Withdrawal Of Drug Treatment Research Articles

Tacrolimus- and sirolimus-induced human β cell dysfunction is reversible and preventable.

Posttransplantation diabetes mellitus (PTDM) is a common and significant complication related to immunosuppressive agents required to prevent organ or cell transplant rejection. To elucidate the effects of 2 commonly used agents, the calcineurin inhibitor tacrolimus (TAC) and the mTOR inhibitor sirolimus (SIR), on islet function and test whether these effects could be reversed or prevented, we investigated human islets transplanted into immunodeficient mice treated with TAC or SIR at clinically relevant levels. Both TAC and SIR impaired insulin secretion in fasted and/or stimulated conditions. Treatment with TAC or SIR increased amyloid deposition and islet macrophages, disrupted insulin granule formation, and induced broad transcriptional dysregulation related to peptide processing, ion/calcium flux, and the extracellular matrix; however, it did not affect regulation of β cell mass. Interestingly, these β cell abnormalities reversed after withdrawal of drug treatment. Furthermore, cotreatment with a GLP-1 receptor agonist completely prevented TAC-induced β cell dysfunction and partially prevented SIR-induced β cell dysfunction. These results highlight the importance of both calcineurin and mTOR signaling in normal human β cell function in vivo and suggest that modulation of these pathways may prevent or ameliorate PTDM.

Nuclear receptor agonist-driven modification of inflammation and amyloid pathology enhances and sustains cognitive improvements in a mouse model of Alzheimer\u2019s disease

BackgroundAlzheimer’s disease (AD) is a highly prevalent neurodegenerative disorder characterized by pathological hallmarks of beta-amyloid plaque deposits, tau pathology, inflammation, and cognitive decline. Treatment remains a clinical obstacle due to lack of effective therapeutics. Agonists targeting nuclear receptors, such as bexarotene, reversed cognitive deficits regardless of treatment duration and age in murine models of AD. While bexarotene demonstrated marked efficacy in decreasing plaque levels following short-term treatment, prolonged treatment did not modulate plaque burden. This suggested that plaques might reform in mice treated chronically with bexarotene and that cessation of bexarotene treatment before plaques reform might alter amyloid pathology, inflammation, and cognition in AD mice.MethodsWe utilized one-year-old APP/PS1 mice that were divided into two groups. We treated one group of mice for 2 weeks with bexarotene. The other group of mice was treated for 2 weeks with bexarotene followed by withdrawal of drug treatment for an additional 2 weeks. Cognition was evaluated using the novel-object recognition test either at the end of bexarotene treatment or the end of the withdrawal period. We then analyzed amyloid pathology and microgliosis at the conclusion of the study in both groups.ResultsBexarotene treatment enhanced cognition in APP/PS1 mice similar to previous findings. Strikingly, we observed sustained cognitive improvements in mice in which bexarotene treatment was discontinued for 2 weeks. We observed a sustained reduction in microgliosis and plaque burden following drug withdrawal exclusively in the hippocampus.ConclusionsOur findings demonstrate that bexarotene selectively modifies aspects of neuroinflammation in a region-specific manner to reverse hippocampal-dependent cognitive deficits in AD mice and may provide insight to inform future studies with nuclear receptor agonists.

