lines that are likely to be mediated through both of these actions.     

Congenital esophageal cysts in adults

Sixteen adult patients with congenital esophageal cysts were operated on between 1957 and 1979. Preoperatively, 7 patients (44%) were asymptomatic and the cyst was found incidentally on a routine chest roentgenogram. Esophageal symptoms were present in only 3 patients (19%), whereas most symptomatic patients had precordial sensations or arrhythmias. A correct preoperative diagnosis was made in only 1 patient. After enucleation of the cyst, preoperative symptoms were alleviated in all patients and short-term results were excellent. However, long-term follow-up 13.2 +/- 5.6 (+/- standard deviation) years later revealed moderate reflux in 9 (64%) of the surviving 14 patients. During esophagoscopy, macroscopic esophagitis was found in 12 (92%) of 13 patients. On histological examination of specimens obtained by forceps biopsy, esophagitis was present in 10 (77%) of 13 patients and included Barrett esophagus in 2. We conclude that, despite excellent early results, long-term follow-up of patients who undergo operation for congenital esophageal cysts is indicated because of the increased incidence of reflux esophagitis.     

Articular ossification after malignant neurolepsis. A case of schizophrenia treated with phenothiazines

Following administration of phenothiazines for schizophrenia, a 25-year-old patient developed a malignant neuroleptic syndrome followed by bilateral periarticular ossification of the knees, with severely limited motion. Two years later, the patient regained useful motion after bilateral excision of the ossified tissue and intensive physiotherapy. No recurrence of ossification was observed 3 years after operation, and the patient has maintained almost normal motion.