DESOXYRIBONUCLEIC ACID SYNTHESIS (DNA) IN THE RAT OVARY AFTER TREATMENT WITH ORAL CONTRACEPTIVES

ABSTRACT The radioactively labelled ovaries of Wistar rats were examined by autoradiography and activity measurement after long-term treatment of varying duration with an oral contraceptive (Lyndiol®). The administration of Lyndiol® led to the absence of the normal oestrous cycle and, after more prolonged treatment, to a reduction both in the number and size of follicles and to atrophy of the ovaries. As calculated per 1 mg dry organ weight, the DNA values found were within the range of the cycle-dependent fluctuations; however, they were a great deal lower when the reduced organ weight was taken into account.

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JAK1-dependent transphosphorylation of JAK2 limits the antifibrotic effects of selective JAK2 inhibitors on long-term treatment

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2016-210911 ◽

2017 ◽

Vol 76 (8) ◽

pp. 1467-1475 ◽

Cited By ~ 18

Author(s):

Yun Zhang ◽

Ruifang Liang ◽

Chih-Wei Chen ◽

Tatjana Mallano ◽

Clara Dees ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Chronic Treatment ◽

Term Treatment ◽

Janus Kinase ◽

Prolonged Treatment ◽

Therapeutic Effects ◽

Long Term Treatment ◽

Jak2 Inhibition ◽

Jak2 Inhibitors

ObjectivesJanus kinase 2 (JAK2) has recently been described as a novel downstream mediator of the pro-fibrotic effects of transforming growth factor-β. Although JAK2 inhibitors are in clinical use for myelodysplastic syndromes, patients often rapidly develop resistance. Tumour cells can escape the therapeutic effects of selective JAK2 inhibitors by mutation-independent transactivation of JAK2 by JAK1. Here, we used selective JAK2 inhibition as a model to test the hypothesis that chronic treatment may provoke resistance by facilitating non-physiological signalling pathways in fibroblasts.MethodsThe antifibrotic effects of long-term treatment with selective JAK2 inhibitors and reactivation of JAK2 signalling by JAK1-dependent transphosphorylation was analysed in cultured fibroblasts and experimental dermal and pulmonary fibrosis. Combined JAK1/JAK2 inhibition and co-treatment with an HSP90 inhibitor were evaluated as strategies to overcome resistance.ResultsThe antifibrotic effects of selective JAK2 inhibitors on fibroblasts decreased with prolonged treatment as JAK2 signalling was reactivated by JAK1-dependent transphosphorylation of JAK2. This reactivation could be prevented by HSP90 inhibition, which destabilised JAK2 protein, or with combined JAK1/JAK2 inhibitors. Treatment with combined JAK1/JAK2 inhibitors or with JAK2 inhibitors in combination with HSP90 inhibitors was more effective than monotherapy with JAK2 inhibitors in bleomycin-induced pulmonary fibrosis and in adTBR-induced dermal fibrosis.ConclusionFibroblasts can develop resistance to chronic treatment with JAK2 inhibitors by induction of non-physiological JAK1-dependent transactivation of JAK2 and that inhibition of this compensatory signalling pathway, for example, by co-inhibition of JAK1 or HSP90 is important to maintain the antifibrotic effects of JAK2 inhibition with long-term treatment.

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Long-term treatment with the dopamine agonist quinagolide of patients with clinically non-functioning pituitary adenoma

Acta Endocrinologica ◽

10.1530/eje.0.1430615 ◽

2000 ◽

pp. 615-621 ◽

Cited By ~ 28

Author(s):

FR Nobels ◽

WW de Herder ◽

WM van den Brink ◽

DJ Kwekkeboom ◽

LJ Hofland ◽

...