DEMOGRAFINIŲ VEIKSNIŲ SĄSAJOS SU KLINIKINE GREIVSO LIGOS IŠRAIŠKA IR BAIGTIMI

Graves‘ disease is an autoimmune thyroid disorder characterized by the presence of autoantibodies against thyrotropin receptor. Antithyroid drugs are effective in controlling hyperthyroidism, but only one-third of patients achieve long-term remission after antithyroid drug treatment withdrawal. Influence of demographic factors (such as age and gender) on clinical features and outcome of Graves’ disease remains unclear despite decades of scientific research. The aim of the study was to determine the influence of age and gender on clinical features and outcome of Graves’ disease. Matherial and methods. We performed a retrospective study of 194 adult patients with newly diagnosed Graves’ disease. Outcome after antithyroid drugs was defined as remission or failed. Results. The mean age of males was greater than females (p=0,022). Males and females had the same outcome after medical therapy. The presence of large goiter was associated with lower mean age at diagnosis in both females and males. Patients less than 40 yr. of age were more likely to have large goiter (grade III) than smaller goiter (grade I/II) compared with older patients (OR 2.81, 95% CI 1.35 –5.84). Age at disease onset had no significant relationship with the medical treatment failure. Conclusions. Age less than 40 yr. is a significant predictor for the presence of large goiter at diagnosis. Age and gender did not predict the outcome of Graves’ disease.

Regression of Normalized Left Ventricular Systolic Function After Discontinuation of Treatment in Patients With Dilated Cardiomyopathy

Regression of Normalized Left Ventricular Systolic Function After Discontinuation of Treatment in Patients With Dilated Cardiomyopathy

Suppression of autoimmune disease in NZB/W F1 mice by treatment with the novel immunomodulator BTS 63155.

Autoimmune disease in NZB/W F1 mice was treated from 23 weeks of age with the novel immunomodulator BTS 63155 and, for comparative purposes, the established immunosuppressive agent cyclosporin A. Both drugs significantly improved survival compared with untreated controls. Lupus nephritis was also significantly reduced in the drug-treated groups, and this was related to reduced glomerular deposition of IgG. Autoantibody (ANA) levels were lowered by treatment with cyclosporin A, but not by BTS 63155. This latter finding may indicate a different mode of action for the two drugs. In a long term study, neither drug effected a complete cure, as autoimmune disease recurred on withdrawal of drug treatment.

The effect of long-term exposure to combinations of growth promoters in Long Evans rats: Part 2. Adrenal morphology (histopathology and immunochemical studies)

The aim of the study was to investigate the effects of long-term exposure (45 days) to growth promoters: clenbuterol (CB: 1mgkg−1bw) and/or dexamethasone (DEX: 0.1mgkg−1bw), in adrenal gland morphology, and the possibility of recovery after the withdrawal of drug treatment. Animals were sacrificed at different days of withdrawal (W0, W5, W10, W15 and W20), and adrenal glands processed for histopathology and immunohistochemistry. Adrenals of CB treatment showed typical features of long-term administration of β-agonists at W0 such as capillary dilatation in the fasciculata-reticularis zone, and this feature was also presented at W20. Adrenals of CB+DEX treatments showed the same results of CB treatment at days W0 and W20. However, DEX treatment presented the typical results of the exposure to corticoids with the atrophy of adrenal cortex. Immunohistochemistry of adrenal cortex steroidogenic enzymes (P450: scc, 3β-HSD, aromatase) denoted that neither positive staining nor localization was affected by treatments. Aromatase enzyme was immunolocalized in adrenal medulla cells in controls as well as in treated groups. The immunolocalization of glucocorticoid receptors showed an increase in CB (+++) and CB+DEX (++) treatments compared to the control group (0) and DEX treatment (0). Histopathological and immunohistochemical results are closely related to those found for adrenal endocrine function. We can conclude that chronic administration of growth promoters influence adrenal morphology and glucocorticoid receptor expression.

Effect of long-term exposure to combinations of growth promoters in Long Evans rats: Part 2: ovarian morphology

The aim of the study was to investigate the effects of long-term exposure (45 days) to growth promoters: clenbuterol (CB, 1 mg kg −1 bw) and/or dexamethasone (DEX, 0.1 mg kg −1 bw), in ovarian morphology, and the possibility of recovery after the withdrawal of drug treatment. Animals were sacrificed at different days of withdrawal (W0, W5, W10, W15 and W20). Ovaries of CB treatment showed typical features of long-term administration of β-agonists at W0 with antral and atretic follicles, and the absence of corpora lutea, indicating disrupted cyclicity of rats. However, at W20 ovaries showed cyclic features with corpora lutea, antral follicles, and even recently ovulated follicles. Ovaries of CB+DEX and DEX treatments showed features of disrupted cyclicity at W0 also with cystic follicles, and fewer healthy antral follicles than those of treatment I, these same features also being observed at W20. Immunohistochemistry (IHC) of ovaries denoted that neither positive staining nor localization of steroidogenic enzymes were affected by treatments. We can conclude that treatments can disrupt the reproductive function.

