Clinical Experience with Tixocortol Pivalate

Tixocortol pivalate, the 21-thiol derivative of hydrocortisone. is a 
newly synthesized steroid with topical anti-inflammatory properties but is devoid of 
systemic glucocorticoid and mineralocorticoid activities and toxicity. The mechanism 
of action appears to be similar to that of other corticosteroids with regard to steroid 
binding sites and prostaglandin biosynthesis, however. the disassociation between 
local and systemic effects is due to a 'first pass' liver metabolism and rapid transformation 
with in red blood cells. ln both open and controlled studies in patients with 
acute or recurrent distal colitis, clinical efficacy has been noted at doses of 250 mg to 
1000 mg in 100 ml solution without an effect on scrum cortisol levels or blood 
chemistries. Tixocortol pivalate has consistently shown to be as effective as systemically 
absorbed steroids for the treatment of distal ulcerative colitis with out the undesirable 
effects associated with currently available steroid preparations.


U LCERATIVE COLITIS REMAINS A DIS·
order of unknown etiology ( l). Despite potentially li fe threatening pancolonic and transmural inflammation , the inflammatory response is limited to the mucosa of the rectum and sigmoid in the majority of cases (2). The superfi cial nature and limited extent of the inflammauon often make ulcerative colitis amenable to local (int rarectal} treatment Shortly after the introduction of oral cortisone as therapy for ulcerative colitis. Truelove (3, 4) described the use of topical hydrocortisone by rectal drip. Su b seq uent randomized, controll ed trials by Truelove (5) and Watkinson (6) confirmed the effectiveness of 100 mg intrarectal doses of hydrocorti sonc hemisuccinate solutions compared to placebo in ach ieving clinical, sigmoidoscopic and histologic improvement of active dis- ease. In the United States, 100 m~ hyd rocortisone rctcn tion enemas (Corccnema, Reid-Rowell) have become the most widely prescribed local ther· apy for distal colitis. However. contmu· ous therapy with topical hydroconi,one is complicated by the conscquenct's ot significant syste mic absorption propor· tional to the administered dose and chronicity of treatmen t (7-9).
Tixocor to! piva late ( pregn-4-cne· 3.20-dione-2 l-thiol-llb. 17 dihydroxy· 21-pivalatc), the 21-thiol derivative of hydrocorcisone ( Figure  properties in animal models of inflammation (Sandoz Pharmaceuticals, d ata on file). Moreover, it has the unique feature of topical an ti-inflammatory effects without the typical hormonal and metabolic effects of systemic ab orption ( ll). Hence, tixocortol pivalatc is considered the first of a new class, the 'nonsystemic' steroids.
The mechanism of action of tixocorcol p1valate appears co be similar to that of other corticosteroids with regard to steroid binding site~ a nd proscagland in b io- Symptoms of diarrhea, rectal bleeding, abdominal pain, rectal pain and general malaise statistically improved in both treatment groups, as did the n umber of bowel movements and the n umber of bowel movements accompanied by blood. There was a direct correlation with the severity of the symptoms at baseline and th e degree of improvement; worse initial symptoms were associated with a greater degree of improvement. Likewise, endoscopic findings of colonic hyperemia, ulceration and the physician's overall rating of the colitis improved in both treatment groups by week 2 and conti n ued to improve, such that by the end of the th ree week study, 68% of the tixocorcol pivalare and 7 5% of the hydrocortisone group had improved, and 34% of the tixocortol patients and 36% of the related side effects were observed in the tixocorrol treated patients. T he only consistently significant laborator y parameters found to be altered were the white blood count which was increased (increased neutrophils, decreased lymphocytes and eosinophils) and the scrum potassium w h ich was decreased in the hydrocortisone treated patien ts. Serum cortisol determinations, when measured, were not reduced in either grou p at three weeks.
Hence, after three weeks, tixocorcol pivalate was equall y effective as hydrocortisone therapy without systemic glucocorticoid or mincralocorticoid effects.
Su bsequen tly, a short term , four day study was performed comparing 250 mg ti xocorco l pivalate to a saline placebo enema in 24 patients with ulcerative colitis or Croh n's disease of the rectum. During this brief study, the symptoms of diarrhea. rectal b leeding a n d number of bowel movements, as well as p roctoscopic signs of crythcma, gran u la rity, mucopu s and overall rating of colitis improved in the tixocortol patients, whereas no changes in symptoms or signs of inflammatory bowel disease were observed in the placebo group (Tables I  and 2   At th e conclusion of the study, no dose response was identified in the entire group (Figure 3) or after analysis of the subgroups of sulfasa la zin e tre a ted or refractory patients.

CONCLUSION
Tixocorto l pivalate, the firs t of a new class of nonsystemic steroids devoid of glucocorticoid a nd mineralocorticoid effects, has co nsistently bee n shown to be as effective as systemically absorbed steroids for the treatment of distal ulcerative colitis. Thus, it appears th at therapy with ti xocortol pivalate offers the advantaf.e of steroid therapy without the undesirable effects previously associated with currencly available steroid pre parations. Future studies will focus on longe r du ration placebo co ntrolled enema trials as well as the development of oral. targeted d elivery systems for the potenti al u se in proximal colitis and Crohn's disease. .,