Keyword(s):

Dopamine Agonist ◽

Tumor Volume ◽

Term Treatment ◽

Alpha Subunit ◽

Prolonged Treatment ◽

Visual Field Defects ◽

Entire Treatment Period ◽

Long Term Treatment ◽

Serum Gonadotropin

OBJECTIVE: This study was performed to evaluate the effect of prolonged treatment with the dopamine agonist quinagolide on serum gonadotropin and alpha-subunit concentrations and tumor volume in patients with clinically non-functioning pituitary adenomas (CNPA). DESIGN: Ten patients with CNPA were treated with quinagolide (0.3 mg daily). The median duration of treatment was 57 months (range 36-93 months). Blood samples for measurement of serum gonadotropin and alpha-subunit concentrations were drawn before treatment, after 5 days, and at each outpatient visit. Computerized tomography or magnetic resonance imaging of the pituitary region and Goldmann perimetry were done before and at regular intervals during treatment. RESULTS: A significant decrease of serum FSH, LH or alpha-subunit concentrations was found in nine patients. The levels remained low during the entire treatment period. In two out of three patients with pre-existing visual field defects a slight improvement was shown during the first months of treatment, but eventually deterioration occurred in all three patients. A fourth patient developed unilateral ophthalmoplegia during treatment. During the first year tumor volume decreased in three patients, but in two of them regrowth occurred after a few months. In six patients progressive tumor growth occurred despite sustained suppression of gonadotropin or alpha-subunit levels. CONCLUSIONS: Long-term treatment of patients with CNPA with high doses of the dopamine agonist quinagolide could not prevent progressive increase in tumor size in most patients. It remains unproven whether quinagolide retards CNPA growth. Additional studies are needed to investigate whether subgroups of patients, e.g. those with positive dopamine receptor scintigraphy or those with marked hypersecretion of intact gonadotropins or subunits, will respond more favorably to treatment with dopamine agonists.

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A longitudinal study of psychotropic drug prescription

Psychological Medicine ◽

10.1017/s0033291700043464 ◽

1982 ◽

Vol 12 (1) ◽

pp. 201-206 ◽

Cited By ~ 58

Author(s):

P. Williams ◽

J. Murray ◽

A. Clare

Keyword(s):

Longitudinal Study ◽

Psychotropic Drug ◽

Drug Prescription ◽

Term Treatment ◽

Psychological Morbidity ◽

Prolonged Treatment ◽

Cross Sectional ◽

Long Term Treatment ◽

Cross Sectional Studies

SynopsisWhile many of the characteristics of psychotropic drug consumers have been established by means of cross-sectional studies, little is known about new consumers and the factors which predispose to long-term treatment. We report on a longitudinal study of 153 general practice patients beginning a new course of psychotropic drug treatment and characterized by extensive physical and psychological morbidity. About 1 in 5 were still receiving psychotropic drugs 6 months later and this prolonged treatment was associated with increased age, previous psychotropic drug-use, higher levels of psychological morbidity at the inception of treatment and, for the women only, social problems as perceived by the general practitioners.

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Active postoperative acromegaly: sustained remission after discontinuation of somatostatin analogues

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-16-0092 ◽

2016 ◽

Vol 2016 ◽

Cited By ~ 2

Author(s):

Cristina Alvarez-Escola ◽

Jersy Cardenas-Salas

Keyword(s):