Effect of long-term exposure to combinations of growth promoters in Long Evans rats: Part 1. Endocrine ovarian function

The aim of the study was to investigate the effects of long-term exposure (45 days) to growth promoters: clenbuterol (CB; 1 mg kg −1 body weight) and/or dexamethasone (DEX; 0.1 mg kg −1), in rat endocrine ovarian function and the possibility of recovery after the withdrawal of drug treatment. Animals were sacrificed at different days of withdrawal (W0–W20). Hormone profiles were as follows. Progesterone: CB-treated rats showed significantly lowered plasma ( P<0.01) and elevated ovarian levels until 10 days of withdrawal ( P<0.01); (CB+DEX)-treated rats showed both increased plasma and ovarian levels ( P<0.001); DEX-treated rats showed elevated plasma and lowered ovarian levels during the whole withdrawal. 17β-Estradiol: CB-treated rats showed significantly elevated plasma until 10 days of withdrawal and lowered ovarian levels during the whole withdrawal ( P<0.001); (CB+DEX)-treated rats showed significantly elevated plasma and lowered ovarian levels during the whole withdrawal ( P<0.001); DEX-treated rats showed increased plasma and ovarian levels ( P<0.001). It was concluded that long-term administration of clenbuterol and/or dexamethasone causes an endocrine ovarian disruption with changes in ovarian steroid secretion. However, after a 20-day withdrawal period, ovarian endocrine function was recovered in CB-treated rats.

Supraventricular tachycardia in infants, children and adolescents: diagnosis, and pharmacological and interventional therapy.

Supraventricular tachycardia is the most frequent form of symptomatic tachydysrhythmia in children. Neonates and infants with paroxysmal supraventricular tachycardias generally present with signs of acute congestive heart failure. In school-aged children and adolescents, palpitations are the leading symptom. Chronic-permanent tachycardia results in a secondary form of dilated cardiomyopathy. Therapy for episodes of tachycardia depends on the individual situation. In severe haemodynamic compromise, or if ventricular tachycardia is suspected, tachycardia should immediately be terminated by external cardioversion during deep sedation. Vagal manoeuvres are effective in patients with atrioventricular reentrant tachycardias. Adenosine is the drug of first choice in any age group for tachycardias involving the atrioventricular node; its advantages include short half-life and minimal or absent negative inotropic effects. Adenosine may also be used in patients with wide QRS complex tachycardia. Intravenous verapamil is contraindicated in neonates and infants because of the high risk of electromechanical dissociation. In older children (>5 years) and adolescents, verapamil may be administered with the same restrictions as in adult patients (wide QRS complex tachycardia, significant haemodynamic compromise). Spontaneous cessation of tachycardia can be expected in most neonates and infants during the first year of life. Prophylactic pharmacological treatment in this age group is advisable because recognition of tachycardia is often delayed until the occurrence of symptoms. Withdrawal of drug treatment should be attempted around the end of the first year. However, in older children, spontaneous cessation of tachycardia is rare. Prophylactic drug therapy is performed on an empirical basis. Digoxin may be administered in all forms of supraventricular tachycardia in which the atrioventricular node is involved, except in patients with pre-excitation syndrome aged >1 year. In patients with atrioventricular reentrant tachycardia, class IC drugs such as flecainide and propafenone are effective. Sotalol is also effective in atrioventricular reentrant tachycardia, as well as in primary atrial tachycardia. Although amiodarone has the highest antiarrhythmic potential, it should be used with caution because of its high rate of adverse effects. In school-aged children and adolescents, radiofrequency catheter ablation of the anatomical substrate is an attractive alternative to drug therapy, with a rate of permanent cessation of the tachycardia of up to 90%. Despite the clear advantages of this procedure, it should be performed only with unquestionable indication; the long term morphological and electrophysiological sequelae on the growing atrial and ventricular myocardium are still unknown.

