[in Japanese]

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Twenty-one nongonococcal urethritis patients by Chlamydia trachomatis infection were treated with doxycycline (DOXY, Vibramycin®) 200mg/day orally for 2 weeks.
The age of these patients were ranged from 17 t 52.
C. trachomatis was eradicated 8 (89%) of 9 cases on 3rd day and never reisolated on 7th day after treatment.
Ten (83%) of 12 patients on 7th day and any patients on 14th day were not suffered from symptoms after treatment.
Urethral discharge was not seen macroscopically, 11 (92%) of 12 patients on 7th day and any patients on 14th day.
According to the criteria for urethritis requiring at least 4 WBC per high power field in urethral smear and/or first voided urine, the overall clinical efficacy rate was 44% (4/9) on 3rd day, 83% (10/12) on 7th day and 100% (9/9) on 14th day.
No side effects were recognized in any cases.
In conclusion, DOXY was thought to be useful and safe drug in the treatment of nongonococcal urethritis by C. trachomatis.

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Nineteen patients of male NGU and 8 patients of female NGC were treated with doxycycline (DOXY, 200mg/day for 14 days).
1. C. trachomatis positive rate of male NGU was 12/19 (63%), and that of female NGC was 4/8 (50%).
2. C. trachomatis positive rate of male NGU after treatment of DOXY for 3 days, 7 days and 14 days, was 83%, 17% and 0%, respectively. Serous discharge after treatment of DOXY for 3 days, 7 days, 14 days, was continued in 100%, 33%, 0%. Administration of DOXY (200mg/day for 14 days) was considered good treatment for male C. trachomatis positive NGU.

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A well-controlled comparative study was conducted in order to evaluate the efficacy, safety and usefulness of the monobactam antibiotic aztreonam (AZT) in complicated urinary tract infections (UTI) using cefoperazone (CPZ) as the control drug.
1. Patients with complicated UTI due to Gram-negative bacteria were examined. However, in polymicrobial infections, the cases caused by Gram-negative and Gram-positive bacteria were also examined. Both drugs were administered 1 g, twice a day by intravenous drip infusion for 5 days. Overall clinical efficacy was evaluated by the criteria proposed by the UTI committee in Japan.
2. Of the total 394 cases, the clinical efficacy was evaluated for 152 cases in the AZT group and 143 cases in the CPZ group excluding 99 cases of exclusion or dropout. There was no statistically significant difference in the back ground characteristics between the 2 groups. The overall clinical efficacy rate was 55.3% for AZT and 55.2% for CPZ with difference not significant.
As for clinical efficacy, in the monomicrobial infection after postprostatectomy (G-2), AZT was superior to CPZ (P<0.05), whereas in the polymicrobial infection without indwelling catheter (G-6), CPZ was superior to AZT (P<0.1).
3. The overall bacteriological eradication rate was 77.2% for AZT and 74.5% for CPZ. For Gram-negative bacteria only the eradication rate for AZT (83.2%) was superior to that for CPZ (74.6%). This was probably due to the stability of AZT to β-lactamase.
4. Side effects were observed in 3 cases out of 201 in the AZT group and 5 cases out of 189 in the CPZ group. No severe abnormal laboratory finding was observed in any group; there was no significant difference between the 2 groups.
Consequently, AZT was judged to be an antibiotic with clinical usefulness equal to, or even superior to that of CPZ.

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In 11 patients, the concentration of cefoperazone (CPZ) in the lung tissue were studied after a 2 g intravenous bolus injection. Samples of lung tissue and blood were taken during surgery at 15, 30, 60, 120, 180, 240, and 300 minutes after administration of CPZ. All samples were assayed by the paper disc method using Micrococcus luteus ATCC 9341 as the indicator strain. All assay results of lung tissue were corrected for the amount of blood contained in the tissue samples by the hemoglobin content in the homogenate of lung tissue. The CPZ levels in the lung tissue were 116.2μg/g at 15 min., 94.1μg/g at 30 min., 74.6μg/g at 60 min., 67.9μg/g at 120 min., 54.6 μg/g at 180 min., 29.2μg/g at 240 min. and 22.7μg/g at 300 min. after administration, respectively. These values were higher than MIC₉₀, values of CPZ for Pseudomonas aeruginosa, Streptococcus pneumoniae, Haemophilus influenzae and Enterobacteriaceae. The level of CPZ in the lung tissue was higher than 50% of the level in the serum until 180 minutes after administration of CPZ.