Low Dose ◽

Disease Recurrence ◽

Somatostatin Analogues ◽

Term Treatment ◽

Treatment Discontinuation ◽

Treatment Withdrawal ◽

Prolonged Treatment ◽

Sustained Remission ◽

Long Term Treatment

Summary In patients with active acromegaly after pituitary surgery, somatostatin analogues are effective in controlling the disease and can even be curative in some cases. After treatment discontinuation, the likelihood of disease recurrence is high. However, a small subset of patients remains symptom-free after discontinuation, with normalized growth hormone (GH) and insulin-like growth factor (IGF1) levels. The characteristics of patients most likely to achieve sustained remission after treatment discontinuation are not well understood, although limited evidence suggests that sustained remission is more likely in patients with lower GH and IGF1 levels before treatment withdrawal, in those who respond well to low-dose treatment, in those without evidence of adenoma on an MRI scan and/or in patients who receive long-term treatment. In this report, we describe the case of a 56-year-old female patient treated with lanreotide Autogel for 11 years. Treatment was successfully discontinued, and the patient is currently disease-free on all relevant parameters (clinical, biochemical and tumour status). The successful outcome in this case adds to the small body of literature suggesting that some well-selected patients who receive long-term treatment with somatostatin analogues may achieve sustained remission. Learning points: The probability of disease recurrence is high after discontinuation of treatment with somatostatin analogues. Current data indicate that remission after treatment discontinuation may be more likely in patients with low GH and IGF1 levels before treatment withdrawal, in those who respond well to low-dose treatment, in those without evidence of adenoma on MRI, and/or in patients receiving prolonged treatment. This case report suggests that prolonged treatment with somatostatin analogues can be curative in carefully selected patients.

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The Influence of Long-Term Treatment with Asenapine on Liver Cytochrome P450 Expression and Activity in the Rat. The Involvement of Different Mechanisms

Pharmaceuticals ◽

10.3390/ph14070629 ◽

2021 ◽

Vol 14 (7) ◽

pp. 629

Author(s):

Przemysław J. Danek ◽

Ewa Bromek ◽

Władysława A. Daniel

Keyword(s):

Growth Hormone ◽

Cytochrome P450 ◽

Term Treatment ◽

Prolonged Treatment ◽

Cytochrome P450 Enzymes ◽

Protein Levels ◽

Liver Cytochrome ◽

Long Term Treatment ◽

Expression And Activity

Therapy of schizophrenia requires long-term treatment with a relevant antipsychotic drug to achieve a therapeutic effect. The aim of the present study was to investigate the influence of prolonged treatment with the atypical neuroleptic asenapine on the expression and activity of rat cytochrome P450 (CYP) in the liver. The experiment was carried out on male Wistar rats. Asenapine (0.3 mg/kg s.c.) was administered for two weeks. The levels of CYP mRNA protein and activity were determined in the liver and hormone concentrations were measured in the pituitary gland and blood serum. Asenapine significantly decreased the activity of CYP1A (caffeine 8-hydroxylation and 3-N-demethylation), CYP2B, CYP2C11 and CYP3A (testosterone hydroxylation at positions 16β; 2α and 16α; 2β and 6β, respectively). The neuroleptic did not affect the activity of CYP2A (testosterone 7α-hydroxylation), CYP2C6 (warfarin 7-hydroxylation) and CYP2E1 (chlorzoxazone 6-hydroxylation). The mRNA and protein levels of CYP1A2, CYP2B1, CYP2C11 and CYP3A1 were decreased, while those of CYP2B2 and CYP3A2 were not changed. Simultaneously, pituitary level of growth hormone-releasing hormone and serum concentrations of growth hormone and corticosterone were reduced, while that of triiodothyronine was enhanced. In conclusion, chronic treatment with asenapine down-regulates liver cytochrome P450 enzymes, which involves neuroendocrine mechanisms. Thus, chronic asenapine treatment may slow the metabolism of CYP1A, CYP2B, CYP2C11 and CYP3A substrates (steroids and drugs). Since asenapine is metabolized by CYP1A and CYP3A, the neuroleptic may inhibit its own metabolism, therefore, the plasma concentration of asenapine in patients after prolonged treatment may be higher than expected based on a single dose.

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Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer’s disease

Science Advances ◽

10.1126/sciadv.aav0316 ◽

2019 ◽

Vol 5 (3) ◽

pp. eaav0316 ◽

Cited By ~ 27

Author(s):