Abnormal expression of brain-derived neurotrophic factor and its receptor in the corticolimbic system of schizophrenic patients.

Previous neuropathological studies have revealed that the corticolimbic system of schizophrenic patients expresses abnormal levels of various synaptic molecules, which are known to be influenced by the neuronal differentiation factors, neurotrophins. Therefore, we determined levels of neurotrophins and their receptors in the postmortem brains of schizophrenic patients and control subjects in relation to molecular impairments in schizophrenia. Among the neurotrophins examined, levels of brain-derived neurotrophic factor (BDNF) were elevated specifically in the anterior cingulate cortex and hippocampus of schizophrenic patients, but levels of nerve growth factors and neurotrophin-3 showed no change in any of the regions examined. In parallel, the expressions of TrkB receptor and calbindin-D, which are both influenced by BDNF, were reduced significantly in the hippocampus or the prefrontal cortex. However, neuroleptic treatment did not appear to mimic the neurotrophic change. Neither withdrawal of drug treatment in patients nor chronic administration of haloperidol to rats altered levels of BDNF. These findings suggest that neurotrophic abnormality is associated with the corticolimbic structures of schizophrenic patients and might provide the molecular substrate for pathological manifestations of the illness.

Attenuation of genetic hypertension after short-term vasopressin V1A receptor antagonism.

Abnormalities of the vasopressin system are found in genetic hypertension. This study compares the delayed effects of a brief period of vasopressin V1A receptor blockade and angiotensin-converting enzyme inhibition in young female and male spontaneously hypertensive rats (SHR) on the development of hypertension in adult life. In a separate study, the role of vasopressin in the maintenance of blood pressure in adult SHR was assessed. Young SHR received either the nonpeptide vasopressin V1A receptor antagonist OPC-21268, the angiotensin-converting enzyme inhibitor ramipril, or vehicle from 6 to 10 weeks of age. During the treatment period, OPC-21268 and ramipril reduced systolic blood pressure compared with control SHR (P < .001). Blood pressure in male SHR 7 weeks after treatment withdrawal was 178 +/- 1 mm Hg in ramipril-treated, 184 +/- 1 mm Hg in OPC-21268-treated, and 200 +/- 2 mm Hg in control SHR (P < .001). Similar results were seen in female SHR, although both OPC-21268 and ramipril were less effective antihypertensive agents in female compared with male SHR. The sustained attenuation in blood pressure was not associated with significant cardiovascular structural changes (left ventricular-to-body weight ratio, renal weight-to-body weight ratio, mesenteric resistance artery media-to-lumen ratio). Results of vasopressin V1A receptor binding kinetics and plasma renin or aldosterone concentrations did not suggest a lasting effect of OPC-21268 on the vasopressin system or of ramipril on the renin-angiotensin system following treatment withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)

Stopping antihypertensive drug therapy in elderly people—a dangerous experiment?

