Chemical synthesis and molecular pharmacology of hydroxylated 1-(1-phenylcyclohexyl-piperidine derivatives.

The following monohydroxy derivatives of 1-(1-phenylcyclohexyl)piperidine (phencyclidine, PCP) were synthesized: o-, m-, and p-phenols of PCP, 1-(1-phenylcyclohexyl)-4-piperidinol, and two stereoisomeric pairs of 3-phenyl-3-(1-piperidinyl)cyclohexanol and 4-phenyl-4-(1-piperidinyl)cyclohexanol. Inhibition of specific binding of tritiated PCP, morphine, or quinuclidinyl benzylate (QNB) in rat brain homogenates was measured for these compounds. Inhibition of PCP binding for selected compounds correlated with mouse rotarod assay activity. The most characteristic effects of hydroxylation of PCP on the cyclohexyl, piperidine, or phenyl moieties are the following: (i) it generally decreases its activity in inhibiting [3H]PCP binding by a factor of 10 to 80; (ii) it does not produce a large variation in the affinity for the morphine receptor; (iii) it produces a considerable decrease of the affinity for the muscarinic receptor. An important exception to these general observations was the metaphenolic derivative of PCP. This PCP derivative has an affinity for the [3H]PCP binding sites that is 8 times higher than that of PCP itself; its affinity for the muscarinic receptor is only twice lower than that of PCP, but its affinity for the morphine receptor is 430 times higher than that of PCP and only one order of magnitude lower than that of morphine itself.

Interaction of antimycobacterial and anti-pneumocystis drugs with phospholipid membranes.

Liposomes can be used as carriers of drugs in the treatment of viral, bacterial and protozoal infections. The potential for liposome-mediated therapy of Mycobacterium avium-intracellulare complex infections, one of the most common opportunistic infections in AIDS, is currently under study. Here, we have investigated the effect of the lipid-soluble antimycobacterial drugs ansamycin, clofazimine and CGP7040 on the thermotropic behavior of liposomes composed of dipalmitoylphosphatidylcholine (DPPC) or dipalmitoylphosphatidylglycerol (DPPG) using differential scanning calorimetry (DSC). In the presence of ansamycin (rifabutine), the peak gel-liquid crystalline phase transition temperature (Tm) of DPPG was reduced, as was the sub-transition temperature (Ts), whereas the Tm of DPPC was reduced only slightly. The temperature of the pre-transition (Tp) of DPPC was lowered, while the pre-transition of DPPG was abolished. Ansamycin also caused the broadening of the transition endotherm of both lipids. Equilibration of the drug/lipid complex for 1 or 5 days produced different thermotropic behavior. In the presence of clofazimine, the cooperativity of the phase transition of DPPG decreased. Above 10 mol% clofazimine formed two complexes with DPPG, as indicated by two distinguishable peaks in DSC thermograms. The Tm of both peaks were lowered as the mole fraction increased. Clofazimine had minimal interaction with DPPC. In contrast, CGP7040 interacted more effectively with DPPC than with DPPG, causing a reduction of the size of the cooperative unit of DPPC even at 2 mol%. The main transition of DPPC split into 3 peaks at 5 mol% drug. The pre-transition was abolished at all drug concentrations and the sub-transition disappeared at 10 mol% CGP7040. These studies suggest that maximal encapsulation of clofazimine in liposomes would require a highly negatively charged membrane, while that of CGP7040 would necessitate a zwitterionic membrane. We have also investigated the interaction of the water-soluble antibiotic pentamidine, which has been used against Pneumocystis carinii, the most lethal of AIDS-related opportunistic pathogens. Aerosol administration of this drug leads to long-term sequestration of the drug in the lungs. The DPPG/pentamidine complex exhibited a pre-transition at 3.5 degrees C, an endothermic peak at 42 degrees C, and an exothermic peak at 44.5 degrees C, followed by another endothermic peak at 55 degrees C. The exotherm depended on the history of the sample, requiring pre-incubation for several minutes below the 42 degrees C transition. These observations suggest that upon melting of the DPPG chains at 42 degrees C, the DPPG crystallizes as a DPPG/pentamidine complex that melts at 55 degrees C.

Pancreatic necrosis and acute pancreatitis.

With reference to 115 cases of acute pancreatitis which were either operated on or confirmed, the authors stress the seriousness of the lesion to the glandular parenchyma; it is also difficult to recognise during peroperative exploration. The necrosis, which is sometimes limited to the peripheral and interstitial tissue, sparing the gland itself (its prognosis is less serious) has led many surgeons to perform surgical excision. However, the problems encountered postoperatively have given rise to doubts a posteriori as to whether this is legitimate. Reference is made to the decapsulation of the pancreas described by Romanian authors, and a method for future operative diagnosis of glandular necrosis is proposed.

[Use of histological criteria to evaluate the quality of vagotomy operations. Does ascending degeneration of the nerve exist? (author's transl)]. / Recherche d'un critère histologique de la qualité de la vagotomie. Existe-t-il une "dégénérescence ascendante" du nerf?

Following vagotomy it is a common finding to observe a neuroma at the upper extremity of the nerve. Furthermore, Tinel, quoting Ranson, believes that the sensory fibers of the sectioned pneumogastric may be affected by ascending degeneration. In fact, during thoracic vagotomy after an unsuccessful abdominal vagotomy, histological examination of the resected right thoracic nerve demonstrated disorganization with the appearance of partial ascending degeneration. It appeared possible, therefore, to assess the quality of a vagotomy, by studying the histological appearance of the resected vagus when a further operation using the thoracic approach is necessary. An experimental study was conducted in dogs and the results confirmed the presence, at the upper extremity, of both an amputation neuroma and neuronal changes, though these latter lesions were limited to a region 3 cm above the section level. It is reasonable to assume, therefore, that the lower segment of a vagus resected by the thoracic approach, after an unsuccessful abdominal vagotomy, should show degenerative lesions if the vagotomy had been effective, but these lesions are limited in extent.