Jong-Hyun Park ◽

Yeon Ha Ju ◽

Ji Won Choi ◽

Hyo Jung Song ◽

Bo Ko Jang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Term Treatment ◽

Prolonged Treatment ◽

Compensatory Mechanisms ◽

Short Term Treatment ◽

Mao B ◽

Gaba Production ◽

Long Term Treatment

Monoamine oxidase–B (MAO-B) has recently emerged as a potential therapeutic target for Alzheimer’s disease (AD) because of its association with aberrant γ-aminobutyric acid (GABA) production in reactive astrocytes. Although short-term treatment with irreversible MAO-B inhibitors, such as selegiline, improves cognitive deficits in AD patients, long-term treatments have shown disappointing results. We show that prolonged treatment with selegiline fails to reduce aberrant astrocytic GABA levels and rescue memory impairment in APP/PS1 mice, an animal model of AD, because of increased activity in compensatory genes for a GABA-synthesizing enzyme, diamine oxidase (DAO). We have developed a potent, highly selective, and reversible MAO-B inhibitor, KDS2010 (IC50= 7.6 nM; 12,500-fold selectivity over MAO-A), which overcomes the disadvantages of the irreversible MAO-B inhibitor. Long-term treatment with KDS2010 does not induce compensatory mechanisms, thereby significantly attenuating increased astrocytic GABA levels and astrogliosis, enhancing synaptic transmission, and rescuing learning and memory impairments in APP/PS1 mice.

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Lentivirus Mediated siRNA against GluN2B Subunit of NMDA Receptor Reduces Nociception in a Rat Model of Neuropathic Pain

BioMed Research International ◽

10.1155/2014/871637 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Feixiang Wu ◽

Ruirui Pan ◽

Jiaying Chen ◽

Megumi Sugita ◽

Caiyang Chen ◽

...

Keyword(s):

Neuropathic Pain ◽

Chronic Constriction Injury ◽

Term Treatment ◽

Prolonged Treatment ◽

Small Interference Rna ◽

Study Results ◽

Long Term Treatment ◽

Mrna And Protein Expression ◽

Promising Treatment

Although neuropathic pain (NP) is still not fully understood by scientists and clinicians alike, studies suggest that N-methyl-D-aspartate (NMDA) receptors play an important role in the induction and maintenance of NP. A promising treatment for NP is through the downregulation of NMDA subunit GluN2B by RNA interference; however, naked siRNA (small interference RNA) is not effective in long-term treatments. In order to concoct a viable prolonged treatment for NP, Lv-siGluN2B (lentivirus carrying siRNA targeting GluN2B subunit) was prepared and the antinociception effects were observed in chronic constriction injury (CCI) rats in the present study. Results showed that Lv-siGluN2B was transduced into spinal cord cells after intrathecal injections and effectively reduced the nociception induced by sciatic nerve ligation while inhibiting the mRNA and protein expression of GluN2B. This antinociception effect lasted approximately 7 weeks. These findings suggest that GluN2B subunit could be a target for NP treatment and Lv-siGluN2B represents a new potential option for long-term treatment of NP.

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Social adaptation of children with cancer after prolonged treatment

Journal of Modern Foreign Psychology ◽

10.17759/jmfp.2020090312 ◽

2020 ◽

Vol 9 (3) ◽

pp. 127-142

Author(s):

Yu.E. Kurtanova ◽

Yu.A. Burdukova ◽

A.M. Shcherbakova ◽

V.D. Shchukina ◽

A.A. Ivanova

Keyword(s):

Emotional Disorders ◽

Term Treatment ◽

Social Adaptation ◽

Psychological State ◽

Prolonged Treatment ◽

Social Maladjustment ◽

Children With Cancer ◽

Long Term Treatment ◽

Close Relatives

The article is an overview of foreign studies on the socialization of children with cancer in medical history. Studies show that the presence of cancer diagnosis is the strongest stress factor for the child, as well as his long-term hospitalization, painful medical procedures, asthenization, emotional deprivation, separation from the usual lifestyle and close relatives. All this negatively affects the psychological state of the child and his reintegration into society after a long-term treatment. Particular attention is paid to publications about the difficulties a child faces when returning to society. They show that children with cancer (cured or in the state of remission) have difficulties in social interaction, learning problems, cognitive difficulties, which can lead to emotional disorders. The studies aimed at assessing the family situation of children with cancer have been analyzed. The article also describes potential strategies aimed at preventing and correcting social maladjustment of children as well as at psychological support of children with cancer and their families.

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