The pharmacokinetics and metabolism of CP-191,166, an angiotensin II receptor antagonist, in rats and dogs

CP-191,166 is an orally active, non-peptide angiotensin II (AII) receptor antagonist developed for the treatment of hypertension and congestive heart failure (CHF). In this study, the intravenous (iv) and oral (po) single dose pharmacokinetics (PK), oral multiple dose PK and P450-mediated metabolism of CP-191,166 were determined in rats and dogs. CP-191,166 was administered in both single and multiple (22-29 day) doses to Sprague-Dawley rats (3 mg/kg iv and 5, 10, 25 and 200 mg/kg po) and to beagle dogs (5 mg/kg iv and 5, 15 and 50 mg/kg po). Blood samples were collected between 0 and 48 h and plasma CP-191,166 concentrations were determined using high performance liquid chromatography (HPLC) with ultraviolet (UV) detection. The in vitro metabolism of CP-191,166 was also evaluated with rat and dog liver microsomes. The results of these studies suggest that in both species, there may be saturable clearance occurring with higher doses, T(max) was at or near the earliest sample time point for all doses, suggesting that the drug was rapidly absorbed, and CP-191,166 was eliminated with t(1/2) values of 8-9 h. No rat or dog microsomal metabolism was observed, suggesting that metabolites detected in vivo in dogs were non-P450-mediated.     

Is the Degree of Arrhythmia Suppression a Predictor of Survival?

The effectiveness of an antiarrhythmic drug is judged by the degree of ventricular arrhythmia (VA) suppression. We evaluated the relationship between the degree of VA suppression and survival in a dose-adjusted trial of 110 symptomatic patients treated with amiodarone. Cohorts had left-ventricular ejection fraction (LVEF) of 41 plus minus 18%, ventricular premature contractions (VPCs) of 445 plus minus 571 h, couplets (C) of 733 plus minus 1498 24 h and nonsustained (N) ventricular tachycardia (VT) of 65 plus minus 217 24 h; these conditions were followed for 15 plus minus 11.5 months. Amiodarone was initiated with an oral loading of 670 plus minus 111.7 mg per day for 10 days and continued on maintenance of 274.9 plus minus 102 mg per day. Survival rates of responders and nonresponders with VPCs <70%, 70--89%, greater-than-or-equal90%; C greater-than-or-equal 90%; NVT (100%); and the response to all 3 criteria (suppresion of VPCs greater-than-or-equal70%, C greater-than-or-equal 90% and complete abolition of NVT) were not statistically significant. Survival rates as a function of LVEF <40% (51 patients) or greater-than-or-equal40% (59 patients), as well as responders or nonresponders to all three criteria, were not significant (p = NS). We conclude that, in patients treated with low-dose amiodarone, the degree of VA suppression of PVCs, C and NVT does not predict survival; the survival of patients with LVEF <40% improved irrespective of VA suppression; and criteria for VA suppression should be reassessed at lower levels of suppression for the improvement of the drug risk:benefit ratio. More improvement is not necessarily better.     

Antihyperglycaemic effect of saccharin in diabetic ob/ob mice

1. The effect of chronic saccharin (benzosulphimide) consumption on glucose homeostasis was examined in normal lean +/+ mice and genetically obese hyperglycaemic insulin-resistant ob/ob mice.
2. Consumption of a 5% (w/v) sodium saccharin solution for 7 weeks prevented the development of hyperglycaemia, improved glucose tolerance (area under curve decreased by 51%), reduced the extent of hyperinsulinaemia (by 21%), and reduced excessive weight gain (by 18%) in ob/ob mice.
3. Consumption of 5% (w/v) sodium saccharin temporarily decreased hyperphagia at the beginning of treatment, decreased hepatic glycogen content (by 47%), increased abdominal muscle glycogen content (by 82%), but did not significantly alter the hypoglycaemic response to exogenous insulin in ob/ob mice.
4. Consumption of a 1% (w/v) sodium saccharin solution did not prevent the development of hyperglycaemia in ob/ob mice.
5. Normal lean +/+ mice consuming 5% (w/v) sodium saccharin solution showed a marginal decrease (by 8%) in glycaemia, and glucose tolerance was improved (area under curve decreased by 30%) without a significant change in the insulin response to glucose or the hypoglycaemic effect of exogenous insulin.
6. The results suggest that chronic consumption of saccharin can defer the development of hyperglycaemia and improve glucose homeostasis in insulin-resistant ob/ob mice through a mechanism that is independent of insulin.

