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PubMed1989

Thiorphan and retro-thiorphan display equivalent interactions when bound to crystalline thermolysin.

The three-dimensional structures of (S)-thiorphan and (R)-retro-thiorphan bound to thermolysin have been determined crystallographically and refined to residuals of 0.183 and 0.187 at 1.7-A resolution. Thiorphan [N-[(S)-2-(mercaptomethyl)-1-oxo-3-phenylpropyl]glycine] [HSCH2CH(CH2C6H5)CONHC-H2COOH] and retro-thiorphan [[[(R)-1-(mercaptomethyl)-2-phenylethyl] amino]-3-oxopropanoic acid] [HSCH2CH(CH2C6H5)NHCOCH2COOH] are isomeric thiol-containing inhibitors of endopeptidase EC 24-11 (also called "enkephalinase"). The mode of binding of thiorphan to thermolysin is similar to that of (2-benzyl-3-mercaptopropanoyl)-L-alanylglycinamide [Monzingo, A.F., & Matthews, B.W. (1982) Biochemistry 21, 3390-3394] with the inhibitor sulfur atom coordinated to the active site zinc and the peptide portion forming substrate-like interactions with the enzyme. The isomeric inhibitor retro-thiorphan, which differs from thiorphan by the inversion of an amide bond, utilizes very similar interactions with enzyme. Despite the inversion of the -CO-NH- linkage the carbonyl oxygen and amide nitrogen display very similar hydrogen bonding, as anticipated by B.P. Roques et al. [(1983) Proc. Natl. Acad. Sci. U.S.A. 80, 3178-3182]. These results explain why thermolysin and possibly other zinc endopeptidases such as endopeptidase EC 24-11 fail to discriminate between these retro-inverso inhibitors.

Crystallization↗
PubMed1985

Relationship between enkephalinase inhibition of thiorphan in vivo and its analgesic activity.

The relationship between enkephalinase inhibition by thiorphan in vivo and analgesic activity in nociceptive tests was studied. The analgesic activity of thiorphan in various nociceptive tests was compared with that of a narcotic analgesic, morphine and antipyretic analgesic, antipyrine. Tail-flick test revealed that thiorphan applied intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) in rats markedly potentiated the analgesic activity of [D-Ala2, Met5]-enkephalin administered i.c.v. The amount of thiorphan in the mouse brain and the fragments of Met-enkephalin degraded by brain homogenate were assayed after intraperitoneal administration of 300 mg/kg thiorphan. The concentration of thiorphan in the brain arised to 18.2 +/- 2.4 nmol/g brain 30 min after intraperitoneal administration of thiorphan and then it quickly disappeared from the brain. As to the fragments of Met-enkephalin degraded by brain homogenate after i.p. administration of thiorphan, the concentration of tyrosine and tyrosyl-glycine (Tyr-Gly) was the same as that of the vehicle control, whereas only the amount of tyrosyl-glycyl-glycine (Tyr-Gly-Gly) decreased to 21.5% of the control value after 30 min, and then it recovered to 75% after 180 min. Thus, thiorphan inhibited enkephalinase activity alone demonstrating selective activity. Thiorphan at doses of 30-300 mg/kg demonstrated analgesic activity in the nociceptive tests of acetic acid writhing, hot-plate and tail-flick, whereas it did not have any activity in the tail-pinch test. Morphine showed analgesic activity in the four nociceptive tests employed. Antipyrine showed analgesic activity in three nociceptive tests but not in the tail-flick test. The dose response curves for morphine and antipyrine were parallel. The slope of the dose response curve for thiorphan, however, was shallower than those for two reference analgesics used. The role of main enkephalin degrading enzymes in the brain was discussed with respect to the analgesic action of thiorphan and its concentration in the brain.

Amino Acids, Sulfur↗
PubMed1994

Neutral endopeptidase inhibitor thiorphan increases airway narrowing to inhaled sodium metabisulfite in normal subjects.

