Development of a Colon Delivery Capsule and the Pharmacological Activity of Recombinant Human Granulocyte Colony-stimulating Factor (rhG-CSF) in Beagle Dogs

A peroral dosage form was examined to deliver recombinant human granulocyte colony-stimulating factor (rhG-CSF) to the colon in beagle dogs. A new gelatin capsule with its inside surface coated with ethylcellulose was prepared for this purpose. RhG-CSF was dissolved with propylene glycol and was filled in the capsule. Several kinds of ethylcellulose-gelatin capsules with an ethylcellulose layer of thickness 46 to 221 mm were used. The capsule was filled with propylene glycol solution containing fluorescein as an absorption marker, castor oil derivative and citric acid. The hardness of the capsule was tested after the gelatin layer was dissolved using a hardness tester and was dependent on the thickness of the ethylcellulose layer of the capsule. The time, T_max, at which plasma fluorescein level reaches its maximum following oral administration of ethylcellulose capsules was used as a parameter for the in-vivo disintegration time of the ethylcellulose capsule into the colon. Capsules of thickness 84 mm with a T_max of 4–6 h were filled with rhG-CSF solution containing fluorescein and were administered to dogs. After administration, blood samples were collected for 96 h and the blood total leucocyte (BTL) counts were measured as a pharmacological index of rhG-CSF. The maximum BTL count appeared at 10 h then gradually decreased and returned to its normal level at 48 h. These results suggest the usefulness of ethylcellulose capsules for the delivery of rhG-CSF to the colon and the possibility of a new oral rhG-CSF dosage form has been elucidated.     

Effects of antidepressants on thyroid stimulating hormone release in rats under ether stress

Abstract We found inhibitory effects of antidepressants (clomipramine, maprotyline, mianserin and zimelidine) and 5-hydroxytryptophan (5-HTP) on thyroid stimulating hormone (TSH) release induced by ether stress in freely moving rats. We confirmed that ether stress suppressed the plasma TSH levels after 30 min. We then injected intravenously 250 ng thyrotropin releasing hormone (TRH), 0.1 mg/kg clomipramine, 2.5 mg/kg maprotyline, 2.5 mg/kg mianserin, 0.5 mg/kg zimelidine and 25 mg/kg 5-HTP simultaneously. These materials blocked the influences on plasma TSH levels by the ether stress. Serotonergic antidepressants (clomipramine, zimelidine) and 5-HTP (precursor of serotonin) had a higher potency against the ether stress. These results suggest that antagonizing effects against the ether stress may involve the serotonergic system in the pituitary gland.     

Permeability of NS-3, a Thyrotropin-releasing Hormone Analogue,into the Brain After Its Systemic Administration in Rats: A Microdialysis Study

The concentration of NS-3 (montirelin hydrate, CG 3703), a thyrotropin-releasing hormone (TRH) analogue, in the cerebral cortex of urethane-anaesthetized rats was measured after its systemic administration (1 mgkg^?1, i.v.), using in-vivo microdialysis coupled with a radioimmunoassay. The concentration in microdialysates was highest (24nM) during the first 20 min after injection, and it fell below the detection limit (3.5 nM) 100 min after treatment. The maximal interstitial concentration was estimated to be 0.51 μM. From these results, it is suggested that NS-3 can readily penetrate into the brain.     

Pharmacological Properties of Pteleprenine,a Quinoline Alkaloid Extracted from Orixa japonica,on Guinea-pig Ileum and Canine Left Atrium

We have investigated the pharmacological properties of pteleprenine, a quinoline alkaloid, on contractile responses of the guinea-pig ileum and on inotropic responses of the canine left atrium. Although pteleprenine (0·1–1 μM) had no effect on the contraction of the ileum induced by acetylcholine at 10 μM it significantly inhibited acetylcholine-induced contraction of the ileum. Pteleprenine (0·1–10 μM) reduced nicotine induced-contraction of the ileum in a concentration-dependent manner yet had no maximum relaxant effect even at a concentration of 10 μM From Schild analysis the pA₂ of pteleprenine on the guinea-pig ileum was found to be 6-6. The contraction of the ileum induced by 10 μM 1,1-dimethyl-4-phenylpiperazinium, a specific agonist of nicotinic acetylcholine. receptors, was concentration-dependently suppressed by 10 nM-10 μM pteleprenine. In contrast, 0.1–10 μM pteleprenine did not antagonize the acetylcholine- and nicotine-induced negative inotropic contractile responses of the canine left atrium. These results show that pteleprenine has inhibitory action against nicotinic acetylcholine receptors in the guinea-pig ileum but not in the canine left atrium. Our findings also suggest that pteleprenine might be a novel lead compound as a nicotinic receptor antagonist.     

