The mechanism of bioactivation and antigen formation of amodiaquine in the rat.

A glutathione conjugate of amodiaquine has been isolated and characterized from rat bile after administration of [14C]amodiaquine (50 mumol/kg, 5.0 muCi/rat) to anaesthetized male Wistar rats. Thioether conjugates of amodiaquine in rat bile accounted for a total of 12% of the dose, 5 hr after administration of the drug. In addition, 1% of the dose remained in the liver covalently bound to tissue proteins after 5 hr. These findings provide direct evidence that a chemically reactive metabolite, amodiaquine quinoneimine, has been formed from the drug in vivo. A second major metabolite, desethylamodiaquine, accounting for 14% of the given dose, was present in the liver after 5 hr. Enzyme inhibition studies with ketoconazole-pretreated rats showed that both amodiaquine quinoneimine and desethylamodiaquine formation can be catalysed by cytochrome P450. The demonstration that amodiaquine readily and extensively forms a metabolite in vivo, with strong reactivity towards protein and non-protein thiol groups, may help to explain the idiosyncratic toxicity observed in man.     

Ictal brain imaging in presurgical evaluation of patients with medically intractable complex partial seizures

At the Indiana University Medical Center, 99 patients with medically intractable complex partial seizures (MI-CPS) had presurgical evaluation with subsequent anterior temporal lobectomy. The majority of the patients had single photon emission tomography (SPECT) performed interictally as well as during an actual epileptic seizure (ictal scan). Decreased regional cerebral perfusion (rCP) was seen in 54/94 (57%) of the interictal scans corresponding to the eventual site of the surgery. However, ictal scans provided a higher yield; increased rCP in the temporal lobe during an actual seizure was observed in 60/82 (73%) concordant to the side of surgery. SPECT is a useful, noninvasive method of localizing the epilepti-form focus in patients with MI-CPS considered for resective surgery. Both interictal and ictal SPECT need to be performed; combined interictal hypo-perfusion and ictal hyperperfusion in the same focal area are unique to epileptogenic lesions. Ictal SPECT studies can be performed in the majority of patients during the period of continuous video/EEG monitoring with only a little additional effort. Combining the results of functional brain imaging (interictal and ictal SPECT, PET) with clinical semiology of seizures, surface and sphenoidal EEG, magnetic resonance imaging and other non-invasive tests, anterior temporal lobectomy can be recommended in approximately two-thirds of the patients without resorting to potentially dangerous intracranial EEG monitoring.     

An Unusual Form of Skin Tuberculosis Following B.C.G. Vaccination

A 25-year-old female has had brown to erythematous telangiectatic patches and grouped papules on her face, neck, arm, and trunk since childhood following B.C.G. vaccination. Histopathologically, the lesions consisted of hyperkeratosis, slight acanthosis, tuberculoid granulomas with some Langerhans type giant cells in the mid-dermis. Although various forms of cutaneous tuberculosis after B.C.G. vaccination have been reported, it was difficult for us to assign the patient's skin lesion to any specific disease entity. Remission of her cutaneous lesions occurred clinically and histopathologically after treatment with isoniazid and rifampin.     

Long-term results and complications of preoperative radiation in the treatment of rectal cancer

A retrospective study of 149 patients with rectal cancer diagnosed between 1972 and 1979 was undertaken to compare survival, disease-free survival, recurrence sites, and long-term complications of 40 patients who received 4000 to 4500 rads of preoperative adjuvant radiotherapy (radiation group) with those of 109 patients treated by resection alone (control group). After a mean follow-up of 84 months and 99 months, respectively, survival of the irradiated patients was significantly better than that of controls (68% versus 52%, p less than 0.05). Disease-free survival of those patients rendered free of disease by treatment was also superior for the irradiated group (84% versus 57%, p less than 0.005). Local recurrence without signs of distant metastases developed only one-third as often in irradiated patients (6% versus 18%). Distant metastases, alone or in combination with local recurrence, were also less common after radiation (12% versus 27%). Second primary tumors developed in 15% and 10% of the respective groups, a difference that was not statistically significant. When we consider the survival benefit of preoperative radiation therapy, long-term complications were relatively mild. Delayed healing of the perineum was noted in two irradiated patients. Persistent diarrhea was severe enough to warrant treatment in only one case, and one patient required a colostomy for intestinal obstruction from pelvic fibrosis.     

