Electrical switching of magnetic order in an orbital Chern insulator.

Magnetism typically arises from the joint effect of Fermi statistics and repulsive Coulomb interactions, which favours ground states with non-zero electron spin. As a result, controlling spin magnetism with electric fields-a longstanding technological goal in spintronics and multiferroics1,2-can be achieved only indirectly. Here we experimentally demonstrate direct electric-field control of magnetic states in an orbital Chern insulator3-6, a magnetic system in which non-trivial band topology favours long-range order of orbital angular momentum but the spins are thought to remain disordered7-14. We use van der Waals heterostructures consisting of a graphene monolayer rotationally faulted with respect to a Bernal-stacked bilayer to realize narrow and topologically non-trivial valley-projected moiré minibands15-17. At fillings of one and three electrons per moiré unit cell within these bands, we observe quantized anomalous Hall effects18 with transverse resistance approximately equal to h/2e2 (where h is Planck's constant and e is the charge on the electron), which is indicative of spontaneous polarization of the system into a single-valley-projected band with a Chern number equal to two. At a filling of three electrons per moiré unit cell, we find that the sign of the quantum anomalous Hall effect can be reversed via field-effect control of the chemical potential; moreover, this transition is hysteretic, which we use to demonstrate non-volatile electric-field-induced reversal of the magnetic state. A theoretical analysis19 indicates that the effect arises from the topological edge states, which drive a change in sign of the magnetization and thus a reversal in the favoured magnetic state. Voltage control of magnetic states can be used to electrically pattern non-volatile magnetic-domain structures hosting chiral edge states, with applications ranging from reconfigurable microwave circuit elements to ultralow-power magnetic memories.

Imaging orbital ferromagnetism in a moiré Chern insulator.

Electrons in moiré flat band systems can spontaneously break time-reversal symmetry, giving rise to a quantized anomalous Hall effect. In this study, we use a superconducting quantum interference device to image stray magnetic fields in twisted bilayer graphene aligned to hexagonal boron nitride. We find a magnetization of several Bohr magnetons per charge carrier, demonstrating that the magnetism is primarily orbital in nature. Our measurements reveal a large change in the magnetization as the chemical potential is swept across the quantum anomalous Hall gap, consistent with the expected contribution of chiral edge states to the magnetization of an orbital Chern insulator. Mapping the spatial evolution of field-driven magnetic reversal, we find a series of reproducible micrometer-scale domains pinned to structural disorder.

Intrinsic quantized anomalous Hall effect in a moiré heterostructure.

The quantum anomalous Hall (QAH) effect combines topology and magnetism to produce precisely quantized Hall resistance at zero magnetic field. We report the observation of a QAH effect in twisted bilayer graphene aligned to hexagonal boron nitride. The effect is driven by intrinsic strong interactions, which polarize the electrons into a single spin- and valley-resolved moiré miniband with Chern number C = 1. In contrast to magnetically doped systems, the measured transport energy gap is larger than the Curie temperature for magnetic ordering, and quantization to within 0.1% of the von Klitzing constant persists to temperatures of several kelvin at zero magnetic field. Electrical currents as small as 1 nanoampere controllably switch the magnetic order between states of opposite polarization, forming an electrically rewritable magnetic memory.

Propranolol in the control of blood pressure: a dose-response study.

In a double-blind crossover study, it has been shown that the hypotensive response to propranolol in 24 patients with essential hypertension was no greater at doses of 80, 160, or 240 mg twice daily than at 40 mg twice daily. A relationship was observed between dose and response as defined by the ability to achieve a standing diastolic blood pressure of 95 mm Hg. Four patients with low plasma renin activity (PRA) had no fall in blood pressure even at highest dose levels. Plasma propranolol levels in the groups were related to dose, and up to a concentration of 300 ng/ml, with degree of beta-adrenoceptor blockade; there was, however, no correlation with hypotensive response.

Interaction between diflunisal and warfarin.

The effect of diflunisal on steady-state warfarin dynamics and kinetics was studied in five healthy men taking daily subtherapeutic doses of warfarin. Diflunisal 500 mg twice daily for 2 wk increased the percentage unbound warfarin from 1.02% to 1.24% and lowered total warfarin from 741 to 533 ng/ml, but did not alter the anticoagulant response (prothrombin complex activity, PCA). When diflunisal was discontinued but warfarin continued, there was a loss of anticoagulant effect and a difference in the rates at which percentage unbound warfarin and total warfarin concentration returned to prediflunisal levels. There was a correlation between plasma diflunisal and percentage unbound warfarin. Diflunisal reduced both the maximum plasma protein-binding capacity for warfarin and the apparent association constant.