Liver cell adenoma: A case report and a review of 30 cases reported in Japan

A 38 year old man with a huge liver cell adenoma extending to the pelvis was treated by left lateral lobectomy. The tumour, which was well-encapsulated by fibrous membrane, was 18 × 19 × 6 cm in size and weighed 1500g. Histopathologically, this tumour was composed of well-differentiated liver cell trabeculae and a small number of pseudobiliary ducts, but no Glisson sheaths. For the past 4 years 8 months he has remained asymptomatic. Thirty cases of liver cell adenoma found in Japanese literature are reviewed here and possible pathogenic implications are discussed.     

T-Cell-Dependent Production of IgG by Human Cord Blood B Cells in Reconstituted SCID Mice

Reconstitution of severe combined immunodeficient (SCID) mice with human lymphocytes has recently allowed the elucidation of abnormalities of immune responses in various immunological disorders. In the present study, mononuclear cells (MNC) from neonatal cord blood and adult peripheral blood were intraperitoneally injected into SCID mice to examine induction of human Ig in respective mice recipients. Human IgG was consistently detected in the serum of SCID transferred with adult MNC, but only a few SCID recipients of cord blood MNC showed detectable but low levels of IgG in the serum. The combination experiments of isolated B and T cells disclosed that some interactions between B and T cells might be necessary for IgG production in transferred SCID mice. Notably, transfer of cord blood B cells with adult but not cord blood T cells resulted in efficient induction of IgG, associated with a change in subclass distribution. The results suggest that inability of neonatal B cells to produce IgG can be overcome by transfer with adult mature T cells into SCID mice.     

CD34 expression in endothelial cells of small hepatocellular carcinoma: Its correlation with tumour progression and angiographic findings

The angiogenic process plays an important role in tumour growth and metastasis during hepatocarcinogenesis, but it is still uncertain when the process begins during tumour formation. Forty-two small hepatocellular carcinomas (HCC) that measured either less than or equal to 2 cm in diameter were studied by comparing the histologic findings with the angiographic findings, and with immunohistochemical expression of endothelial marker QB-end/10 (QB), a new monoclonal antibody raised against CD34, in the sinusoidal wall. Twenty (91%) of 22 moderately or poorly differentiated HCC revealed a positive reaction for QB, while only eight (40%) of 20 well differentiated HCC demonstrated a positive reaction (P < 0.01). In the tumours showing a ‘nodule in nodule’ appearance, the less differentiated areas were more reactive for QB. Twenty-three (82%) of 28 QB positive tumours were hypervascular, while only three of 14 (21%) QB negative tumours were hypervascular (P < 0.01) by angiography. All six of the poorly differentiated and 13 (81%) of the 16 moderately differentiated tumours were hypervascular, while only seven (35%) of 20 well differentiated HCC were hypervascular (P < 0.01). These results indicate that as the tumour becomes less differentiated, the QB positive areas become wider and angiography demonstrates hypervascularity. We therefore speculate that the HCC sinusoids acquire the characteristics of capillary and precapillary blood vessels during de-differentiation from well to moderate, and thus the tumour begins to reveal hypervascularity on angiography. The above process may be correlated with the stepwise progression of HCC.     

Correlation between Dose and Tumor Response in the Radiotherapy of Lung Cancer of Various Histological Types

Correlation between dose and tumor response by cell types wasdetermined in 50 patients with lung cancer in order to predictthe possibility of further tumor regression. The TDF (time-dose-fractionation)concept was used as dose factor. The radiation source was a cobalt-60 -ray or linear accelerator10 MV X-ray. As a routine regime a fraction dose of 2 Gy fivetimes per week was given to 39 of the 50 patients, but a doseof 2 Gy three times per week or of 1.5 Gy five times per weekwas given to seven and four patients, respectively. Radiation response was the best in small cell carcinoma andbetter in adenocarcinoma than in squamous cell carcinoma, showinga tumor regression rate of 50% or more in 90%, 80% and 58% ofthe patients, respectively. The correlation between tumor regression rate and TDF valueswas good in squamous cell carcinoma (r=0.73) and small cellcarcinoma (r=- 0.72), but poor in adenocarcinoma (r=- 0.10).These results suggest that in squamous cell carcinoma improvementof tumor regression can be expected by increasing TDF values,and in adenocarcinoma and small cell carcinoma the optimal TDFvalues are about J00 and 60 to 80, respectively.     

"Flare" Followed by Successful Tamoxifen Therapy in Two Cases of Advanced Breast Cancer

An antiestrogen, tamoxifen, is an effective drug in the treatmentof advanced breast cancer. The drug is generally very well toleratedand serious side effects such as the so-called "flare in thetumor" have rarely been observed. We have had two patients withadvanced breast cancer who showed the "flare" soon after theinitiation of tamoxifen therapy, and both patients finally achievedpartial response to tamoxifen. It is important not to misinterpretthe "flare" as progressive disease during tamoxifen therapy.