Possible mechanisms involved in inhaled sodium metabisulfite (MBS)-induced bronchoconstriction include cholinergic reflex and release of tachykinins from sensory nerve endings. Tachykinins are potent bronchoconstrictors cleaved and inactivated by neutral endopeptidase (NEP) in the airways. To investigate the role of tachykinins in airway response to MBS, we assessed the effect of NEP-inhibitor thiorphan on airway response to MBS in nine nonatopic, nonasthmatic subjects. Two inhalational challenges with doubling doses of MBS (0.03 to 16 mumol) were performed 3 d apart. Ten minutes before MBS challenge, subjects randomly inhaled either thiorphan (1.25 mg) or placebo according to a double-blind cross-over design. Airflow at 30% of vital capacity (V30p) from partial expiratory flow-volume curves was measured at baseline, 10 min after thiorphan or placebo, and 2 min after each MBS dose. The dose of MBS causing 40% fall in V30p (PD40V30p) was calculated. Neither thiorphan nor placebo affected baseline airway caliber. Thiorphan caused a leftward shift of the dose-response curve to MBS. After placebo a measurable PD40V30p was obtained in four of nine subjects. In these subjects PD40V30p fell significantly after thiorphan inhalation. Four of five subjects who did not exhibit PD40V30p after placebo showed measurable PD40V30p after thiorphan. Percent fall in V30p caused by highest dose of MBS was significantly greater after thiorphan compared with placebo (55.9 +/- 4.6% versus 30.8 +/- 5.6%; mean +/- SE; p < 0.001). Results of this study demonstrate that the NEP-inhibitor thiorphan increases MBS-induced bronchoconstriction in normal subjects, suggesting that tachykinins are involved in airway responses to inhaled MBS.

Adult↗
PubMed2003

Effects of the neutral endopeptidase inhibitor thiorphan on cardiovascular and renal function in cirrhotic rats.

1. Cirrhosis is associated with cardiovascular and renal dysfunction including sodium retention. Many vasoactive peptides such as atrial natriuretic peptide (ANP) and endothelin-1 (ET-1) are degraded by neutral endopeptidase 24.11 (NEP). We investigated the hemodynamic and renal effects of thiorphan, a NEP inhibitor, in a rat cirrhosis model. 2. Cirrhosis was induced by chronic bile duct ligation, and controls had sham operation. Systemic and renal hemodynamics in conscious, restrained animals were determined using radiolabeled microspheres, and glomerular filtration rate (GFR) was measured by (3)H-inulin clearance. Plasma ANP and ET-1, and renal cGMP and Na(+) - K(+) ATPase activity were assayed. These variables were measured at baseline and after intravenous infusion of thiorphan (0.5 mg kg(-1) loading dose followed by 0.1 mg kg(-1) min(-1) x 30 min). 3. Thiorphan significantly decreased cardiac output, and increased systemic vascular resistance in controls, whereas in cirrhotic rats these variables were unchanged. 4. Compared to the controls, cirrhotic rats showed a decreased baseline GFR and urine sodium excretion, and the latter was significantly increased by thiorphan. 5. Thiorphan increased plasma ET-1 levels in controls, but not cirrhotic rats. ANP levels were not significantly increased in either group by thiorphan. 6. Thiorphan significantly increased cGMP concentrations and decreased Na(+) - K(+) ATPase activity of renal medulla but not cortex in cirrhotic rats; no effect was observed in the control rats. 7. We conclude that thiorphan induces natriuresis in cirrhotic rats by a direct renal medullary mechanism via cGMP and Na(+) - K(+) ATPase, without affecting systemic hemodynamics. This may potentially be useful in patients with ascites.

Animals↗
PubMed2006

Thiorphan, a neutral endopeptidase inhibitor used for diarrhoea, is neuroprotective in newborn mice.

