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At least 19 recordsLinked to original sources
PubMed1976

On the occurrence of argyrophil cells in salivary glands.

Salivary glands (parotid, submandibular and sublingual glands) of nine mammalian species were investigated with respect to presence and localization of argyrophil and argentaffin cells. With the exception of the parotid gland of the rat, no positive staining was observed within the examined glands. In the rat parotid distinctly argyrophil cells could be demonstrated in the intercalated ducts. Histochemical studies of the cells, ultrastructural analysis of their cytoplasmic granules as well as their reactions to certain drugs indicate that these cells are of exocrine rather than of endocrine nature. After a subcutaneous injection of pilocarpine, the intensity of the argyrophil staining was markedly reduced. No specific catecholamine fluorescence could be detected within the cells, not even after pretreatment of the animals with high doses of L-DOPA. The membrane-bounded cytoplasmic granules of the intercalated duct cells furthermore displayed a strong positive staining reaction after treatment of ultrathin Vestopal sections with the periodic acid-chromic acid-silver technique of Rambourg et al. (1969).

Animals↗
PubMed1975

Biodegradation of alpha-hexachlorocyclohexane. IV. The extent of degradation of single doses in vivo.

1. Urine and stools were collected daily of 4 adult rats kept in single cages and injected once i.p. with alpha-hexachlorocyclohexane (alpha-HCH; dose per animal 126-150 mumoles), labelled uniformly with 14-C (10.8-14.0 X 10(6) dpm per animal). 2. In 4 weeks, 65% of the label was excreted through the kidneys and 16% by way of the intestine, with an estimated 8% being retained in depot fat. 3. GLC-analysis of the pooled urine showed it to contain very little unchanged drug, on average 0.05% of the dose. The time-course of the renal excretion of 14-C-labelled substance corresponded rather closely to the excretion of organically bound 36-Cl seen in earlier experiments with 36-Cl-labelled drug, indicating that the majority of urinary metabolites, presumably, still bear chlorine. 4. All or nearly all of the faecal 14-C was found by GLC to be accounted for by the stool's content of unchanged alpha-HCH. 5. Taken together, the results indicate a mean extent of alpha-HCH-degradation in the rat in the order of 80-85% of a dose. 6. Two rats were given 400 mg/kg of "cold" alpha-HCH by mouth 4 days before i.p. application of 14-C-labelled drug and were found to excrete more label through the kidneys in the first week than did the non-pretreated rats. This indicates that the drug stimulates its own degradation.

Adipose Tissue↗
PubMed1979

The pharmacokinetics and biotransformation of the new benzodiazepine lormetazepam in humans. I. Absorption, distribution, elimination and metabolism of lormetazepam-5-14C.

The pharmacokinetics and metabolism of the new benzodiazepine lormetazepam were investigated in five male volunteers using the 14C-labelled drug (position 5). Lormetazepam was administered intravenously and orally, at a dose of 0.2 and 2 mg respectively, to each of the test subjects. Measurements of total radioactivity showed that the drug was absorbed completely and eliminated almost exclusively by the renal route. Maximum plasma level of active ingredient and total radioactivity were observed about 2 hours and 5 hours following oral administration. As early as 30 min following oral administration, concentration of active ingredient amounted to 80% of the maximum values. After both treatments the terminal half-life of total radioactivity and lormetazepam glucuronide in plasma corresponded to the half-life of elimination in urine of about 13 hours. After enzymatic hydrolysis with beta-glucuronidase/arylsulphatase, an average of 90% of total radioactivity from various urine and plasma samples was extractable with ether. Extracts from plasma contained only unchanged drug, indicating free and conjugated lormetazepam as ingredients of total radioactivity. Extracts from urine could be separated into lormetazepam and its N-demethylation derivative lorazepam. The relative amount of excreted lorazepam conjugate was demonstrated to be time-dependent, probably due to enterohepatic circulation. Since less than 6% of the total dose was demethylated by both routes of administration, it can be assumed that lormetazepam is the active product.

Absorption↗
PubMed1978

Neocarzinostatin induction of DNA repair synthesis in HeLa cells and isolated nuclei.