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A multicenter trial consisting of 164 institutions through out Japan, has been conducted to study the transfer of cefoperazone (CPZ) into the cerebrospinal fluid (CSF), and the clinical effectiveness of CPZ as a therapeutic or prophylactic agent in neurosurgery.
1. The levels of CPZ in serum and CSF were determined in 96 patients. After initial dose of 2 g CPZ (intravenous drip infusion for 30 minutes), the serum level of CPZ after 1 hour was 124.5±6.6μg/ml (Mean±S. E.), and even after 6 hours, it maintained as high as 47.8±16.6μg/ml.
The peak CPZ levels in CSF in patients with normal or minimal impairment in blood-CSF-barrier (BCB)(group I) and in those of localized impairment in BCB (group II) were 1.0±0.5μg/ml at 2 hours and 3.0±1.8μg/ml at 3 hours, respectively. The highest CSF level was seen in patients with meningitis (group III) and showed 5.0±2.4μg/ml at 6 hours.
After multiple dose of 2g CPZ (intravenous drip infusion for 30 minutes), the serum kinetics of CPZ were not significantly different from those obtained after initial dose. However, the CPZ levels in CSF were higher than those observed after initial dose in all 3 groups and were higher than MIC75 against relevant pathogens for meningitis such as Escherichia colt, Klebsiella pneumoniae and Staphylococcus aureus. Moreover, in group III peak level of CPZ in CSF exceeded the MIC75 against Pseudomonas aeruginosa which is also frequently isolated from patients with meningitis in neurosurgery.
2. As a therapeutic agent CPZ administered as sole agent was effective in 42 out of 55 cases (76.4%) in meningitis, in 78 out of 116 cases (67.2%) in pneumonia and in 36 out of 47 cases (76.6%) in urinary tract infection (UTI). Its efficacy rate against all infections treated was 72.2% (184/255).
3. Regarding CPZ's prophylactic use, 39 out of 514 cases (7.6%) were judged as having or possibly having infections as follows; meningitis (13/514, 2.5%), pneumonia (15/514, 2.9%), UTI (2/514, 0.4%).
4. In prophylactic use of CPZ, the incidence rates of postoperative meningitis and other central nervous system (CNS) infection following ventricular drainage and supratentorial craniotomy for aneurysm were higher than those observed in other types of operation, 12.0% (3/25) and 6.2% (8/130), respectively.
5. Also, regarding prophylactic use of CPZ, the organisms isolated by culture from 13 cases of postoperative CNS infections included 2 strains of Staphylococcus sp., 1 strain of Serratia sp. and 3 strains of other Gram-negative bacteria (GNB).
6. The types and incidence of side effects (0.8%, 7/898 cases) of CPZ were quite comparable to those observed with cephalotin or cefazolin.

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Clinical studies of cefoperazone (CPZ) were performed in 65 patients of obstetrics and gynecology, and the following results were obtained.
1. When comparing the fever index of cases treated by CPZ to those by another prophylactic antibiotics, CPZ showed the lowest level comparable to CMX and LMOX.
2. Clinical effects: The effectiveness of CPZ was 75% (excellent in 3 cases, good in 3 cases, poor in 2 cases) in 8 infectious cases.
3. No side effects due to CPZ were noted.

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Susceptibilities of 175 strains of 27 bacterial species to ceftizoxime (CZX) were determined by the 2-fold agar dilution method in parallel with the diameter of inhibition zones by the single-disc method under the experimental conditions established by KANAZAWA.
The experiments demonstrated a significant correlation between MIC by the dilution method and diameter of inhibition zone in each of the conventional assay of over-night (about 16 hours) incubation, the delayed assay (about 24 hours incubation), and the rapid assay (about 3-4 or 5-6 hours incubation), thus confirming the applicability of the single-disc assay for CZX.
Analysis of the data obtained by using CZX disc containing 30μg revealed the primary regression equation to be: D (diameter, mm)=27.3-9.7 log MIC (μg/ml) in conventional assay, D=32.5-12.3 log MIC (μg/ml) in delayed assay, D=22.8-7.5 log MIC (μg/ml) in 5-6 hours rapid assay, and D=17.9-5.1 log MIC (μg/ml) in 3-4 hours rapid assay, respectively.
The range of variations in MICs estimated from the diameter of inhibition zone by the disc test was then calculated in comparison with that in MIC determined by the 2-fold agar dilution test, as a reference for the experimental errors which may be involved in the estimation of MIC of CZX by the single-disc assay.

