Protease Inhibitors and Benzodiazepines

[James Howard]

Protease Inhibitors and Benzodiazepines
James Howard

Since some questions have been posted here regarding protease inhibitors 
and benzodiazepines, I thought I would use my theory of the pineal 
hormone, melatonin, and the adrenal hormone, DHEA, to attempt to answer 
it.  The questions were: "Some bezodiazepines are contraindicated with 
protease inhibitors while others are not. Why is this the case? What is 
it about certain
benzodiazepines that causes them to interact with PI's?"  I suggest the 
connection of protease inhibitors and benzodiazepines is directly tied 
to effects of these drugs on the melatonin - DHEA cycle.  (For further 
reference, please see my theory of sleep at 
http://www.naples.net/~nfn03605 on the web.)  I want to address my 
response to the questons in two sections.  The first is simply a copy of 
one of my recent newsgroup posts of 18 Jun, 1997; this very briefly 
describes my explanation of how protease inhibitors work in relation to 
the recent findings that protease inhibitors may trigger diabetes in 
some who use them.  (This post will direct you to where to read my idea 
in more detail, as well as tie it to another recently appearing problem 
with protease inhibitors.)

"I have posted my hypothesis, 09/08/96, that protease inhibitors work by 
reducing production of DHEA, as "Ritonavir works by reducing DHEA."  
Since DHEA is the major steroid hormone produced from cholesterol, my 
hypothesis was supported by some anecdotal posts that cholesterol levels 
increase, upon using protease inhibitors.  (To date, I have not found 
any reports regarding protease intake for AIDS and cholesterol levels.) 
 Since my work suggests that DHEA exerts its action, in transcription of 
DNA, along with proteins, I suggest that diabetes of old age [type II] 
results from loss of sufficient DHEA to work with insulin.  (DHEA 
naturally begins to decline after age 25 years.)  So, in some people, 
who are predisposed to disturbances in insulin function, loss of DHEA 
will lead to this type of diabetes in old age.  Consider this:

Am. J. Med. Sci. 306 (5): 320-324 (Nov., 1993) "DHEA improved insulin 
sensitivity and reduced fasting and oral glucose tolerance test glucose 
levels and ameliorated the diabetic state."

Now, if protease inhibitors reduce DHEA, then some individuals should 
exhibit this type [type II] of insulin problem.  I suggest this is why 
some individuals, who take protease inhibitors are developing diabetes."

I suggest protease inhibitors exert their actions, in vivo, by reducing 
the production of DHEA.  The following, second section, will demonstrate 
that the benzodiazepines may exert their actions by increasing the 
effects of DHEA.  That is, the benzodiazepines may produce opposite 
effects of protease inhibitors.

My theory of sleep suggests that melatonin and DHEA act in a cycle, with 
melatonin high at night/low in the day and DHEA high in the day/low at 
night.  My idea is that DHEA activates the brain and body, and melatonin 
reduces the production of DHEA at night.  The hormone, prolactin, 
stimulates DHEA, and melatonin reduces prolactin (citations follow).  
So, when melatonin rises at night, it reduces prolactin, and the 
production of DHEA is reduced.  My theory of sleep suggests that DHEA 
"rebounds" to the reductions induced by melatonin.  This mechanism may 
be directly involved in effects of many kinds of drugs that produce 
addiction, including the benzodiazepines.  (I will tie this directly to 
benzodiazepines, following these citations.)

Melatonin reduces prolactin:
"The results suggest that melatonin has a single effect in alteration of 
gestation in mink, i.e. the prevention of prolactin secretion." J. Repro 
Fert 1990; 89: 423

"Melatonin treatment appeared more efficient than an artificial 
photoperiod in reducing plasma prolactin conentrations." J Endocrin 
1986; 108: 287

Prolactin stimulates DHEA:
"Dehydroepiandrosterone [DHEA] formation was increased 3.5 fold and five 
[fold] by adrenocorticotropic hormone and prolactin respectively." Am J 
Obstetrics and Gynecology 1987; 156: 1275

"These findings indicate that the majority of serum androgens in young 
baboons is of adrenal origin.  Therefore we conclude that PRL 
[prolactin], in addition to ACTH, may also be an adrenocorticotrophic 
factor in baboon infants.  However in contrast to ACTH, the action of 
PRL on the adrenal is apparently specific for androgen [DHEA] 
production."  Endocrinology 1985; 117: 1968

Based on my preparation for this, I suggest that the "sedative-hypnotic" 
effects of the benzodiazepines result from a disruption of the 
melatonin-DHEA cycle.  Some benzodiazepines have been found to disrupt 
melatonin production.

"These results show that, although the benzodiazepine flunitrazepam 
improves sleep, it reduces the nocturnal secretion of melatonin, and 
therefore alters the circadian rhythm of a hormone which is supposed to 
play a special role in circadian sleep-wake rhythmicity."  Eur 
Neuropsychopharmacol 1996; 6: 149

"These results indicate benzodiazepine-mediated suppression of brain 
melatonin binding sites that can be abrogated by melatonin 
administration."  J Pineal Res 1996; 20: 65

If melatonin reduces prolactin, then, by interfering/reducing melatonin, 
 benzodiazepines should increase prolactin.  This is the case.  (By 
interfering with melatonin action/receptors, the benzodiazepines 
increase the "rebound" effect and increase DHEA.)

"In conclusion, bedtime administration of 10 mg zolpidem, a standard 
clinical dosage, systematically induces a transient moderate 
hyperprolactinemia, but does not alter other sleep-related hormonal 
secretions or endocrine markers of circadian rhythmicity." Sleep 1995; 
18: 417  (Zolpidem is a short-acting benzodiazepine.)

For this post, I will not attempt to show how this information fits with 
my theory of sleep.  I will try to answer the particular questions 
posed: "Some bezodiazepines are contraindicated with protease inhibitors 
while others are not. Why is this the case? What is it about certain
benzodiazepines that causes them to interact with PI's?"  I suggest the 
problem with some benzodiazepines and protease inhibitors is that some 
benzodiazepines are raising DHEA.  This increase counteracts what I 
think is the main function, in vivo, of the protease inhibitors, i.e., 
decreasing DHEA.  Since some benzodiazepines are short-acting and some 
are long-acting, I suggest that this peculiarity results in some 
benzodiazepines interfering with the function of protease inhibitors.
James Howard