The antitumor antibiotic neocarzinostatin that causes DNA strand breaks in vivo and in vitro is shown to induce DNA repair synthesis in HeLa S3 cells. In the repair assay, the parental DNA was prelabeled with 32P and a density label (bromodeoxyuridine) was introduced into the new synthesized DNA. Quantitation of the repair synthesis as measured by the incorporation of [3H]thymidine into the light parental DNA at varying doses of the drug indicate that there is a significant repair response at low levels of the drug (0.2--0.5 microgram/ml) which cause DNA strand breakage and inhibition of DNA synthesis. In isolated HeLa nuclei neocarzinostatin stimulates the incorporation of dTMP many-fold. This enhancement of dTMP incorporation, which requires the presence of a sulfhydryl agent, is a consequence of the drug-induced DNA strand breakage and is in the parental DNA. These results suggest that an intact cell membrane is not required for DNA strand breakage and its subsequent repair.

Antibiotics, Antineoplastic↗
PubMedDate not supplied

Herpes simplex keratitis.

This article reviews the current concepts for the diagnosis and treatment of Herpes simplex keratitis and its complications, discussing characteristics of the virus, the prevalence of the disease, chemical and clinical differentiation between Types I and II Herpesvirus hominis, and the many clinical presentations of Type I disease. The antiviral agents commonly in use are reviewed, covering the historical development of the drugs, indications for their use and the associated toxic and untoward reactions. An outline for the medical treatment of the different forms of Herpes simplex keratitis is given, as well as the indications for surgical intervention in the treatment of the disease. The surgical complications and results following keratoplasty are discussed.

Animals↗
PubMed2026

Tumor microenvironment-simulated organoids for personalized therapy prediction in head and neck squamous cell carcinoma.

Patient-derived organoids (PDOs) have emerged as promising models for predicting personalized drug responses in cancer therapy. However, the absence of essential immune and stromal components limits their ability to recapitulate the tumor microenvironment. Here, we established a total of 30 patient-derived organoids (PDOs) from 79 patients with locally advanced (LA) and recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). These PDOs maintained sustained expansion capacity and preserved the histopathological characteristics and genomic heterogeneity of their parental tumors. By integrating autologous immune cells and cancer-associated fibroblasts (CAFs) into PDOs, respectively, microenvironment-simulated PDOs (MS-PDOs) were established using a feasible co-culture condition. Compared with conventional PDOs, MS-PDOs-PBMC exhibited specific cytotoxicity and responses to PD-1/PD-L1 inhibitors, while MS-PDOs-CAFs showed enhanced tolerance to chemotherapy drugs, indicating that microenvironment components modulate therapeutic responses in HNSCC. The drug response profiles of MS-PDOs exhibited diverse sensitivity to PD-1/PD-L1 inhibitors, chemotherapy drugs, and combination regimens. Notably, the therapeutic predictions of MS-PDOs were consistent with clinical treatment outcomes, supporting their translational relevance. Collectively, MS-PDOs serve as a robust platform for modeling the tumor microenvironment and predicting therapeutic responses, supporting precision medicine-guided clinical decision-making and offering personalized treatment strategies for HNSCC patients.

Humans↗
PubMed1977

Efficacy and tolerance of Flunixin (SCH 14714) in the treatment of postoperative pain, with observations on the methodology of postoperative pain studies.

A new anti-inflammatory, antipyretic and analgesic drug 2(2'-methyl-3'-trifluoromethylanilino)-nicotinic acid (Flunixin, Sch 14714) was compared with aspirin and a placebo in a double-blind study of pain after four different types of operation. Sch 14714 proved to be superior to the two other drugs after herniorraphy and venous surgery of the leg. The frequency of adverse effects after this drug was, at most. 1.2% which did not differ from the side-effect rates of aspirin or placebo. The second and third days after operation yielded a very high rate of optimal pain relief scores resulting in poor discrimination. Thus cross-over studies seem to be superfluous in the study of pain-relieving drugs in the period following surgery. The patients' rather low demand of analgesic drugs indicated that more stringent enrollment criteria should be adhered to. It was also shown that radical venous surgery constituted a good model for pain studies.

Aniline Compounds↗
PubMed1979

Metronidazole in the treatment of tropical phagedenic ulcers.