Excitotoxic damage appears to be a critical factor in the formation of perinatal brain lesions associated with cerebral palsy (CP). When injected into newborn mice, the glutamatergic analogue, ibotenate, produces cortical lesions and white matter cysts that mimic human perinatal brain lesions. Neuropeptides are neuronal activity modulators and could therefore modulate glutamate-induced lesions. However, neuropeptides are rapidly degraded by peptidases. Racecadotril, which is rapidly metabolized to its active metabolite thiorphan, is a neutral endopeptidase (NEP) inhibitor used in clinical practice for diarrhoea with a remarkable safety profile. This study aimed to test the original hypothesis that thiorphan could be neuroprotective against ibotenate-induced lesions in newborn mice. Intraperitoneal administration of thiorphan reduced ibotenate-induced cortical lesions by up to 57% and cortical caspase-3 cleavage by up to 59%. This neuroprotective effect was long-lasting and was still observed when thiorphan was administered 12 h after the insult, showing a remarkable window for therapeutic intervention. Further supporting the neuroprotective effect of pharmacological blockade of NEP, mouse pups with a genetic deletion of NEP displayed a significantly reduced size of the ibotenate-induced cortical grey matter lesion when compared with wild-type animals. Thiorphan effects were mimicked by substance P (SP) and, in a less potent manner, by neurokinin A. Thiorphan effects were inhibited by blockers of NK1 and NK2 receptors. Real-time reverse transcription-polymerase chain reaction, autoradiography and immunohistochemistry confirmed the expression of NK1 and NK2 receptors in the neonatal murine neocortex. These data demonstrate that thiorphan prevents neonatal excitotoxic cortical damage, an effect largely mediated by SP. Thiorphan could represent a promising drug for the prevention of CP, which remains a challenging disease. In a broader context, these results also raise potential implications for the prevention of neurodegenerative diseases involving glutamate-mediated excitotoxic neuronal death.

Animals↗
PubMedDate not supplied

The effect of thiorphan and epithelium removal on contractions and tachykinin release produced by activation of capsaicin-sensitive afferents in the guinea-pig isolated bronchus.

(1) We have studied the effect of epithelium removal (rubbing) and the endopeptidase 24.11 inhibitor, thiorphan, on the contractile response of the guinea-pig isolated bronchi (atropine and indomethacin in the bath) produced by electrical field stimulation, capsaicin or exogenously administered tachykinins (substance P and neurokinin A). (2) The response to field stimulation, thought to involve release of endogenous tachykinins, was potentiated by thiorphan in both epithelium-free and intact bronchi. However, at low frequencies (1-5 Hz), the effect of thiorphan was more evident in intact preparations. (3) The response to capsaicin was enhanced by both epithelium removal and thiorphan administration. (4) The response to exogenous substance P or neurokinin A was potentiated by thiorphan both in epithelium-free and intact bronchi. (5) Capsaicin (1 microM) evoked a consistent release of substance P-like immunoreactivity (determined by radioimmunoassay) and tachykinin-like immunoreactivity (determined by a novel immunoenzyme assay), which was enhanced by thiorphan in both epithelium-free and intact bronchi. (6) These findings suggest that a thiorphan-sensitive mechanism, presumably 'enkephalinase' (endopeptidase 24.11), plays a major role in inactivating endogenous tachykinins released from sensory nerves and that this enzymatic activity is still present after removal of the bronchial epithelium.

Animals↗
PubMed1986

Potentiation of phencyclidine-induced stereotyped behaviors in rats by thiorphan and bestatin.

We investigated the effects of thiorphan, a specific inhibitor of enkephalinase A and bestatin, a specific inhibitor of aminopeptidase, on the stereotyped behaviors induced by phencyclidine (PCP) in cannulated rats. The PCP-induced turning was significantly potentiated when thiorphan (50 micrograms) and bestatin (50 micrograms) were injected simultaneously into the rat lateral ventricle. The increase of PCP-induced turning was completely antagonized by the pretreatment with naloxone. Thiorphan (50 micrograms) or bestatin (50 micrograms) alone failed to potentiate PCP-induced turning. Thiorphan and/or bestatin did not affect significantly the PCP-induced head weaving and back-pedalling except that thiorphan (50 micrograms) potentiated the PCP-induced head weaving 15-18 min after the PCP injection. The combination of thiorphan and bestatin alone did not induce any behavioral change. These results suggest that thiorphan and bestatin produce an increase of endogenous enkephalins and that as a result, PCP-induced turning may be enhanced.

Amino Acids, Sulfur↗
PubMed1983

Complete differentiation between enkephalinase and angiotensin-converting enzyme inhibition by retro-thiorphan.

