[Retrospective analysis of the combined therapy of terazosin with chlormezanone for chronic prostatitis/chronic pelvic pain syndrome].

OBJECTIVE: To investigate the efficacy and safety of the alpha1-receptor inhibitor terazosin combined with chlormezanone in the treatment of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: A total of 168 CPPS patients, aged 20 -50 (mean 32.9) years and with the disease course of 3 months to 7 years (mean 17 months), were equally randomized into a terazosin group (n = 58), a chlormezanone group (n = 38) and a terazosin + chlormezanone (T + C) group (n = 72), and treated accordingly for 4 weeks. All the patients were scored on NIH-CPSI (National Institute of Health-Chronic Prostatitis Symptom Index) after the treatment and the therapeutic effects were compared among the three groups. RESULTS: Of the total number of patients, 159 completed the treatment and were evaluated, including 55 of the terazosin group, 35 of the chlormezanone group and 69 of the T + C group. After the treatment, the NIH-CPSI scores of the three groups decreased from 24.05 +/- 3.02 to 16.15 +/- 3.25 (mean 7.90), from 23.43 +/- 3.58 to 17.51 +/- 3.08 (mean 5.92), and from 23.93 +/- 3.30 to 15.01 +/- 3.08 (mean 8.92), respectively, with statistically significant differences from pretreatment (P < 0.05) as well as between the combined therapy group and the other two (P < 0.05). The adverse events included postural hypotension (17.1% in the terazosin group and 15.4% in the T + C group), dysspermatism (3.4% in the terazosin group only), lassitude, fatigue and anorexia (18.5% in the chlormezanone group and 12.6% in the T + C group). Nine of the patients failed to accomplish the treatment because of adverse events, 3 (5.2%) in the terazosin group, 3 (7.9%) in the chlormezanone group and 3 (12.6%) in the T + C group. CONCLUSION: Both terazosin and chlormezanone can relieve the symptoms in CP/CPPS patients and improve their life quality, but their combined use may produce a better efficacy than either terazosin or chlormezanone used alone.

Retrospective analysis of the combined therapy of terazosin with chlormezanone for chronic prostatitis/chronic pelvic pain syndrome / 中华男科学杂志

<p><b>OBJECTIVE</b>To investigate the efficacy and safety of the alpha1-receptor inhibitor terazosin combined with chlormezanone in the treatment of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).</p><p><b>METHODS</b>A total of 168 CPPS patients, aged 20 -50 (mean 32.9) years and with the disease course of 3 months to 7 years (mean 17 months), were equally randomized into a terazosin group (n = 58), a chlormezanone group (n = 38) and a terazosin + chlormezanone (T + C) group (n = 72), and treated accordingly for 4 weeks. All the patients were scored on NIH-CPSI (National Institute of Health-Chronic Prostatitis Symptom Index) after the treatment and the therapeutic effects were compared among the three groups.</p><p><b>RESULTS</b>Of the total number of patients, 159 completed the treatment and were evaluated, including 55 of the terazosin group, 35 of the chlormezanone group and 69 of the T + C group. After the treatment, the NIH-CPSI scores of the three groups decreased from 24.05 +/- 3.02 to 16.15 +/- 3.25 (mean 7.90), from 23.43 +/- 3.58 to 17.51 +/- 3.08 (mean 5.92), and from 23.93 +/- 3.30 to 15.01 +/- 3.08 (mean 8.92), respectively, with statistically significant differences from pretreatment (P < 0.05) as well as between the combined therapy group and the other two (P < 0.05). The adverse events included postural hypotension (17.1% in the terazosin group and 15.4% in the T + C group), dysspermatism (3.4% in the terazosin group only), lassitude, fatigue and anorexia (18.5% in the chlormezanone group and 12.6% in the T + C group). Nine of the patients failed to accomplish the treatment because of adverse events, 3 (5.2%) in the terazosin group, 3 (7.9%) in the chlormezanone group and 3 (12.6%) in the T + C group.</p><p><b>CONCLUSION</b>Both terazosin and chlormezanone can relieve the symptoms in CP/CPPS patients and improve their life quality, but their combined use may produce a better efficacy than either terazosin or chlormezanone used alone.</p>

Adjuvant laser acupuncture in the treatment of whiplash injuries: a prospective, randomized placebo-controlled trial.

