Post by Max on Jul 6, 2005 5:36:22 GMT -5
(Ro)accutane induced irreversible proteinuria
Hoffman la Roche itself has seen an association between proteinuria and exposure of (Ro)accutane in human subjects [0]. It is here suggested to be an overall effect rather than a side-effect. An important part of all the (Ro)accutane induced major alterations of endocrine function are with high certainity due to significant interference with/inhibition of/aggregation of the cubulin/megalin receptors, predominantly located in renal proximal tubes (in certain kidney cells).
(Ro)accutane is found to cause a statistically significant induction of TGF-beta1 in several independent studies. Six weeks of isotretinoin treatment caused a statistically significant 19% increase in suction blister fluid TGF-beta1 [1]. There are no measured values of the cumulative effect after 3-4 months exposure, which is common in acne-subjects. Various studies have shown that significantly increased TGF-beta1 correlate with with the amount of urinary protein excretion (proteinuria and albumineria), in a dose, but also importantly time dependent manner. This due to failure in the kidney, of renal proximal tubular protein reabsorbtion. This is of major importance, because a significant failure in reabsorbtion leads to the loss of important vitamins, hormones and amino-acids [2].
Findings in the urinary system that Hoffman la Roche itself reports include glomerulonephritis and nonspecific urogenital findings [0].
(Ro)accutane induced alterations in control of micturition and urine storage suggested to be partially due to effects on the spinal cord and GABA
The micturition reflex is one of the autonomic reflexes, but the release of urine is regulated by voluntary neural mechanisms that involve centers in the brain and spinal cord. The micturition reflex is a bladder-to-bladder contraction reflex for which the reflex center is located in the rostral pontine tegmentum (pontine micturition center: PMC). There are two afferent pathways from the bladder to the brain. One is the dorsal system and the other is the spinothalamic tract. Afferents to the PMC ascend in the spinotegmental tract, which run through the lateral funiculus of the spinal cord. The efferent pathway from the PMC also runs through the lateral funiculus of the spinal cord to inhibit the thoracolumbar sympathetic nucleus and the sacral pudendal nerve nucleus, while promoting the activity of the sacral parasymapathetic nucleus. Inhibition of the sympathetic nucleus and pudendal nerve nucleus induces relaxation of the bladder neck and the external urethral sphincter, respectively. There are two centers that inhibit micturition in the pons, which are the pontine urine storage center and the rostral pontine reticular formation. In the lumbosacral cord, excitatory glutamatergic and inhibitory glycinergic/GABAergic neurons influence both the afferent and efferent limbs of the micturition reflex. The activity of these neurons is affected by the pontine activity. There are various excitatory and inhibitory areas co-existing in the brain, but the brain has an overall inhibitory effect on micturition, and thus maintains continence. For micturition to occur, the cerebrum must abate its inhibitory influence on the PMC [3].
Hoffman la Roche itself has seen an association between proteinuria and exposure of (Ro)accutane in human subjects [0]. It is here suggested to be an overall effect rather than a side-effect. An important part of all the (Ro)accutane induced major alterations of endocrine function are with high certainity due to significant interference with/inhibition of/aggregation of the cubulin/megalin receptors, predominantly located in renal proximal tubes (in certain kidney cells).
(Ro)accutane is found to cause a statistically significant induction of TGF-beta1 in several independent studies. Six weeks of isotretinoin treatment caused a statistically significant 19% increase in suction blister fluid TGF-beta1 [1]. There are no measured values of the cumulative effect after 3-4 months exposure, which is common in acne-subjects. Various studies have shown that significantly increased TGF-beta1 correlate with with the amount of urinary protein excretion (proteinuria and albumineria), in a dose, but also importantly time dependent manner. This due to failure in the kidney, of renal proximal tubular protein reabsorbtion. This is of major importance, because a significant failure in reabsorbtion leads to the loss of important vitamins, hormones and amino-acids [2].
Findings in the urinary system that Hoffman la Roche itself reports include glomerulonephritis and nonspecific urogenital findings [0].
(Ro)accutane induced alterations in control of micturition and urine storage suggested to be partially due to effects on the spinal cord and GABA
The micturition reflex is one of the autonomic reflexes, but the release of urine is regulated by voluntary neural mechanisms that involve centers in the brain and spinal cord. The micturition reflex is a bladder-to-bladder contraction reflex for which the reflex center is located in the rostral pontine tegmentum (pontine micturition center: PMC). There are two afferent pathways from the bladder to the brain. One is the dorsal system and the other is the spinothalamic tract. Afferents to the PMC ascend in the spinotegmental tract, which run through the lateral funiculus of the spinal cord. The efferent pathway from the PMC also runs through the lateral funiculus of the spinal cord to inhibit the thoracolumbar sympathetic nucleus and the sacral pudendal nerve nucleus, while promoting the activity of the sacral parasymapathetic nucleus. Inhibition of the sympathetic nucleus and pudendal nerve nucleus induces relaxation of the bladder neck and the external urethral sphincter, respectively. There are two centers that inhibit micturition in the pons, which are the pontine urine storage center and the rostral pontine reticular formation. In the lumbosacral cord, excitatory glutamatergic and inhibitory glycinergic/GABAergic neurons influence both the afferent and efferent limbs of the micturition reflex. The activity of these neurons is affected by the pontine activity. There are various excitatory and inhibitory areas co-existing in the brain, but the brain has an overall inhibitory effect on micturition, and thus maintains continence. For micturition to occur, the cerebrum must abate its inhibitory influence on the PMC [3].