     

Extradural total petrous apex resection with trigeminal translocation for improved exposure of the posterior cavernous sinus and petroclival region

We have analyzed a strategy for improved exposure of the posterior cavernous sinus and petroclival region through an extradural subtemporal approach to be utilized in the removal of neoplastic processes with involvement of the apical petrous bone and posterior cavernous sinus. This surgical approach includes the following elements for improved exposure of the posterior cavernous sinus through the middle fossa corridor: (1) maximal extradural exposure and mobilization of the trigeminal nerve complex, allowing its elevation and anterior displacement, (2) complete extradural removal of the anterior petrous pyramid from the porus acousticus to the petrous apex under direct vision, (3) total exposure of the abducens nerve from the posterior fossa to its point of cross over the intracavernous carotid artery, and (4) wide extradural exposure of the cavernous carotid artery in the foramen lacerum region. This strategy can be combined with other related approaches; specifically, frontotemporal or posterior transpetrosal exposures for extensive lesions.Microsurgical dissection and morphometric analysis were performed in 20 fixed cadaver specimens for the purposes of validating the method for clinical application and determining the key elements to maximization of exposure. The trigeminal complex could be anteromedially retracted 4.8 mm +/- 1.3 (range = 3 to 6 mm) without skeletonization of V(2) and V(3). Liberating these two divisions from their bony canals to their first peripheral branch (10.4 mm +/- 2.5 and 5.4 mm +/- 1.1, respectively) resulted in increased mobilization an average of 9.1 mm +/- 1.7 (7 to 14 mm). Further mobilization is achieved by dividing the attachment between the trigeminal connective tissue sheath and the fibrous carotid ring at the foramen lacerum. An average of 13.0 mm +/- 3.1 (7 to 20 mm) of the posterior intracavernous carotid artery was exposed. Detailed microanatomic observations and a comprehensive morphometric analysis of the relevant anatomic relationships were made.     

Human tumor cell strains defective in the repair of alkylation damage

We have previously identified four human astrocytoma cell strainsas defective in the repair of N-methyl-N'-nitro-N-nitrosoguanidine(MNNG) damaged adenovirus 5. We now show that two of these strains(the only two tested), in comparison to other tumor strainsor normal human skin fibroblasts, are very sensitive to MNNG-producedkilling as measured by colony forming ability, but are normallysensitive to ultraviolet light. Further, such repair deficientcells may be cultured from tumors of the colon, lung, skin,and neck. The phenotype of deficient repair of MNNG-treatedadenovirus 5 has now been found in a subgroup of 9 of the 39human tumor strains tested. We propose to call this phenotypethe Mer^– phenotype. None of the 22 strains of normal humanskin fibroblasts tested showed deficient repair of MNNG damage.MNNG treatment (80 µM) causes a decrease in semi-conservativeDNA synthesis from which Mer^– tumor cells do not recover,but from which cells capable of normal repair of MNNG damage(Mer⁺) do. Somewhat paradoxically, Mer^–cells show moreMNNG-stimulated DNA synthesis (‘repair synthesis’)than do Mer⁺ cells. Besides being deficient in the repair ofMNNG-damaged adeno-viruses Mer– cells also have difficultyin repairing viruses damaged either by other N-alkyl-N'-nitro-N-nitrosoguanidines,or by N-methyl- or N-ethyl-N-nitrosoureas.     

Is the retractile testis a normal,physiological variant or an anomaly that requires active treatment?

Conventional teaching states that the retractile testis is a normal, physiological variant that descends spontaneously by puberty and requires no active treatment. Critical review of the literature, however, suggests that this complacent view may be inappropriate. Substantial overlap exists between the three seemingly separate entities of the late descending, the ascending and the retractile testes. This overlapping group probably accounts for the recently observed increased incidence of orchidopexies. Retractile testes that spend most of the time in an extrascrotal position are subject to the same adverse effects of higher temperatures as true undescended testes, regardless of whether they can be manipulated into the scrotum; what matters is where they actually reside most of the time. The evidence suggests that such retractile testes suffer similar pathological changes to true undescended testes if left to await spontaneous descent. Evidence is presented to support a radical, novel proposal that the retractile testis is a variant of the spectrum of pathological maldescended testes and requires active treatment. A new strategy is proposed for the management of this common pathology. Correspondence to: D. W. Goh