UNLABELLED: Following introduction of the compulsory use of seat belts in cars, whiplash injuries of the cervical spine have become common in everyday practice. Current treatment approaches lead to resolution of the symptoms within a short time in most cases but cannot prevent a small proportion of patients developing persistent health problems. The effects of adjuvant treatment with laser acupuncture on the acute symptoms and the results one year after the injury were studied in this prospective, randomized, placebo-controlled single-blind study. One group of patients (n = 23) were treated with laser acupuncture (5 mW HeNe laser on 22 acupuncture points for 15 s each) plus cervical collar and a combination of paracetamol and chlormezanone; a second group (n = 22) received the same treatments but with the use of a placebo laser. The treatment was given three times per week until the patient was asymptomatic. No statistically significant advantage of the laser acupuncture treatment was found in the acute phase (mobility in all three planes, duration of pain and duration of use of a cervical collar) or the chronic phase (drug use and the incidences of chronic recurrent problems such as myofascial pain, headaches, vertigo and tinnitus). CONCLUSION: Adjuvant laser acupuncture with a 5 mW HeNe laser and an irradiation time of 15 s appears to be ineffective in the management of whiplash injuries.

Investigations of interactions of chlormezanone racemate and its enantiomers on human keratinocytes and human leucoytes in vitro.

Chlormezanone is a centrally acting muscle relaxant introduced in human therapy as a racemic substance. The following investigation was performed in order to investigate whether the racemate and both enantiomers differ in their potential cytotoxicty in vitro. We investigated antiproliferative effects and cytotoxicity (PicoGreen and ATP assay) for human HaCaT keratinocytes, production of oxygen radicals (ROS) by human interleukin-3-stimulated leukocytes (Lucigenin assay) and production of sulfoleukotrienes (Cellular Antigen Stimulation Test - CAST) by human leukocytes. In the dosage range of 0.001 to 0.1 mg/ ml chlormezanone, no antiproliferative effects were measured with the racemate and both enantiomers. At 1.0 mg/ml, a decrease of proliferative activity was seen after 48 h incubation time of about 50% for the enantiomers and of about 80% for the racemate (PicoGreen) and 50% (enantiomers) or 21% (racemate) in the ATP assay, respectively. ROS production was significantly inhibited at concentrations < or =0.01 mg/ ml by the racemate and the (+)-enantiomer, whereas the (-)-enantiomer was less effective. There was no stimulation of sulfidoleukotrienes in human leukocytes by chlormezanone. Present data argue for absence of significant cytotoxicity against human HaCaT keratinocytes and a dose-dependent suppression of ROS production by human leukocytes that is not uniform among the racemate and its enantiomers.

[New findings on the synthesis of the centrally acting muscle relaxant chlormezanone and its resolution of a gram scale using a Chiralcel OD column]. / Neue Befunde zur Synthese des chiralen Muskelrelaxans Chlormezanon und dessen Racematspaltung an einer präparativen Chiralcel OD-Säule.

2-(4-Chlorophenyl)-4-metathiazanone (2) is the intermediate product for the two step-synthesis of chlormezanone (1), a centrally acting muscle relaxant. The second step includes the oxidation of its sulfur atom. It has been found that the foregoing reaction of 4-chlorobenzaldehyde with methylamine forming the hemiaminale and the subsequent addition of beta-mercaptopropionic acid leads to a remarkable better yield (67% of th.) than the route via the hemimercaptale (42% of th.). 2 could be oxidized with sodium perborate superior to potassium permanganate. The racemic chlormezanone (1) is resolved quickly on a gram scale by preparative column chromatography on a Chiralcel OD column (tris(3,5-dimethyl-phenyl-carbamoyl)cellulose on silicagel). The resolution needed only 40 min, if flow rate, composition of the mobile phase and temperature as the most important factors are determined prior with an analytical column. Both dissociation constants could be determined for the first time with the aid of a log pKa-Titrator of the Sirius Co., which needs for the registration of the curves only 15-17 min in the pH range of 2-12. This speed outplayed the disturbing cleavage of the S-C bond of chlormezanone at strong acidic and alkaline pH values.