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Ceftizoxime (CZX) was given in daily doses of 4-6 g by intravenous drip infusion to 30 patients with infection accompanying lung cancer to investigate the usefulness of the drug for infectious disease:
The rate of effectiveness (marked and moderate) was 73.3% (22/30 patients). Of the 30 patients, 2 had drug fever; 1, arthralgia ; and 1, eosinophilia. These side effects improved after the drug was withdrawn. CZX is a very useful antibiotic with high effectiveness and safety in immunocompromised patients with infection accompanying advanced lung cancer.

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The effect of ceftizoxime suppository (CZX-S), a new rectal preparation of ceftizoxime (CZX), against cecal microflora of mice following consecutive rectal administration was compared with that after subcutaneous administration of CZX. The numbers of aerobic and anaerobic bacteria except Enterobacteriaceae of cecal microflora were not markedly changed by the rectal administration of CZX-S at a dose of 25mg/kg 3 times daily for 10 days. Although the number of Enterobacteriaceae was decreased, recovery was rapidly observed after completion of the administration period. In the case of subcutaneous administration, a decrease in Enterobacteriaceae was also observed, but this was no more remarkable than that occurring with rectal administration. Moreover, effects on the state of feces, i.e., diarrhea, were not observed in any of the mice. The peak level of CZX in the cecum contents when administered rectally at a dose of 25mg/kg was 13.8μg/g at 4 hours, while it was less than the determination limit (2.0μg/g) when administered subcutaneously at the same dose.

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Cefotiam (CTM) in a dose of 2 g was given by intravenous bolus injection to 16 patients with breast cancer operated upon radical mastectomy with suction drainage. The materials of exudate from drain were taken at intervals by sterilized paper disc and determined by the paper disc method with Proteus mirabilis ATCC 21100 as the test organism to CTM concentrations. CTM concentrations in exudate from suction drain of patients increased quickly after intravenous injection, and reached to peak early time on 2 to 3 days after operation. While on 6 days after operation, the CTM con-centrations were comparatively lower and reached to peak at 2-3 hours after injection. The CTM concentrations in exudate exceed the antibacterial levels of CTM and are thought to be sufficient to produce prophylactic effects in the operation.

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Cefotiam (CTM) levels in the exudate from wounds of patients with breast cancer who were operated upon for radical mastectomy were analyzed with a modified three-compartment model for a number of days after the operation. A considerable change was observed between the mean pharmacokinetic profiles in the exudate during the first 3 days after the operation and those during the next 3 days. During the first 3 days, the peak concentrations (C_max) and times of the peak concentrations (T_max) calculated from the profiles ranged from 36.2 to 41.5μg/ml and 1.15 to 1.17 hours after the administration, respectively. Thereafter they were in the range of 21.0 to 27.6μg/ml and 1.73 to 1.97 hours, respectively. The low C_max and slow Tmas values of the profiles from 4 to 6 days after the operation were attributed to a decrease of the transfer rate constant from the exudate to blood. On the other hand, the apparent transfer ratios (F₂) of CTM from blood to the exudate were approximately constant for the 6 days. The mean value of individual elimination half-lives in the exudate during 4-6 days was statistically longer than that during the first 3 days. It was clear that the transfer of CTM from blood to the exudate from wounds of patients with breast cancer who were operated upon for radical mastectomy is fairly good judging from the large values of 1.02 to 1.42 for F₂.

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To investigate efficacy of mezlocillin (MZPC) in the treatment of biliary tract infection, the time course concentrations of MZPC in the bile of patients with, in particular, liver dysfunction were measured. MZPC concentrations in the bile decreased with the increase in the severity of liver dysfunction. However, the bile concentration was maintained more than 50μg/ml even in cases of severe cholangitis with obstructive jaundice. These results indicate that MZPC is an useful antibiotic for the treatment of biliary tract infection.

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We examined 91 clinically significant isolates of P. maltophilia for susceptibilities to 27 antimicrobial agents currently available; 6 penicillins, 8 cephem antiobiotics 7 aminoglycosides, 3 tetracyclines, CP, NA and PPA. MINO and DOXY were the most effective agents; almost all of the isolates were inhibited by 6.25 and all of isolates by 12.5μg or less per ml, respectively. A large number of the isolates tested were highly resistant to β-lactam antibiotics except to LMOX. LMOX was fairly active, and 74% of the isolates were inhibited by 25μg or less per ml. Aminoglycosides tested had a wide distribution of MIC that 83-93% of the isolates were not inhibited at 6.25μg or less per ml. TC, CP, NA and PPA were less active. Yearly changes of the activities of the antimicrobial agents tested against P. maltophilia were not significant with the exception of TC to which a 3-fold increase of resistance have been shown.