Drug interactions with warfarin.

Drugs may interact with warfarin through pharmacodynamic or pharmacokinetic mechanisms. Examples of the former include alteration of the bioavailability of vitamin K by antibiotics, mineral oils or cholestyramine; oestrogens, diuretics and hypolipidaemic agents such as clofibrate may influence vitamin K-dependent clotting factor synthesis, and drugs which affect haemostasis, e.g. via platelet function, will enhance the anticoagulant effect of warfarin. Pharmacokinetic interactions are better understood. Few drugs have been shown to alter warfarin absorption, the importance of protein binding displacement has been exaggerated, and since warfarin is not eliminated to any extent unchanged by the kidney, the most important kinetic interactions are those due to inhibition or induction of its hepatic metabolism. Isomeric differences in metabolism form an important basis for stereoselective metabolic interactions, especially inhibition; this has been demonstrated with phenylbutazone, metronidazole and co-trimoxazole. Enzyme induction, although recognised for many years, may still pose problems in therapeutics, usually on withdrawal of the inducing agent.

Bioavailability and pharmacokinetics of norethisterone in women after oral doses of ethynodiol diacetate.

Measurement by radioimmunoassay of plasma norethisterone (NE) has been used to compare the bioavailability of tablets containing ethynodiol diacetate (EDA) with that of a standard oral solution of this progestogen in 12 normal women. The tablets investigated were from three batches which showed different in vitro dissolution rates. There were no significant differences in the bioavailability of the tablet formulations, which were essentially bioequivalent to the solution. Peak blood levels of NE were reached within 4h of EDA administration in solution or tablets. After the peak, NE plasma levels declined in two phases, with a mean terminal elimination half lives of 4 to 6.9h. The pharmacokinetics of NE after EDA administration showed some similarity to those observed by other workers after oral doses of NE itself.

PIP: Bioavailability and pharmacokinetics of norethisterone (NE) were studied in 12 women, aged 21-37 years, after oral doses of ethynodiol diacetate (EDA). Plasma NE levels, measured by radioimmunoassay, were used to compare the bioavailability of EDA tablets (Ovulen 50; 1 mg EDA plus .05 mg ethinyl estradiol) with that of a standard oral solution of EDA. The 3 different batches of tablets studied showed different in vitro dissolution rates, 82.6%, 94.6%, and 99% at 3 hours. No marked differences were seen in the bioavailability of the tablet formulations, which were essentially bioequivalent to the solution. Peak plasma NE levels were reached within 4 hours of EDA administration in solution or tablets. Following the peak, NE plasma levels declined in 2 phases, with mean terminal elimination 1/2-lives of 4-6.9 hours. These results have shown that small variations in in vitro dissolution rates do not affect the bioavailability of NE from tablets containing EDA.

Labetalol in essential hypertension.

1 Labetalol is an effective agent in essential hypertension as documented in open studies and controlled studies in which its efficacy has been compared with both placebo and a variety of other anti-hypertensive drugs. 2 Labetalol given by mouth lowers blood pressure rapidly. There is no evidence of tolerance to its anti-hypertensive action. 3 Adverse effects include excessive hypotension, but only when the drug is given in large doses. Epigastric discomfort and scalp tingling have been documented especially after intravenous administration. 4 From a pharmacokinetic and pharmacodynamic point of view, labetalol can be given once daily, but postural hypotension after large (greater than 1 g) single doses may limit the usefulness of once daily regimes. Twice daily administration appears an acceptable compromise.

Lack of effect of ranitidine on warfarin action.

1 In five volunteers taking daily subtherapeutic doses of warfarin the addition of ranitidine 200 mg twice daily for 14 days did not affect prothrombin time or plasma warfarin concentration. 2 Ranitidine had no effect on the single dose pharmacodynamics and pharmacokinetics of warfarin in the rat. 3 Ranitidine had no effect on pentobarbitone sleeping time in the rat whereas cimetidine significantly prolonged the sleeping time. 4 The interaction between cimetidine and oral anticoagulants is unrelated to histamine H2-receptor antagonism.

Inter-relationship among individual vitamin K-dependent clotting factors at different levels of anticoagulation.

1. The effect of subtherapeutic doses of warfarin on the activities of the four vitamin K-dependent clotting factors was studied at steady state in five patients each of whom had completed a therapeutic course of anticoagulation. 2. The four clotting factor activities were shown to be depressed to a similar extent for a given dose of warfarin. 3. The prothrombin complex activity was significantly lower than that of any of the clotting factors.

Possible role of the V3 domain of gp120 in resistance to an amphotericin B derivative (MS8209) blocking human immunodeficiency virus entry.