In an uncontrolled preliminary trial, metronidazole administered orally to 30 patients was effective in resoving tropical phagedenic ulcers within a period of one to two weeks. The efficacy of this drug indicates the important role played by fusospirochetes in causing tropical ulcers.

Fusobacterium Infections↗
PubMed1977

Acute effect of delta1-tetrahydrocannabinol on the hypothalamo-pituitary-ovarian axis in the rat.

Administration of delta1-tetrahydrocannabinol (delta1-THC), the principal psychoactive ingredient of cannabis, to proestrous rats (2 mg/rat, i.p., between 12.00 and 16.00 h) suppressed the proestrous rise in the plasma levels of LH, FSH and prolactin (Prl) and caused a 24 h delay in ovulation. Furthermore, the increased accumulation of prostaglandins of the E-type (PGE) in the ovaries, normally seen on the evening of proestrus, was prevented. Earlier (08.00-10.30 h) or later (18.00 h) administration of the drug on the day of proestrus was only partially effective in inhibiting ovulation. The suppressive effects of delta1-THC on ovulation and gonadotropin secretion were prevented by administration of gonadetropin releasing hormone (GnRH, 0.2 microgram/rat) 1 h after the drug, indicating that the central action of delta1-THC was exerted on the hypothalamus and not on the pituitary gland. Administration of ovine luteinizing hormore (oLH, 2.5 microgram/rat at 16.30 h on the day of proestrus restored ovulation and ovarian PGE accumulation in Nembutal-treated rats, but not in delta1-THC-treated rats; higher doses of oLH (5-10 microgram/rat) reversed the action of delta1-THC on these two parameters.

Animals↗
PubMed2024

Shared etiology of Mendelian and complex disease supports drug discovery.

BACKGROUND: Drugs targeting disease causal genes are more likely to succeed for that disease. However, complex disease causal genes are not always clear. In contrast, Mendelian disease causal genes are well-known and druggable. Here, we seek an approach to exploit the well characterized biology of Mendelian diseases for complex disease drug discovery, by exploiting evidence of pathogenic processes shared between monogenic and complex disease. One way to find shared disease etiology is clinical association: some Mendelian diseases are known to predispose patients to specific complex diseases (comorbidity). Previous studies link this comorbidity to pleiotropic effects of the Mendelian disease causal genes on the complex disease. METHODS: In previous work studying incidence of 90 Mendelian and 65 complex diseases, we found 2,908 pairs of clinically associated (comorbid) diseases. Using this clinical signal, we can match each complex disease to a set of Mendelian disease causal genes. We hypothesize that the drugs targeting these genes are potential candidate drugs for the complex disease. We evaluate our candidate drugs using information of current drug indications or investigations. RESULTS: Our analysis shows that the candidate drugs are enriched among currently investigated or indicated drugs for the relevant complex diseases (odds ratio = 1.84, p = 5.98e-22). Additionally, the candidate drugs are more likely to be in advanced stages of the drug development pipeline. We also present an approach to prioritize Mendelian diseases with particular promise for drug repurposing. Finally, we find that the combination of comorbidity and genetic similarity for a Mendelian disease and cancer pair leads to recommendation of candidate drugs that are enriched for those investigated or indicated. CONCLUSIONS: Our findings suggest a novel way to take advantage of the rich knowledge about Mendelian disease biology to improve treatment of complex diseases.

Humans↗
PubMed1975

Differential changes in the 5-hydroxytryptamine and insulin content of guinea-pig B-cells.

In the guinea-pig pancreas, 5-hydroxy-tryptamine (5-HT) occurs in the B-cells as well as in enterochromaffin cells scattered in the exocrine parenchyma. In the present study we examined the effects on the pancreatic 5-HT and insulin content of drugs known to affect the B-cells. For this purpose a radioimmunoassay of guinea-pig insulin was developed. Streptozotocin reduced the number of detectable B-cells and partially degranulated those that remained. It also lowered the insulin content of the pancreas and the 5-HT content of the B-cells but did not affect the 5-HT content of the enterochromaffin cells. Reserpine lowered the 5-HT content of both B-cells and enterochromaffin cells. The number and ultrastructure of the B-cells and the pancreatic insulin content was not affected. Streptozotocin + reserpine seemed to have additive effects of B-cell 5-HT. The results with these 2 drugs indicate that roughly 50% of pancreatic 5-HT is contained in the B-cells. Diazoxide markedly increased the pancreatic insulin content without affecting pancreatic 5-HT. Despite the fact that 5-HT and insulin are stored together in the cytoplasmic granules of the B-cells, 5-HT was differentially depleted from this store by reserpine. A marked disproportionality between 5-HT and insulin content was also induced by diazoxide.