Thiorphan, N-[(R,S)-3-mercapto-2-benzylpropanoyl]glycine is a highly potent inhibitor (Ki = 3.5 nM) of "enkephalinase," a metalloendopeptidase cleaving the Gly-Phe bond (positions 3 and 4) of enkephalins in brain tissue. In accordance with this property, thiorphan displays antinociceptive activity after systemic administration. However, thiorphan also inhibits to a lesser extent (Ki = 140 nM) the widely distributed angiotensin-converting enzyme, a carboxydipeptidase implicated in blood pressure regulation. Therefore, in view of an eventual clinical use of enkephalinase inhibitors, it was very important to develop fully specific compounds. Such derivatives were obtained taking into account that N-methylation of the ultimate amide bond of dipeptides strongly decreases enkephalinase affinity without affecting angiotension-converting enzyme recognition, whereas retro-inversion of the amide bond leads to the inverse effect. Thus, the retro-inverso dipeptide (R)-H2N-CH(CH2 phi)-NHCO-CH2-CO2H exhibits an inhibitory potency on enkephalinase (IC50 approximately equal to 12 muM) close to that of the natural dipeptide L-Phe-Gly (IC50 approximately equal to 3 muM). This result shows the topological analogy between the crucial components involved in enkephalinase recognition both in active dipeptides and structurally related retro-inverso isomers. Taking into account these observations, retro-thiorphan, (R,S)-HS-CH2-CH-(CH2 phi)-NHCO-CH2-COOH, was prepared. As compared to thiorphan, the retro isomer is 50% as potent (Ki = 6 nM) on enkephalinase but displays a drastic loss of potency on angiotension-converting enzyme (IC50 greater than 10,000 nM). This specificity was interpreted as a consequence of differences in the stereochemical constraints involving enzyme-inhibitor hydrogen bonding. This hypothesis is supported by reported crystallographic studies on related enzymes such as thermolysin and carboxypeptidase A. As expected, retro-thiorphan exhibits about the same analgesic potency as thiorphan on the hot plate and writhing tests in mice. Therefore, the topological concept of retro-inverso isomers could be extended to other enkephalinase inhibitors, allowing the design of potent and highly selective compounds occurring as new classes of analgesic and psychoactive agents.

Amino Acids, Sulfur↗
PubMed1989

Effect of thiorphan on tachykinin-induced potentiation of nerve-mediated contractions of the rat isolated vas deferens.

We have assessed the ability of thiorphan, an inhibitor of enkephalinase, to influence the potentiation of the nerve-mediated contractions of the rat isolated vas deferens (pars prostatica) by mammalian tachykinins [substance P, (SP); neurokinin A (NKA); and neurokinin B (NKB)] and selective tachykinin agonists. In the absence of thiorphan, the rank order of potency of mammalian tachykinins was NKA greater than NKB much greater than SP. The maximal response to SP did not exceed 40% of that to NKA or NKB. Thiorphan (10 microM) had no effect on twitches per se, but increased the potency and maximum effect of mammalian tachykinins. [Pro9]-SP sulfone, a selective NK-1 receptor agonist had no effect, either in the absence or presence of thiorphan. [MePhe7]-NKB had some potentiating effect, but only at micromolar concentrations. [Nle10]-NKA (4-10) and [beta-Ala8]-NKA (4-10), two selective NK-2 agonists displayed good activity. [Nle10]-NKA (4-10) was potentiated by thiorphan. On the other hand, the action of [beta Ala8]-NKA (4-10) was completely thiorphan-resistant. These findings indicate that estimate of activity of tachykinins and tachykinin related peptides in this bioassay is influenced markedly by peptide degradation via a thiorphan-sensitive mechanism. NK-2 receptors are the main if not the sole mediators of the response to tachykinins in this bioassay organ.

Animals↗
PubMed1993

Disposition of thiorphan in DOCA-salt and spontaneously hypertensive rats.

Thiorphan was administered intravenously (i.v.) at 10 mg/kg to conscious rats in two different models of hypertension to allow a comparison of pharmacokinetics. The two models were: 1) Deoxycorticosterone acetate (DOCA)-salt uninephrectomized rats; 2) Spontaneously hypertensive rats (SHR), and their respective normotensive controls; 3) Sprague-Dawley (SD) rats; and 4) Wistar-Kyoto rats (WKY). Pharmacokinetic parameters were calculated for total and unbound thiorphan in plasma. In normotensive SD and WKY rats, the volume of distribution, clearance and plasma protein binding of thiorphan were not significantly different. Furthermore, the apparent elimination half-life was not significantly different for total or unbound thiorphan amongst all models. The volume of distribution and plasma clearance for both unbound and total thiorphan, however, were lower in DOCA-salt rats when compared to normotensive control rats by 61-66% and 46-51%, respectively. In contrast, pharmacokinetic parameters for both unbound and total thiorphan were not significantly different between SHR and WKY rats. These results indicate that reduced clearance of thiorphan in DOCA-salt rats may be due to the co-administration of DOCA-salt or altered renal function of the hypertrophic remaining kidney and not solely due to hypertension.