[Heterotopic pancreas. Report of 8 new cases (author's transl)]. / Les hétérotopies pancréatiques. A propos de 8 nouveaux cas.

The authors report 8 new cases of heterotopic pancreas and the clinical signs of each case. The emphasise the difficulties of preoperative diagnosis owing to their usually small size and the necessity of surgical treatment justified by the same lesions which affect the normally placed pancreas including cancer.

[Acute pancreatitis. Superficial capsular necrosis and parenchymatous involvement. 115 cases, 11 resections (author's transl)]. / Pancréatites aiguües. Nécrose capsulaire superficielld et atteinte parenchymateuse. 115 observations, 11 exérèses.

The authors report 115 cases of acute pancreatitis who were either operated on or autopsied and emphasise the severity of the glandular parenchymatous involvement which remains, furthermore, difficult to recognise during manual exploration. Necrosis is sometimes limited to the peripheral interstitial tissue and spares the gland itself (the prognosis is then less serious) and has led many surgeons to resections which did not always seem justified a posteriori. The authors refer to pancreatic decapsulation, described by rumanian authors, and suggest a method of operative diagnosis of the extent of glandular necrosis.

[Jejuno-ileal short-circuit operations in the treatment of obesity. 16 personal cases (author's transl)]. / Courts-circuits jéjuno-iléaux dans le traitement de l'obésité. 16 cas personnels.

The authors report a personal experience of 16 cases and in the light of data in the world literature, the authors discuss the controversial method of treatment of very severe obesity when medical treatment has failed. The onset of various complications linked mainly to intestinal malabsorption, should make one careful in the indications for surgery which may, however, be applicable in certain cases.

[Blood gastrin levels after electrical stimulation of the vagus (author's transl)]. / Variations de la gastrinémie après stimulations électrique des pneumogastriques.

Acid secretion from the cells bordering the gastric fundus may be stimulated by a direct action of histamine or pentagastrin... or from electrical stimulation of the vagus as used to control vagotomy. It is not known, however, whether this latter effect is due to direct stimulation of the lining cells or follows hypersecretion of gastrin. In order to clarify this point, a stimulus was applied to the isolated vagus during vagotomy, and gastric acid and peripheral blood gastrin levels measured. Increased or decreased gastrin levels were noted in about the same number of cases. No direct relationship with pH variations was observed, and confirmation that vagal stimulation affects the lining cells through the intermediary of increased systemic blood gastrin levels was not obtained.

[Palilloma and papillary tumor of the gallbladder]. / Papillomes et tumeurs papillaires de la vésicule biliaire

Frequently confused with adenomas or pseudopolyps of the gall bladder, papillomas are rare tumours defined as vegetations covered with an epithelium of gall bladder type in the centre of which is a thin connective tissue axis. They are usually recognised on lyon histological examination of the operative specimen. The uncertainty concerning their course makes them a potentially malignant lesion as shown by the two cases reported here including one personal case concerning a carcinoma situated close to a benign papillomatous lesion. The frequent coexistence with lithiasis which may induce their malignant transformation reinforces the indications for surgery for gall stones.

[Perforation of gastroduodenal ulcers. Therapeutic trends. Apropos of 284 cases]. / Perforation des ulcères gastro-duodénaux. Orientation thérapeutique. A propos de 284 cas

The authors analyse retrospectively 284 case records of perforation of gastric and duodenal ulcers treated between 1961 and 1972 and, from a study of the literature, the authors attempt to draw up prognostic factors which permit one to apply to this complication of ulcer disease, the most efficient short and long-term treatment.

[Sarcomas of the gallbladder]. / Sarcomes de la vésicule biliaire

The authors report two recent personal cases including one explored by retrograde cholangiography and discuss the main clinical, pathological characteristics of this rare disease. They emphasize the severity of the course which does not usually last more than a few weeks after the onset of the first signs.

[Surgical methods in non-traumatic perforations of the colon into the free peritoneum (36 cases)]. / Tactique opératoire dans les perforations non traumatiques du côlon en péritoine libre. (36 observations)

When operating as an emergency for a perforation of the colon should one carry out a by-pass operation, colostomy or restore intestinal continuity? 36 colonic perforations are reported here, as a complication of cancer in 50 p. 100 of cases, or sigmoiditis in 38 p. 100 of cases. The perforation was situated on the sigmoid in 77 p. 100 of cases. 13 by-pass operations were carried out with a 23 p. 100 mortality, 12 colectomies without anastomosis with a 50 p. 100 mortality, and 2 colectomies with restoration of continuity, 9 p. 100 mortality. The overall mortality was 27.7 p. 100 much less than reported by other authors but, nevertheless partly due to the severity of peritonitis due to the presence of feces and, partly due to the operation adopted. The present attitude of the authors depends on the merits of each case. A large incision is made and the peritoneum thoroughly cleaned. If the surgeon is experienced, colonic resection is advisable for perforated cnacer and certain cases of sigmoiditis. Restoration of continuity depends, above all, on the anatomical condition of the colon above the lesion. Hartmann's resections or by-pass operations thus still have indications.