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Twenty patients who were performed pulmonary resection for the disease of the lung were administered 2g of cefmenoxime (CMX) intravenously during the operation.
The CMX levels in serum, lung tissue and thoracic muscle were measured by agar-well technique.
The CMX levels in lung tissue and thoracic muscle were higher than the MIC₈₀ of CMX for Klebsiella pneumoniae, Haemophilus infiuenzae and Streptococcus pneumoniae which were commonly as isolated causative organisms from the patients with pulmonary infection. These results indicate that CMX will be useful agent for the prevention and treatment of pulmonary infection.

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Clindamycin phosphate (CLDM) was administered to 33 surgical cases in orthopedics to treat or prevent infection (600mg in 15 cases and 1,200mg in 18 cases by intravenous drip infusion over 60 minutes) and the concentrations of CLDM in the bone marrow blood and tissue of the operative field as well as in venous blood were determined with the cup plate method of bioassay by collecting specimens immediately after completion of infusion or 30 or 60 minutes later.
1. The concentration of CLDM in bone marrow blood averaged 104.3-105.5% of the corresponding concentration in venous blood in the cases receiving 600mg and 101.3-103.3% in those receiving 1,200mg.
2. The concentration of CLDM in bone marrow tissue averaged 154.0-163.7% of the corresponding concentration in venous blood in the group receiving 600mg but 78.8-86.2% in the group receiving 1,200mg. This difference between the 2 groups was considered to reflect largely the difference in specimens collected. Thus, the concentration of CLDM in bone marrow tissue was interpreted as the amount of drug penetrating and remaining in bone marrow tissue and its adjacent area.
3. The MIC₇₅ of CLDM for clinical isolates were 0.20μg/ml for S. aureus, 0.78μg/ml for B. fragilis and 0.20μg/ml for Peptostreptococcus spp. The concentrations of CLDM attained in bone marrow blood and tissue and its adjacent area after administration of 600mg or 1,200mg were thus sufficient to eliminate these organisms.
The above results indicate that CLDM is a useful antibiotic for treatment and prevention of infection in orthopedics.

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Twenty-four patients with urinary tract infections were treated with fosfomycin (FOM) to evaluate its effectiveness and safety. They all had shown allergic reactions, mainly to beta-lactams. Lymphocyte stimulation test (LST), leukocyte migration inhibition test (LMT), passive cutaneous anaphylaxis (PCA) and the precipitin reaction were performed to test whether FOM would also cause an allergic reaction.
1. FOM was judged by the physician-in-charge to be effective in all 6 patients (100%) with acute simple cystitis and 8 (72.7%) of 11 patients with chronic complicated urinary tract infections. The drug was also effective in 15 (83.3%) of 18 patients with epididymitis, etc.
Regarding the usefulness of FOM, it was judged to be useful in 21 (91.3%) of 23 patients. FOM was very useful in 8 (34.8%) of these 23.
2. In patients tested for LST, the value was lower in cases given FOM than in cases given ampicillin (ABPC), cefazolin (CEZ) or latamoxef (LMOX); there was an especially significant (p<0.01) difference with ABPC. All the drugs tested were negative for the LMT, PCA and precipitin reaction tests.
3. No subjective or objective abnormalities were attributed to the FOM treatment, and there were also no abnormal laboratory test values.
4. FOM was evaluated to be an effective and safe anitibacterial agent without in vitro or clinical allergic

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Studies were done utilizing E. coil No.59 which are resistant against human and mouse serum, and the following results were obtained.
1. The therapeutic effect of cefbuperazone (CPBZ) against systemic infections of mice was much higher than that of cefmetazole (CMZ), cefotetan (CTT), latamoxef (LMOX) and cefoperazone (CPZ).
2. Synergistic bactericidal effect with human polymorphonuclear leukocytes was more marked for CBPZ than CMZ.