Journal of Internal MedicineVolume 235, Issue 6 p. 577-579 Free Access Stopping antihypertensive drug therapy in elderly people—a dangerous experiment? Professor P. Lund-Johansen, Corresponding Author Professor P. Lund-Johansen Department of Heart Disease, Haukeland Hospital, University of Bergen, Bergen, NorwayDepartment of Heart Disease, 5021 Haukeland Hospital, Bergen, Norway.Search for more papers by this author Professor P. Lund-Johansen, Corresponding Author Professor P. Lund-Johansen Department of Heart Disease, Haukeland Hospital, University of Bergen, Bergen, NorwayDepartment of Heart Disease, 5021 Haukeland Hospital, Bergen, Norway.Search for more papers by this author First published: June 1994 https://doi.org/10.1111/j.1365-2796.1994.tb01264.xCitations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References 1 Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure: the Fifth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNCV). Arch Int Med 1993: 153: 154– 83. 2 Zanchetti A., Chalmers JP, Arakawa K.. Gyarfas I., Hamet P., Hansson L., Julius S., MacMahon S., Mancia G., Menard J., Omae T., Reid J., Safar M. The 1993 guidelines for the management of mild hypertension: memorandum from a WHO/ISH meeting. Blood Pressure 1993: 2: 86– 100. 3 SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA 1991: 265: 3255– 64. 4 Veterans Administration cooperative study group. Return of elevated blood pressure after withdrawal of antihypertensive drugs. Circulation 1975: 51: 1107– 13. 5 Medical research council working party on mild hypertension. Course of blood pressure in mild hypertensives after withdrawal of long term antihypertensive treatment. Br Med J 1986: 293: 988– 92. 6 Levinson PD, Khatri IM, Freis ED. Persistence of normal BP after withdrawal of drug treatment in mild hypertension. Arch Intern Med 1982: 142: 2265– 8. 7 Ekblom T., Lindholm LH, Odén A. Dahlöf B., Hansson L., Wester P-O. et al. A 5-year prospective, observational study of withdrawal of antihypertensive treatment in elderly. J Intern Med 1994: 235: 581– 8. 8 Straand J., Fugelli P., Laake K. Withdrawing long-term diuretic treatment among elderly patients in general practice. Family Practice 1993; 10: 38– 42. 9 Langford HG, Blaufox D., Oberman A., Hawkins M., Curb JD, Cutter GR et al. Dietary therapy slows the return of hypertension after stopping prolonged medication. JAMA 1985: 253: 657– 64. 10 Devereux R., Alderman MH. Role of preclinical cardiovascular disease in the evolution from risk factor exposure to development of morbid events. Circulation 1993; 88 (Part 1): 1444– 55. 11 Lund-Johansen P., Omvik P. Hemodynamic patterns of untreated hypertensive disease. In: JH Laragh, B. Brenner, eds. Hypertension: Pathophysiology, Diagnosis and Management. New York: Raven Press, 1990: 305– 27. Citing Literature Volume235, Issue6June 1994Pages 577-579 ReferencesRelatedInformation

Chlorambucil-Associated Pneumonitis

A patient developed an interstitial pneumonitis while receiving chlorambucil for a chronic lymphocytic leukemia (cumulative dose, 8,340 mg). Withdrawal of drug treatment was followed by rapid improvement in the clinical condition. Bronchoalveolar lavage showed a T-lymphocytic alveolitis, whereas blood lymphocytes were predominantly of the B phenotype. The T-lymphocytic alveolitis persisted 6 weeks after drug therapy cessation with a predominant CD8+ phenotype, as observed in some hypersensitivity pneumonitis induced by drugs.

The Mexican Asthma Cure: Systemic Steroids for Gullible Gringos

Asthmatic patients from western Canada and the United States have reported that after visits to an asthma clinic in Mexicali, Mexico, they return home substantially improved or cured having received "a bronchodilator medication unavailable in the United States or Canada because of the big drug companies." Analysis of these medications reveals that the most commonly prescribed combination is the glucocorticoid triamcinolone (unscored white tablets) and the antihistamine chlorpheniramine (coated biconvex orange or red tablets). Occasionally benzodiazepines are added to these medications. The patients are assured that the medications which they have been given are free of side effects and specifically, that corticosteroids are not used. Such therapy is dangerous to the patient who not only is unaware of the medications that he or she is taking, but is unlikely to mention this therapy to his or her physician. These patients risk drug interactions, medication side effects, and the possibility of adrenal failure either with a stress to their system or on withdrawal of drug treatment. Patients are also at risk of abandoning safer forms of asthma therapy for the miracle cure. We, too, are partially responsible for these unethical practices by avoiding the use of steroids and undertreating our patients at times, leaving them unnecessarily restricted and eager for any form of relief.