Studies for Pathogenesis of Fixed Drng Emptions Through the Change of Cytochrome p450 Isozymes / 대한피부과학회지

The reasons of same site recurrence in fixed drug eruptions (FDEs) remain to be clarified. Although the nature of antigen in FDE is unknown, drug metabolites could play a role for antigen formation. Cytochrome p450 isozymes (CYPs) are important enzymes for drug metabolism. This study was done to examine the role of CYPs in FDEs. Provoked lesion was compared with non-provoked lesion by the same drug on the same patient to overcome inter-individual variations of CYPs. The reverse transcriptase-polymerase chain reaction (RT-PCR) with primers for CYPs and the immunohistochemistry (IHC) with anti-CYPs, pancytokeratin, and leukocyte common antigen (LCA) antibodies were conducted. The causative drugs were different in 13 patients who conducted RT-PCR, and the result could not be analyzed by the cause. The levels of CYP2C8/19 and CYP2E1 mRNAs increased significantly in provoked lesions. The keratinocytes in cases of mefenamic acid-induced FDEs stained strongly with anti-CYP2C9 antibody not with the other three antibodies (CYP1A1, CYP2E1, and CYP3A4). The FDE cases from doxycycline, which is not metabolized by CYP2C9 enzyme, and those from chlormezanone did not react to anti-CYP2C9 antibody. The cells stained with CYP antibodies did not react with anti-LCA antibody but with anti-pancytokeratin antibody. The number of cells which reacted to anti-LCA antibody clearly increased in the provoked lesions, regardless of the cause. The above results suggest that CYPs may contribute the drug antigen formation and different levels of CYPs between provoked and non-provoked lesions can play a role for the same site recurrence of lesions in FDEs.

[Important pharmaceutical-chemical characteristics of the central muscle relaxant chlormezanone]. / Wichtige pharmazeutisch-chemische Eigenschaften des zentralen Muskelrelaxans Chlormezanon.

The enantinomers of chlormezanone (1) may be achieved by enantioselective HPLC separation with a yield of 98% using a OD-Daicel column. Both enantiomers bind to human serum albumin (HSA) at pH 7.4 to a range of 11-12%. Binding to the globuline fractions is much less (2-4%, equilibrium dialysis, validation by ultrafiltration). It could be demonstrated by means of 1H-NMR spectroscopy that 1 binds to HSA with the benzene ring as well as with the thiazanone ring. The velocity of racemization could be measured for the first time using a BSA column. The enantiomers undergo racemization at pH 7.4 and 37 degrees C with a halflife of approx. 20.5 h.

Interaction of chlormezanone enantiomers with rat liver microsomes.

Both chlormezanone enantiomers, for the first time obtained by enantiospecific HPLC with a 100% yield, bind to oxidized cytochrome P-450 in rat liver microsomes with a binding curve according to type I, similar to hexobarbital but less pronounced. There are no differences between the binding curves of the two enantiomers. Ethylmorphine N-demethylation, ethoxycoumarin and ethoxyresorufin O-deethylation are inhibited by both chlormezanone enantiomers at 0.1-1 mM concentrations: no differences could be found. Luminol and lucigenin amplified chemiluminescence indicating the formation of reactive oxygen species was not influenced by either enantiomer in concentration ranges between millimolar and micromolar, whereas hydrogen peroxide formation was inhibited. NADPH/Fe stimulated lipid peroxidation was not influenced. Scavenger activity could not be demonstrated: the zymosan stimulated whole blood chemiluminescence was not influenced significantly.