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Preclinical and clinical studies were performed to evaluate usefulness and safety of aztreonam (AZT) in the treatment of acute otitis media, acute exacerbation of chronic otitis media and chronic otitis media and the following results were obtained.
1. MICs for P. aeruginosa, P. mirabilis and P. inconstans isolated from the patients with suppurative otitis media were 1.56μg/ml, ≤ 50.025 μg/ml and 5.0.025μg/ml respectively in their peaks.
2. In the intravenous injection of 1g, AZT concentration in the mastoid cell mucosa was 7.52μg/g on average and serum concentration 51.6 μg/ml sufficiently suggesting clinical efficasy of AZT.
3. In the clinical trial by administering AZT 1-2g/day for the patients with suppurative otitis media, effictive rates were 2/3 (66.7%) for acute otitis media, 16/22 (72.7%) for acute exacerbation of chronic otitis media, 21/34 (61.8%) for chronic otitis media and 6/7 (85.7%) for cholesteatoma of the middle ear.
4. Elimination rate of single Gram-negative pathogens was 82.1% in the bacteriological studies of AZT.
5. As for abnormal laboratory findings, 7 cases showed GOT, GPT elevations. However, they were in minor degree and transient. Side effect was not noted except 1 case of flushing with itching.
It was considered from the above results that AZT is a highly useful antibiotic for suppurative otitis media.

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S6472 is a mixture of 1) cefaclor (CCL) granules with gastric-soluble coating and 2) those with enteric-soluble coating at the ratio (in potency) of 4 to 6. With administration of this formulation, a prolonged blood level of CCL is obtained.
S6472 and CCL were administered orally to 19 healthy male volunteers between 20 and 27 years of age (mean: 23 years) weighing between 51 and 80 kg (mean: 64. 7 kg).
Four subjects were given 2 capsules and 5 subjects were given 4 capsules each containing 187. 5 mg of S6472, 30 minutes after breakfast and supper for 5 days.
Five subjects were given 1 capsule and 5 subjects were given 2 capsules each containing 250 mg of CCL 30 minutes after breakfast, lunch and supper for 5 days. The number of fecal bacteria was examined 5 days before the start of administration, the day of the start of administration, 3 and 5 days after the start of administration, and 3, 5 and 10 days after the end of administration.
Concentration of CCL in feces and susceptibility of isolated fecal bacteria (at the inoculum size of 10⁶ cells/ml) to CCL were examined. Adverse reactions and the effects on laboratory test values were also checked.
1. In 4 subjects receiving 375mg of S6472 twice a day, the mean population of E. coli was 10⁷-10⁹ cells/g feces on all days of observation. There was no effect on the population of Klebsiella sp., Citrobacter sp. Enterobacter sp. and other Enterobacteriaceae. The mean population of all Enterobacteriaceae was 10⁸ 10⁹ cells/g feces on all days of observation.
The population of other Gram-negative bacilli did not show a consistent change, either.
There was no effect on the population of Gram-positive bacteria such as Staphylococcus sp., Enterococcus, sp., Micrococcus sp., and of Candida sp.
Among anaerobic bacteria, Bacteroides sp. showed the mean population of 10¹⁰ cells/g feces on all days of examination. C. difficile was isolated from 2 subjects out of 4 at the level of 10²-10³ cells/g feces 5 days after the start of administration and 3 days after the end of administration. However, there was no production of toxin in either of the 2 subjects. In another subject, C. difficile was isolated at 10²-10⁴ cells/g feces with a toxin titre of 10-3-10-4 3 and 5 days after the start of administration and 10 days after the end of administration.
The total population of anaerobic bacteria was 10¹⁰-10¹¹ cells/g feces on all days of examination.
2. In 5 subjects who received 750mg of S6472 twice a day, the mean population of E. coli was 10⁷-10⁸ cells/g feces on all days of examination. Klebsiella sp. was isolated from 1 to 3 subjects until 5 days after the start of ad-ministration. Three days after the end of administration, however, it was isolated from 4 subjects with a mean population of 10⁷ cells/g feces, 6 with an increase by 10². On the following 2 days of examination, it was isolated from only 2 subjects.
Citrobacter sp. and Enterobacter sp. did not show a consistent change in population. Enterobacteriaceae showed a total population of 10⁷-10⁸ cells/g feces on any day of examination. Other Gram-negative bacilli did not show a consistent change, either.
Among Gram-positive bacteria, Staphylococcus sp., Enterococcus sp. and Micrococcus sp. did not show a consistent change. Candida sp. was isolated in 2 subjects in 2 examinations before the start of administration but was isolated in all subjects in 4 examinations between 3 days after the start of administration and 5 days after the end of administration. Ten days after the end of administration, it was isolated in 3 subjects.