Effect of prolonged clonidine treatment and its withdrawal on noradrenaline turnover in the cerebral cortex and medulla oblongata of the spontaneously hypertensive rat.

We have investigated the effect of prolonged treatment with clonidine (delivered intravenously via osmotic minipumps, 0.5 mg . kg-1 X 24 h-1 for 10 days) and of withdrawal of this treatment on ingestive behaviour and on the cerebral turnover of noradrenaline in the adult spontaneously hypertensive rat (SHR). Clonidine amplified the fall in food and water intakes induced by minipump implantation. Ingestive behaviour returned to normal by the 4th to the 5th day in controls and by the 7th to the 8th day in clonidine-treated SHR. Clonidine withdrawal produced an increase in water intake above pre-implantation values. Body weight fell during clonidine treatment, then recovered slightly during withdrawal. After 5 days' treatment total DOPEG levels (an index of noradrenaline turnover) were reduced in cerebral cortex and medulla oblongata. The noradrenaline metabolite levels increased following withdrawal of drug treatment, the increase being more marked and faster in onset in cerebral cortex than in medulla oblongata. Thus prolonged treatment with clonidine decreases noradrenaline turnover and withdrawal of such treatment increases turnover.

The role of alkaline protease in the development of cardiac lesions in myopathic hamsters: Effect of verapamil treatment

The role of alkaline protease in the development of myocardial lesions in myopathic hamsters was studied. There was abnormal elevation of alkaline protease in the myopathic heart at 1 month of age, preceding the development of cardiac lesions. In vivo treatments of verapamil were carried out in 1-month-old myopathic animals for 30 days. Results indicated that the drug treatment was effective in preventing the occurrence of the severe myocardial lesions found in the untreated animals at 2 months of age. Reduced lesion development was associated concomitantly with lowered levels of alkaline protease activity. Withdrawal of drug treatment caused the return of severe lesions and high levels of alkaline protease. The study of the alkaline protease activity in the skeletal muscle of the myopathic hamster also showed a parallel relationship between the enzyme levels and severity of lesions. The results are discussed in light of possible involvement of a serine protease and a Ca 2+-activated protease in producing the cardiac lesions.

Historical perspective--the long and colorful history of Erythoxylon coca.

Abstract The rate of increase in the use of cocaine among college students has been greater even than the increase in the use of marijuana during the past ten years. Nationwide surveys indicate that 9 million Americans within the 18–25 age group, or 28.7%, have used cocaine. This compares with 2.9 million, or 9.1%, just a decade ago. The history of cocaine begins with the history of the coca plant. Even prior to the inca period the plant was used in South America; for centuries use of the plant remained restricted primarily to that continent. In 1859, an Austrian explorer brought home from Peru coca leaves that he sent to the University of Gottigen where Dr. Albert Niemann extracted and purified a crystalline compound he called cocaine. Several prominent physicians including Sigmund Freud and William Halsted, the father of modern surgery, experimented with cocaine on themselves and on their patients. Their published observations helped effect widespread use of cocaine in patent medicines, tonics, wines, and soft drinks. That earlier epidemic and the rest of the long and colorful history of cocaine brings into perspective the current epidemic of cocaine use. “Mild Hypertension: When and How to Treat,” NORMAN H. KAPLAN. “Early and aggressive” drug therapy for mild hypertension, now widely prescribed in the United States, may be inappropriate for many of the 30 million patients with this condition. Although all of these patients are at greater risks of premature cardiovascular disease, the risks are manifested neither quickly nor uniformly. Drug therapy has not proved beneficial for patients with a diastolic (D) BP reading below 100 mm Hg, particularly those patients who are otherwise at low risk. Those antihypertensive drugs that are available now carry risks along with their benefits. Therefore, persons with mild hypertension who are at low risk should be encouraged to use nondrug therapies for at least six to 12 months. If their DBP remains below 100 mm Hg, they may be better off than if they were given drugs. The drug used in initial therapy has usually been a diuretic. For many patients, however, an adrenergic inhibitor may be a more appropriate choice. (Archives of Internal Medicine, 1983;143:255–259) “Persistence of Normal BP After Withdrawal of Drug Treatment in Mild Hypertension,” PAUL D. LEVINSON, IBRAHIM M. KHATRI, EDWARD D. FREIS. Antihypertensive therapy was discontinued in 24 patients with mild hypertension whose BPs had been well controlled with diuretics alone. Eleven patients (46%) maintained normal diastolic BPs (≤ 90 mm Hg) for six months after stopping treatment and five patients (21%) for 12 months. All patients who remained normotensive for six to 12 months had mean diastolic BPs of 82 mm Hg or less during treatment. There was no signficant correlation between maintenance of normotension and any of the following: pretreatment BP, presence of target-organ damage, duration of known hypertension, family history of hypertension, heart size, body weight, weight gain after stopping diuretic therapy, 24-hour urinary sodium and potassium excretion, serum electrolyte values or renin profile. This study demonstrates that hypertension may be favorably modified, sometimes for many months, by effective antihypertensive treatment. (Archives of Internal Medicine 1982;142:2265–2268)