[Cleavage and biotransformation of the central muscle relaxant chlormezanone]. / Spaltung und Biotransformation des zentralen Muskelrelaxans Chlormezanon.

Chlormezanone, a chiral centrally acting muscle relaxant, will be cleaved at its S-C-1 bond by an autoprotolytic process. The optimum of chemical stability exists between pH 2 up to pH 9 with a maximum at pH 7.4. The plasma half life at 37 degrees C is 76 h. Enzymes do attack the products of cleavage namely 4-chlorobenzaldehyde and 2-carboxyethane-sulfinic-acid-N-methyl-amide. The main metabolite in urine is 4-chlorohippuric acid in the range of up to 70% of the oral administered dose to humans. No cytochrome P-450 is engaged in the cleavage of the S-C-bond.

[Undesired drug effects after taking chlormezanone (Muscle Trancopal) with lethal results]. / Unerwünschte Arzneimittelwirkung nach Einnahme von Chlormezanon (Muskel Trancopal) mit letalem Ausgang.

HISTORY AND CLINICAL FINDINGS: A 34-year-old woman was admitted for treatment of toxic epidermolysis of the skin and mucosa. 16 days previously she had started to take chlormezanone (Muskel Trancopal) and some other medications for pain in the shoulder and neck. On admission she had a fever of 39 degrees C and, in addition to the epidermolysis, diffuse abdominal pain on pressure and blood-streaked stool. INVESTIGATIONS: Liver enzyme activities (GOT 979 U/I, GPT 1496 U/I, gamma GT 201 U/I) alkaline phosphatase 515 U/I), bilirubin (3.9 mg/dl) and pancreatic enzyme activities were raised. Sonography was nondiagnostic, computed tomography demonstrated only a small amount of ascites. TREATMENT AND COURSE: The epidermolytic lesions, cholestatic hepatitis and pancreatitis markedly regressed under aseptic wound treatment, antibiotics and parenteral nutrition. Persistent blood-streaked stools and bilateral pneumonia with progressive respiratory failure developed. Despite intensive medical care the patient died after 14 days from protracted sepsis with multi-organ failure. Autopsy additionally revealed adult respiratory distress syndrome and complete loss of colonic mucosa. CONCLUSION: The severe course of a toxic epidermal necrosis with fatal outcome is the first such case reported in Germany that very probably was caused by chlormezanone. 4 weeks after this case was reported to the German Doctors' Drug Commission, the manufacturers of the drug withdrew it from the market.

Interaction of chlormezanone with rat liver microsomes and its degradation.

Chlormezanone binds to oxidized cytochrome P450 in rat liver microsomes with a binding curve according to type I like hexobarbital but less pronounced and with a general shift to the left. Ethylmorphine N-demethylation, ethoxycoumarin and ethoxyresorufin O-deethylation are inhibited by chlormezanone in mM concentrations only whereas pentoxyresorufin O-depentylation is inhibited by about 50% in microM concentrations. Luminol and lucigenin amplified chemiluminescence indicating the formation of reactive oxygen species was not influenced in concentration ranges between mM and microM, whereas NADPH/Fe stimulated lipid peroxidation showed a tendency of inhibition. But scavenger activity could not be demonstrated: the zymosan stimulated chemiluminescence of whole blood was not influenced significantly. The degradation process of chlormezanone was elucidated. The first step involves ring opening by chemical hydrolysis with subsequent formation of an unstable acylhalfaminal which is the source of 4-chlorobenzaldehyde. This aldehyde undergoes enzymatically controlled oxidation to 4-chlorobenzoic acid which is the parent compound of following phase II reactions. The second degradation product is 2-carboxyethane-sulfinic-acid-N-methylamide, which is hydrolyzed very quickly. Neither oxidation of the sulfinic acid or its N-methylamide derivative could be observed nor N-demethylation of chlormezanone.