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Antibacterial activity of (+)-negamycin (NGM) prepared by a new method was investigated for some bacteria. The results demonstrated that this antibacterial activity of synthesized NGM was almost the same as compared to that of naturally obtained NGM, and was also effective to Pseudomonas aeruginosa harboring multiple drug resistant plasmid kR102.

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A new antitumor anthracycline antibiotic; (2R)-4'-O-tetrahydropyranyladriamycin hydrochloride (THP) was administered to ddY mice via different routes for acute toxicity studies.
The LD₅₀ values were calculated from mortality rates during a 14-day observation period, and were 14-21mg/kg when i. v., i. p. or s. c. route was used and 420-570mg/kg when the drug was given p. o.
Upon administration of the drug, mice showed depression of spontaneous activity, anorexia, diarrhea and slight alopecia.
Autopsy of the mice killed by the drug revealed atrophy of thymus, spleen, testes, uterus and ovaries, and congestion and hemorrhage in the intestines. The mice which survived through the observation period, however, showed only atrophy of thymus and sexual organs.

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(2R)-4'-O-Tetrahydropyranyladriamycin (THP), a new antitumor antibiotic of anthracycline derivative, was given to Jcl-SD strain rats through intravenous (i. v.), intraperitoneal (i. p.), subcutaneous (s. c.) or oral (p. o.) administration routes and the animals were observed in respect of mortality, clinical signs and body weight for 21 days. Autopsy was done and histopathology on the tissues showing macroscopic abnormality was performed. The results were summarized as follows.
1. Values of LD50 were 18.09mg/kg i. v., 22.58mg/kg i. p., 25.39mg/kg s. c. and above 1,013mg/kg p. o. for males and 18.07mg/kg i. v., 20.30mg/kg i. p., 21.76mg/kg s. c. and above 1, 013mg/kg p. o. for females. No significant difference was found in LD₅₀ values of different sexes.
2. When higher than lethal dose levels of THP was given to animals, their clinical signs grew worse and weight loss occurred in about 5 days after the administration of the drug. Thereafter, deaths were observed.
3. Macroscopic and microscopic observations on dead and survived rats revealed atrophy of spleen and thymus, whity clouding of spleen capsule, hemorrhage in mucosa of glandular stomach and congestion and hemorrhage in testes.
These results suggest that THP shows weaker acute toxicity to rats than doxorubicin does, but the toxic effect of THP is approximately the same as that of other anthracycline derivatives.

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(2R)-4'-O-Tetrahydropyranyladriamycin (THP), a new antitumor antibiotic of anthracycline derivative, was given intravenously to male and female Beagle dogs, followed by observations for 2 weeks. The doses were 0.125, 0.25, 0.5 and 1.0mg/kg. Observations were performed on mortality, clinical signs, body weight and temperature, food and water consumption, ECG, ophthalmoscopy, testicular measurement, hematology, serum biochemistry, urinalysis, autopsy, histopathology and electron microscopy. The results were as follows.
1. All animals of 1mg/kg-treated group died but there were no deaths in other groups.
2. All the levels of doses caused vomiting and diarrhea. Furthermore, the highest dose caused bloody diarrhea and decreases in food consumption, motility and body weight, followed by death. These effects may be related to histopathological changes in mucosa of digestive tract.
3. Some changes in water consumption, urine volume and renal histopathology were sporadically observed after treatment, but they were not treatment-related. These results suggest that a treatment with THP does not significantly cause renal disturbance.
4. There were no treatment-related changes in body temperature, ophthalmoscopical observation and testicular measurement.
5. THP produced flattening of T wave and prolongation of QRS interval only at high doses of more than 0.5mg/kg for males and of 1mg/kg for females but did not cause any histopathological or electron microscopical changes in hearts. It seems that the abnormalities caused by THP in ECG traces are due to the deterioration of general conditions rather than the direct effect on heart.
6. High doses produce the significant change s in platelet, WBC, Hb, Neutro.(Seg.), Mono., Hb, RBC and Lymph. and further regressive changes in thymus, spleen and bone marrow. These results suggest that THP causes some effects on hemopoietic tissues.
7. The sporadic changes in serum biochemistry and urinalysis were neither related to the treatment nor to the changes in organ weight, autopsy, histopathology and electron microscopy. Therefore, it is likely that THP does not cause toxicological effect on the other tissues and organs except hemopoietic tissues.

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