BP and Hypertension

To the Editor. —The article entitled Persistence of Normal BP After Withdrawal of Drug Treatment in Mild Hypertension by Levinson et al in the DecemberArchives(1982;142:2265-2268) provides reinforcement of the dangerous philosophy espoused by many physicians and patients. The fact that the antihypertensive effect of various agents persists after the discontinuance of therapy has been shown by my studies and those of others. In 1951 I began uncontrolled clinical studies of the dihydrogenated ergot alkaloids followed five years later by prospective double-blind studies of more than 30 agents. After withdrawing each of the substances being investigated, the patients' conditions were observed at weekly intervals until the BP returned to the levels that had existed prior to the administration of the placebo or drug. Although the time varied from a few weeks to 15 months, the BPs, without exception, returned to pretreatment readings. I have seen innumerable instances in clinical

Extent of BrdUrd-induced prolactin gene amplification in GH cells.

The thymidine analog, 5-bromodeoxyuridine (BrdUrd), induces prolactin (Prl) synthesis and Prl gene amplification in a subclone of GH cells (rat pituitary tumor cells in culture). Withdrawal of drug treatment reverses both processes. Our previous results show that Prl gene amplification is associated with an event involving extrachromosomal DNA. The results presented in this report show that a 20-kb length of DNA, including all the coding sequences of the Prl gene, is amplified following BrdUrd treatment of this strain of GH cells. Amplification of DNA sequences extends about 3 kb upstream from the 5' end and about 7 kb downstream from the 3' end of the Prl gene. The DNA sequences immediately adjacent to these 5'-and 3'-flanking regions of the Prl gene are not affected by BrdUrd treatment. These results suggest that BrdUrd-induced amplification of Prl gene coding and neighboring sequences is restricted to within 3 kb of the 5' end and within 7 kb of the 3' end of the structural gene Analysis of low-molecular-weight extrachromosomal DNA isolated by Hirt's procedure from drug-treated cells reveals a similar pattern of amplification of the Prl gene and its flanking sequences.

Persistence of normal BP after withdrawal of drug treatment in mild hypertension.

Antihypertensive therapy was discontinued in 24 patients with mild hypertension whose BPs had been well controlled with diuretics alone. Eleven patients (46%) maintained normal diastolic BPs (less than or equal to 90 mm Hg) for six months after stopping treatment and five patients (21%) for 12 months. All patients who remained normotensive for six to 12 months had mean diastolic BPs of 82 mm Hg or less during treatment. There was no significant correlation between maintenance of normotension and any of the following: pretreatment BP, presence of target-organ damage, duration of known hypertension, family history of hypertension, heart rate, body weight, weight gain after stopping diuretic therapy, 24-hour urinary sodium and potassium excretion, serum electrolyte values or renin profile. This study demonstrates that hypertension may be favorably modified, sometimes for many months, by effective antihypertensive treatment.