Animals↗
PubMed1983

The analgesic effects of morphine, but not those of the enkephalinase inhibitor thiorphan, are enhanced in arthritic rats.

The effects of various i.v. doses of morphine (0.1, 0.3 and 1 mg/kg) and of thiorphan, an inhibitor of enkephalinase (0.7, 2.5, 5, 10 and 15 mg/kg), were studied upon the vocalization threshold to foot pressure in normal rats and rats with Freund's adjuvant-induced arthritis. The vocalization threshold in arthritic rats was, before any injections, significantly lower than in normal rats (mean pressure threshold for vocalization: 115.2 g +/- 14.7 (n = 152) for arthritic rats vs 182.5 g +/- 21.3 for normal rats (n = 152). The various doses of morphine in raising the vocalization threshold were more efficient in arthritic than in normal rats (maximum vocalization threshold (% of control) following 1 mg/kg morphine = 225.70 +/- 10.21 in arthritic rats vs 140.75 +/- 6.87 in normal rats, n = 9 in each case). This effect was dose-dependent, and in every case, naloxone-reversible. Injected at doses of 5-15 mg/kg, thiorphan increased the vocalization threshold (maximum = 223.91% +/- 11.96 in arthritic rats vs 223.30% +/- 5.93 in normal rats for 15 mg/kg i.v., n = 9 for each group). This effect was not greater in arthritic than in normal rats. The dose of 2.5 mg/kg of thiorphan was insufficient. Administered at 0.7 mg/kg, thiorphan significantly decreased the vocalization threshold in the arthritic rats only. These effects of thiorphan were all naloxone-reversible using doses of naloxone which were one-hundredth of those of thiorphan.

Amino Acids, Sulfur↗
PubMed1983

Enkephalinase 'A' inhibition by thiorphan: central and peripheral cardiovascular effects.

On the basis of the distribution of enkephalins within the central and peripheral nervous systems as well as on responses to their administration, it has been suggested that these peptides participate in the regulation of the circulation. The present series of experiments examined the effects of thiorphan, an inhibitor of enkephalinase A, on cardiovascular responses to intracerebroventricular (i.c.v.) administration of [D-Ala2,Met5]enkephalin (DAME) and its amide and on peripheral interactions with the sympathetic nervous system and vasoactive peptides. Thiorphan (30 micrograms i.c.v.) potentiated the pressor response to i.c.v. DAME and DAMEamide in conscious spontaneously hypertensive rats. Responses to i.c.v. angiotensin I (AI) were unaffected suggesting lack of inhibition of central angiotensin converting enzyme (ACE). Peripheral administration of relatively large doses of thiorphan (30 and 100 mg/kg s.c.) attenuated the pressor response to i.v. AI by 30-40% and enhanced the depressor effect of i.v. bradykinin in anesthetized normotensive rats indicating inhibition of peripheral ACE. Pressor and tachycardic responses to activation of spinal sympathetic outflow were not altered by thiorphan in pithed normotensive rats. Thiorphan itself did not affect baseline blood pressure or heart rate in any of these experiments. In conclusion, inhibition of central enkephalinase A by i.c.v. administration of thiorphan potentiates the pressor response to i.c.v. DAME. The compound inhibits peripheral ACE but has little direct cardiovascular activity in its own right.

Amino Acids, Sulfur↗
PubMed1988

Thiorphan and acetorphan inhibit gastric secretion by a central, non-opioid mechanism in the rat.