Animals↗
PubMed1977

[Pharmacological studies on carprofen, a new non-steroidal anti-inflammatory drug, in animals (author's transl)].

The pharmacological profile of carprofen as a new non-steroidal anti-inflammatory drug has been established in various experimental inflammation models in animals. This compound possesses marked effects on prevention of adjuvant arthritis, cotton-pellet granuloma formation and hyperalgesic edema (scalding) and the extent is similar to that observed with indomethacin and piroxicam. The anti-inflammatory potency of carprofen is markedly stronger than those seen in cases of phenylbutazone, mefenamic acid, ibufenac and acetylsalicylic acid, almost equal to that of diclofenac and slightly lower than that of indomethacin in the following parameters: carrageenin-edema, granuloma-pouch, UV-erythema, and bradykinin and histamine-induced capillary permeability. As is the case with other non-steroidal anti-inflammatory drugs, carprofen has no inhibitory effect on lethal anaphylactic shock, passive cutaneous anaphylaxis and hyperuricemia. Carprofen induces ulcerogenicity and fecal occult bleeding to a extent markedly less than those seen with indomethacin and piroxicam. These investigations on anti-inflammatory drugs indicate a probable dissimilarity to the extent of anti-inflammatory effects and induction of gastrointestinal disturbances. Repeated administration of carprofen has no effect on spontaneous excretion of corticosterone and aldosterone into adrenal vein of rats.

Adrenal Cortex↗
PubMed1979

Bleomycin.

Bleomycin was approved by the Food and Drug Administration in 1975 for therapy against squamous cell carcinomas, testicular cancers, and malignant lymphomas. An extensive bibliography on this drug indicates that there is little evidence of activity against other malignancies. Although initially used exclusively as a single agent, bleomycin has been considered recently for use in combination chemotherapy. Because of associated toxicity involving the lung and mucous membranes, bleomycin should be used cautiously by physicians, particularly in noninvestigational settings.

Bleomycin↗
PubMed1975

Behavioral correlates of serotonin depletion.

Depletion of telencephalic serotonin (5-HT) content by medical forebrain bundle lesions, which interrupt the ascending serotonergic pathways or by DL-p-chlorophenylalanine produces an increased sensitivity to pain as measured by the flinch-jump, stabilimetric, or hot-plate methods. Examination of the effects of a number of other lesions and drugs indicated that dopamine, norepinephrine and acetylcholine are not involved in pain sensitivity. Dosages of 75 mg/kg DL-5-hydroxytryptophan(5-HTP), 37.5 mg/kg L-5-HTP or 50 mg/kg Ro 4-4602 (NI-(DL-seryl)-N2-(2,3,4-trihydroxybenzyl)hydrazine) plus 37.5 mg/kg L-5-HTP administered to medical forebrain bundle lesioned rats returned both the telencephalic content of 5-HT and the pain threshold to normal values. Injection of 37.5 mg/kg of D-5-HTP or an equimolar dose of L-dopa had no effect on pain threshold. Normal animals display increased sensitivity to pain and decreased 5-HT contents in frontal pole, hippocampus, and amygdala during dark as compared to light hours. All three of these telencephalic areas are innervated by the ascending serotonergic pathways, and cells in these areas show inhibition of firing following the iontophoretic application of 5-HT. Taken together these data suggest that the serotonergic system normally acts to inhibit the effects of painful stimuli. A review of a variety of behavioral effects of 5-HT depletion including an enhanced response to lysergic acid diethylamide and amphetamine suggests that the ascending serotonergic system may have a general role in the inhibition of arousal, rather than a specific role with respect to various categories of behavior.

5-Hydroxytryptophan↗
PubMed1975

Chloroquine-resistant malaria in Burma.

