A new phenylpiperidine derivative, FG4963, and several tricyclic antidepressants were compared in various in vitro and in vivo tests for central 5HT- and NA-uptake inhibition. FG4963 was found to be a 5HT-pump blocker with activity similar to that of chlorimipramine. FG4963 inhibited NA-uptake less than the most potent tricyclic thymoleptics. In contrast to imipramine derivatives FG4963 was a weak inhibitor of peripheral NA-uptake. FG4963 seems to produce central 5HT-potentiation without affecting organ functions regulated by the autonomic nervous system as much as tricyclic antidepressants.
Absiruct: 'The tolerance of paroxetinc (FG 7051). as well as its pharmacokinetics and reduction of 5-HT in blood, has been investigated in man. Three normal, healthy volunteers were administered the single doses 10, 25.50, and 75 mg orally, and three volunteers received 10. 25, and 50 mg per day for seven orfourteen days. No toxic effect on blood. kidney, liver. heart or general condition was found by chemical and physical examinations. The pharmacokinetic studies revealed a dose dependent systemic availability, a rather slow elimination (tl,2=approximately 16 hrs), a good fit to a one compartment open model,and analmost complete metabolism of the substance. 25 mg paroxetine per day gave a maximal reduction of 5-HT in the blood within 2-3 weeks (to approximately 0.03 pg/nil). The 5-HT levels returned to the basic levels during a three to four weeks drug-free period.
Investigations of biopsy material from human kidneys with different forms of glomerulonephritis (n = 1,240) and with diabetic glomerulosclerosis (n = 406) performed in order to find changes caused by hyperperfusion of the kidney tissue gave the following results: (1) Hyperperfusion injury occurs in the different forms of glomerulonephritis with varying frequency. It was rarely found in immunologically negative mesangioproliferative glomerulonephritis. The highest incidence was found in patients with membranoproliferative glomerulonephritis type I. (2) Hyperperfusion injury was also found in kidneys with diabetic glomerulosclerosis. The frequency of this finding increased with the degree of the diabetic changes. (3) The hyperperfusion injury was seen as a complication of glomerulonephritis or diabetic glomerulosclerosis only when the patient clinically had developed malignant hypertension and when the serum creatinine level was elevated, a sign of compensated retention. (4) In patients with glomerulonephritis, the hyperperfusion changes occurred more frequently in males than in females. Diabetic glomerulosclerosis was complicated by hyperperfusion injury with the same frequency in both sexes. (5) Patients with hyperperfusion changes of the kidneys always excrete large amounts of protein in the urine. (6) Hyperperfusion changes occur first in the juxtamedullary glomeruli. The intermediate glomeruli are affected later and the subcapsular glomeruli last.
The morphometric investigation of the proximal and distal tubules, the cortical interstitium, the inter-tubular capillaries, the renal corpuscles and the juxtaglomerular apparatuses (JGAs) in 56 cases in the oligoanuric, polyuric, and normuric phases of human acute renal failure (ARF), 6 cases of myeloma kidney with clinically confirmed ARF and 21 control kidneys revealed the following: (1) The main pathological change in human ARF is swelling of the epithelial cells of the proximal and distal tubules. Necrosis of these cells was observed in some cases but usually only as single cell necroses. (2) The interstitium of the cortex and of the outer stripe of the outer medulla is significantly widened in most cases of ARF. (3) In proximal tubules proximal to occluding casts (which were observed only in the plasmacytoma cases), the lumina are not widened but are narrower than normal, and the cross-sectional area of the epithelium is not greater but smaller than normal. (4) The JGAs were significantly larger in kidneys in the oligoanuric phase of ARF (with 1 exception) than in normal kidneys. In the normuric and polyuric phases they were slightly (not significantly) smaller than normal. In myeloma kidneys with occluding casts and/or diffuse interstitial fibrosis, the JGAs were significantly smaller than normal. From these findings it is concluded that: (1) The fall in glomerular filtration rate (GFR) in the postshock phase of ARF is not caused by nonselective back-diffusion of the primary urine through necrotic tubules or by compression of the lumina of the proximal and distal tubules by interstitial edema. A fall in GFR associated with occluding casts in the distal tubules is found only in the myeloma kidney and does not lead to widening of the proximal tubules but to tubular atrophy and narrowing of the lumen. (2) The casts seen in the lumina of the ascending limb of Henle’s loop in some cases of ARF, which consist of hemoglobin, Tamm-Horsfall protein or desquamated blebs, do not occlude the lumen, since they are not associated with atrophy or luminal dilatation of the proximal tubules. (3) The JGAs with their secretory product renin-angiotensin II, together with adenosine, which is released in kidneys with ischemic or toxic damage, play a critical role in the pathogenesis of ARF. (4) In myeloma kidneys with ARF, in which the JGAs are markedly atrophic, the potentiated effect of adenosine that has been observed with a chronic absence of urine flow probably leads to a progressive, irreversible drop in GFR associated with tubular atrophy.
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