Thiorphan and its prodrug, acetorphan, are two inhibitors of enkephalinase (EC 3.4.24.11), a membrane-bound peptidase which plays an important role in the metabolic degradation of enkephalins. Since exogenous opioids have been reported to both stimulate and inhibit gastric secretion, the effects of thiorphan and acetorphan were studied in conscious rats equipped with chronic gastric fistulas. While i.v. thiorphan had no effect, both i.c.v. thiorphan and i.v. acetorphan potently inhibited the basal gastric acid output and the acid output stimulated by pentagastrin. Conversely, neither drug affected the histamine- or methacholine-induced stimulation of acid secretion. Neither thiorphan or acetorphan had any effect on the acid secretion stimulated by a combination of pentagastrin and acetylcholine in vagotomized rats. The results strongly suggest that both drugs inhibit gastric secretion through an effect at the level of the central nervous system, which decreases the vagal drive to the stomach. However, the effects of thiorphan and acetorphan were not prevented by naloxone. This is at variance with most of the effects of these drugs reported to date, including the inhibition of gastric secretion in cats. Furthermore, these effects were observed at doses which could inhibit other enzymes apart from enkephalinase. This suggests that the antisecretory action in rats is related to the protection of some non-opioid peptide(s) from degradation. In conclusion, both peptidase inhibitors inhibit gastric secretion of the rat through a central mechanism involving unknown, non-opioid peptide(s).

Animals↗
PubMedDate not supplied

Thiorphan potentiation of stress-induced analgesia in the mouse.

Experiments were done to examine the analgesic effect of thiorphan alone or in combination with stress in mice. Analgesia was assessed by measuring jump latencies from a 55 degrees C hot plate. Thiorphan exhibited weak analgesic properties evidenced by significant increases in jump latencies only after 300 mg/kg i.p. Additional experiments were done to see the effect of i.c.v. administration of thiorphan in the mouse hot plate test. Control experiments revealed that either i.c.v. saline or sham caused naloxone reversible analgesia which was potentiated by thiorphan (100 mg/kg i.p.). Immobilization stress-induced analgesia was also potentiated by thiorphan (100 mg/kg i.p.) and antagonized by naloxone (10 mg/kg i.p.). The results suggest that stress-induced analgesia in the mouse is associated with an endogenous opioid mechanism which is potentiated when enkephalin degradation is inhibited by thiorphan.

Amino Acids, Sulfur↗
PubMed2000

Effects of a neutral endoprotease enzyme inhibitor, thiorphan, on hemodynamics and renal excretory function in four models of experimental hypertension.

Thiorphan, a neutral endoprotease (NEP) enzyme inhibitor, has been shown to enhance the effects of atrial natriuretic peptide (ANP) in vivo. In this study, we examined the effects of an intravenous (iv) infusion of thiorphan on cardiovascular hemodynamics and excretion of urine volume (UV), sodium (U(Na)V) and potassium (UKV) in four different models of experimental hypertension, namely: 1) SHR, 2) two-kidney, one clip (2K1C),3) one-kidney, 1 clip (1K1C) and. 4) 70% reduced renal mass-salt (RRM-S) hypertensive rats. SHR has normal plasma renin activity, 2K1C is renin dependent, and 1K1C and RRM-S are low renin volume dependent models of hypertension. Rats were divided into experimental and control groups. Under inactin (120 mg/kg, body weight) anesthesia, rats were instrumented to record blood pressure and dP/dt (Millar catheter) and urine was collected through a suprapubic urinary bladder catheter. Experimental animals received an iv infusion of thiorphan, 0.5 mg/kg/min for 120 minutes. Control animals received vehicle only. In some animals, vascular smooth muscle cell membrane potentials (Em) was measured in vivo. In another series of experiments, using the identical protocol, cardiac output was recorded. The thiorphan infusion produced a similar progressive decrease in blood pressure in all models of hypertension. Cardiac output did not change relative to vehicle infused control animals. Thus pressure decreased because of a decrease in total peripheral resistance. The contractility index (dP/dt/P, where P = left ventricular pressure) did not change but vascular smooth muscle cells in tail arteries hyperpolarized in all four models. In spite of a significant decrease in blood pressure, thiorphan infusion either increased or produced no change in urinary volume (UV) and sodium (U(Na)V) excretion. These data show that thiorphan, an NEP inhibitor, decreases the blood pressure of hypertensive rats due to a decrease in total peripheral resistance, perhaps by hyperpolarizing vascular smooth muscle cells. These effects are independent of the mechanism of the hypertension. Increased UV and U(Na)V in the face of decreased pressure suggests a direct renal effect.