Two field trials to detect chloroquine-resistant malaria were conducted according to WHO recommendations in a malaria free area near Rangoon. Peripheral blood smears were examined for asexual forms of P. falciparum on day one through to day seven, on day 14, 21, and 28 after a standard dose of 1500 mg. of chloroquine base. Haskins test to detect chloroquine in urine was done on all cases and plasma chloroquine levels were measured in some. Out of 105 patients tested RI resistance was detected in 66, RII in 19 and RIII in three. Subsequent trials with other anti-malarial drugs indicated that the chloroquine-resistant P. falciparum were also resistant to one day therapy with pyrimethamine 50 mg. or sulphamethoxypyridazine 1 G given singly; and resistant to one day therapy with combinations of pyrimethamine 50 mg. plus sulphamethoxy pyridazine 1 G, pyrimethamine 13 mg. plus dapsone 100 mg., and trimethoprim 320 mg. plus sulphamethoxazole 1600 mg. All those tested were sensitive to quinine sulphate, 0-6 G given three times a day for 10 days, and were also sensitive to one day therapy with combinations of trimethoprim 500 mg. plus sulphalene 1 G, and pyrimethamine 50 mg. plus sulphamethoxine 1 G. Pyrimethamine 12-5 mg. plus dapsone 100 mg. in weekly doses was shown to be an effective chemoprophylaxis. Quinine was tested on 38 subjects while other drug schedule were tested on six to eight subjects.

Chloroquine↗
PubMed1976

The effects of cyclic AMP on leucocyte inhibitory factor (LIF) production and on the inhibition of leucocyte migration.

The effect of drugs known to increase intracellular levels of cyllic AMP were studied in the leucocyte migration ihibition system. It was found that cyclic AMP, dibutyryl cyclic AMP, theophyline, and prostaglandins E1 and E2 inhibited the production of leucocyte inhibiting factor by HA pulsed lymphocytes Inhibition only occured when the drugs were present during or after the PHA pulse. In addition it was found that these drugs enhanced the migration of polymorphonuclear leucocytes (PMN), in this system. Electrophoretic mobility of PMN cells was not altered by these drug indicating that the effect is not due to changes in membrane charge. However, granulocyte adhesion was reduced in the presence of these drug suggesting that adhesion is of primary importance in the migration of polymorphonuclear leucocytes out of capillary tubes. The findings show that cyclic AMP is important in modulating both cell-mediated and inflammatory responses.

Bucladesine↗
PubMed1976

Differential effects of prostaglandin synthetase inhibitors on prostaglandin E2 binding and on prostaglandin- or cholera toxin-induced cyclic AMP accumulation in the rabbit uterus.

Cyclic 3',5'-nucleotide phosphodiesterase (PDE) activity in rabbit uterine homogenate was inhibited by indomethacin (10 mug/ml; 66% inhibition) or flufenamic and (10 mug/ml; 60%). Indomethacin (100 mug/ml) reduced uterine prostaglandin E2 (PGE2) content by 80%, but potentiated the stimulatory action of purified cholera toxin (choleragen; 800%) and of exogenous PGE2 (140%) on cyclic AMP accumulation, probably through its inhibitory effect on cyclic AMP destruction. These findings suggest that endogenous PGE2 is not an essential mediator of choleragen action. By contrast, flufenamic acid abolished choleragen and PGE2 action on cyclic AMP production. Unlabeled PGE2 (10 mug/ml), flufenamic acid, indomethacin, and aspirin (100 mug/ml each) inhibited [3H]PGE2 binding to uterine slices by 78, 73, 62, and 20% respectively. It is concluded that while indomethacin and flufenamic acid have similar effects on prostaglandin biosynthesis and PDE activity, only fenamates have an inhibitory effect on the biological action of exogenous PGE2 and choleragen on the stimulation of cyclic AMP production, probably through the inhibition of the binding of PGE2 and choleragen to its specific receptor sites. The diverse biochemical actions of the above drugs indicate that care has to be taken when using these drugs in analyzing the physiopathological roles of prostaglandins.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1979

A multicentre pilot study of parenteral and rectal administration of domperidone in the treatment of severe vomiting in children.

A small scale pilot study among 41 children with severe vomiting, showed that a single administration of domperidone either intravenously, intramuscularly or rectally, effectively controlled the symptom within 3 hours in 36 (88%) patients. The excellent results together with the safety of this new drug indicate its potential value in these patients.

Adolescent↗