Inhibition of dapsone-induced methaemoglobinaemia in the rat isolated perfused liver

We have investigated the disposition of dapsone (DDS, 1 mg) in the rat isolated perfused liver in the absence and the presence of cimetidine (3 mg). After the addition of DDS alone to the liver there was a monoexponential decline of parent drug concentrations and rapid formation of DDS-NOH (within 10 min) which coincided with methaemoglobin formation (11.7 +/- 3.0%, mean +/- s.d.) which reached a maximum (22.6 +/- 9.2%) at 1 h. The appearance of monoacetyl DDS (MADDS) was not apparent until 30-45 min. Addition of cimetidine resulted in major changes in the pharmacokinetics of DDS and its metabolites. The AUC of DDS in the presence of cimetidine (1018.8 +/- 267.8 micrograms min mL-1) was almost three-fold higher than control (345.0 +/- 68.1 micrograms min mL-1, P less than 0.01). The half-life of DDS was also prolonged by cimetidine compared with control (117.0 +/- 48.2 min vs 51.2 +/- 22.9, P less than 0.05). The clearance of DDS (3.0 +/- 0.55 mL min-1) was greatly reduced in the presence of cimetidine (1.03 +/- 0.26 mL min-1 P less than 0.01). The AUC0-3h for DDS-NOH (28.3 +/- 21.2 micrograms min mL-1) was significantly reduced by cimetidine (8.1 +/- 3.40 micrograms min mL-1, P less than 0.01). In contrast, there was a marked increase in the AUC0-3h for MADDS (32.7 +/- 25.8 micrograms min mL-1) in the presence of cimetidine (166.0 +/- 26.5 micrograms min mL-1 P less than 0.01). The methaemoglobinaemia associated with DDS was reduced to below 5% by cimetidine. Hence, a shift in hepatic metabolism from bioactivation (N-hydroxylation) to detoxication (N-acetylation) caused by cimetidine, was associated with a fall in methaemoglobinaemia. These data suggest that the combination of DDS with a cytochrome P450 inhibitor might reduce the risk to benefit ratio of DDS.     

Antibacterials. synthesis and structure-activity studies of 3-aryl-2-oxooxazolidines. 4. Multiply-substituted aryl derivatives.

The synthesis and structure-activity relationship (SAR) studies of the effect of different polysubstitution patterns in the aromatic ring of 5-(acetamidomethyl)oxazolidinone antibacterials (I) on antibacterial activity are presented. Compounds I were prepared by the six-step synthesis described previously (Gregory, W. A.; et al. J. Med. Chem. [formula: see text] 1989, 32, 1673), electrophilic aromatic substitution reactions of 3-substituted compounds, and functional-group interchange reactions of 3,4-disubstituted compounds. Antibacterial evaluation of compounds I against Staphylococcus aureus and Enterococcus faecalis gave the following results. The 2,4- and 2,5-disubstituted derivatives have weak or no antibacterial activity. Antibacterial activities of 3,4-disubstituted compounds are comparable to those of the 4-monosubstituted analogues for small 3-substituents (smaller than Br), but decline rapidly for larger 3-substituents. 3,4-Annulated derivatives are comparable in activity to their open-chain analogues. 3,5-Disubstituted and 3,4,5- and 2,4,6-trisubstituted derivatives are devoid of antibacterial activity.     

Reduction of flurazepam's antiseizure efficacy persists after stress.

Twenty-four hours after mice were forced to swim for up to 10 min in cold (6 degrees C) water, the ability of flurazepam to antagonize the electrical precipitation of seizures was reduced. This stress-induced reduction in flurazepam's antiseizure efficacy persisted for at least 72 h; but was absent 1 week after the single session of swim stress. The data may be relevant to stress-related psychiatric disorders and suggest that the therapeutic efficacy of benzodiazepines may be altered after a severe stress.     

Recognition and management of patients with high-risk vesicovaginal fistulas: Implications for teaching and research

Vesicovaginal fistulas (VVFs) occurring as a result of obstetric trauma are a vast problem in Nigeria and Ghana, where at least 20 000 women await repair, and fewer than 50 physicians have the necessary expertise. Through a series of conferences those VVFs that are at high risk and those at low-risk for repair failure, were identified. A clinic was established where repair of low-risk VVFs was done on an ongoing basis in a remote region of Ghana. A visiting surgical team was utilized to repair the difficult, or high-risk, VVFs, which included 4–6 cm VVFs (3), recurrent VVF (1), combined VVF and RVF (rectovaginal fistula), a large 5 cm juxtacervical VVF (1), and a vesicouterine fistula (1). Management of these patients and others with VVF repair complications is discussed.