Animals↗
PubMed2000

Thiorphan, an inhibitor of neutral endopeptidase/enkephalinase (CD10/CALLA) enhances cell proliferation in bone marrow cultures of patients with acute leukemia in remission.

Thiorphan, (DL-mercapto-2-benzylpropanoyl)-glycine is a potent and specific inhibitor of membrane metallo-endopeptidase (EC 3.4.24.11, CD10). We explored its effects in short-term clonal cultures of the bone marrow from 10 patients with acute leukemia in remission. The cell suspensions were incubated with thiorphan (10(-13) to 10(-5) M) and seeded for the granulocyte/macrophage-colony forming unit (GM-CFU) assay. In normal bone marrow samples the median seeding efficiency was 119 colonies and clusters per 10(5) cells and thiorphan caused slight stimulation of the clonal growth in concentrations above 10(-9) M. In the leukemic samples, the median seeding efficiency varied from 10 to 366 colonies and clusters per 10(5) seeded cells. Meaningful alterations of the clonal growth were noted in 32 out of 83 thiorphan-treated cultures (39%). In those 32 cultures the stimulatory effects outnumbered the inhibitory effects (24 versus 8). Thus, thiorphan stimulated the progenitor cell proliferation in bone marrow samples from the normal donor and from the patients with acute leukemia in remission. Thiorphan binding to CD10 might interfere with the processing of neuropeptide hemoregulatory factors and thus influence the progenitor cell proliferation.

Acute Disease↗
PubMed1995

Peripheral excitatory effects of two enkephalinase inhibitors, acetorphan and thiorphan, and an enkephalin analogue, [D-Ala2-Met5]-enkephalinamide, on uterine motility in periparturient rats in vivo and in vitro.

The effects of two enkephalinase inhibitors, acetorphan and thiorphan, and the enkephalin analogue [D-Ala2-Met5]-enkephalinamide (DAMEA), on spontaneous uterine contractions were studied at day 21 of pregnancy in rats following treatment in vivo or in vitro. Acetorphan (10 mg kg-1) and thiorphan (1 mg kg-1), immediately after their i.v. administration, increased the duration of spontaneous contractions 3.4- and 4.6-fold, respectively, but did not modify the maximum amplitude. Similarly, thiorphan (40 mumol l-1) increased the duration of contractions when administered in vitro. Thiorphan was ineffective during the first 30 min when given into the cerebral ventricles (50 micrograms per rat). These results suggest that the enkephalinase inhibitors are acting via a peripheral opioid pathway; and this conclusion is supported by the observation that thiorphan potentiated the stimulatory effect of a submaximal dose of DAMEA administered in vitro. The excitatory effects of DAMEA and the enkephalinase inhibitors were blocked by naloxone. This antagonistic effect of naloxone on uterine motility in the periparturient rat uterus, induced by either acetorphan and thiorphan or DAMEA, seems to be regulated by peripheral opiate receptors. Naloxone (10 mg kg-1 s.c.) increased both the amplitude and duration of uterine motility in vivo; however, naloxone (26 mumol l-1 and 52 mumol l-1) produced a paradoxical dose-dependent biphasic effect in vitro.

Animals↗
PubMed1998

A stability study involving HPLC analysis of aqueous thiorphan solutions in the presence of human serum albumin.

The stability of thiorphan (1.0 mg/ml) in normal saline containing 1% human serum albumin (HSA) was determined in order to find the most appropriate storage conditions. Direct liquid chromatographic analysis of this solution was feasible through the use of a micellar chromatographic system and proved to be stability indicating. During 8 weeks the percentages of the initial thiorphan concentration remaining after storage at 4, 20, 30, and 50 degrees C were determined. An Arrhenius plot was composed using the rate constants of thiorphan degradation at these temperatures. The thiorphan solution was stable for at least 2 months if stored at -20 degrees C. Taking into account the oxidative degradation of about 7% after thawing, we determined that the solution can be kept in a refrigerator for 4 days. Storage at room temperature should be limited to 1 day. By identification of the degradation products it could be concluded that thiorphan is degraded mainly via oxidation forming disulfides. Therefore, it is recommended that the solvent be purged with nitrogen before thiorphan is dissolved.

Chromatography, High Pressure Liquid↗