MS8209, an amphotericin B derivative blocking human immunodeficiency virus type 1 (HIV-1) entry after CD4 binding, neutralized the HIV-2 strains EHO and ROD10 but not ROD(CEM). In the V3 domain of gp120, ROD(CEM) differed from ROD10 at two positions (a threonine instead of an isoleucine at position 312 and an arginine instead of a glutamine at position 329), and drug resistance was conferred to HIV-1 by substitution of the ROD(CEM) V3 but not the ROD10 V3. V3 mutations may prevent the interaction of gp120 with MS8209 or modify the mechanism of virus entry, rendering it less accessible to neutralization.

Postgraduate education in therapeutics: experience in Merseyside.

A teaching programme in therapeutics for general practitioners in Merseyside, which was led by a group of clinical pharmacologists, had as its principal aim to emphasise the importance of rational drug prescribing. The course comprised 15 sessions restricted to 25 GPs, and the topics were suggested by both the organisers and the GPs. Though each session was introduced by a clinical pharmacologist, the emphasis was an open discussion and exchange of views. This programme may serve as a pattern for other centres.

Efficacy and adverse effects of captopril in severe refractory hypertension.

Eleven patients with severe, treatment-resistant essential or renovascular hypertension were treated with captopril after withdrawal of various multiple drug regimes. If supine diastolic blood pressure remained greater than 90 mm Hg on a maximum daily dose of 450 mg captopril, a diuretic and then a beta-adrenoceptor blocker were added. Patient-volunteered complaints were carefully noted. Mean (+/- SE) systolic and diastolic blood pressures fell from 225 +/- 6.8/131 +/- 4.4 mm Hg on various multiple drug regimes to 182 +/- 9.0/105 +/- 5.0 mm Hg on a regime including captopril. The reported and observed incidence of adverse effects were as follows: maculopapular rash (one patient); urticaria and pruritus (three patients); loss of taste (one patient); tachycardia (four patients); increased frequency of trivial infections (three patients); severe myalgia (one patient); and deterioration in renal function (one patient). However, these patients were able to continue captopril after either temporary withdrawal or dose reduction. Captopril was discontinued permanently in five patients, in two because of poor blood pressure control, in one who developed persistent severe urticaria, and in one because of marked proteinuria. In the fifth patient intractable diarrhoea occurred. Captopril lowers blood pressure very effectively in patients with severe hypertension refractory to other agents. Adverse effects are common but acceptable in this situation where prognosis is poor if blood pressure is not adequately controlled.

Rate of onset of hypotensive effect of oral labetalol.

1 Labetalol caused a fall in blood pressure within 2 h or oral doses of 100, 200 and 400 mg in six hypertensive patients. 2 This fall which was dose-related was maximal by 3 h and was sustained when the drug was given in doses of 100 mg 8 hourly, 200 mg 8 hourly and 400 mg 8 hourly. 3 This rapid fall in pressure when labetalol is given by mouth which contrasts to that seen on administration of pure beta-adrenoceptor blocking agents is a valuable therapeutic property.

The feasibility of a telecommunications service in support of outpatient congestive heart failure care in a diverse patient population.

A home telemonitoring system for patients with congestive heart failure was studied for feasibility and efficacy in a diverse patient population. Fifty patients used the service, in which they weighed themselves and answered yes/no questions about symptoms. Changes in patient weights or symptoms prompted a nurse to call the patient and/or the physician. Patients were given educational and quality of life surveys at enrollment, at 30 days, and at 6 months. The average daily usage rate was 94%. Patients were contacted 57 times--prompting 57 physician notifications, eight medication changes, and 11 nonroutine clinic visits. Patient response to lifestyle surveys showed an improvement in quality of life and improved understanding of prevention measures. Eighty-four percent of patients and 65% of physicians reported satisfaction with the system. This pilot study suggests that home telemonitoring is feasible and has clinical utility in diverse patient groups, and may improve patients' satisfaction and knowledge of self-care. (c)2000 by CHF, Inc.

The pharmacodynamics and pharmacokinetics of conventional and long-acting propranolol in patients with moderate hypertension.

1 The effects on heart rate and blood pressure after single and multiple dosing (1 month) of a long acting formulation of propranolol 160 mg daily, and conventional propranolol, 80 mg twice daily, or 160 mg daily were compared in 11 moderately hypertensive subjects previously shown to respond to propranolol. 2 After acute dosing all three treatments produced significant reduction in blood pressure. After multiple dosing all three treatments maintained significant reductions in lying, standing and exercise heart rate and blood pressure throughout the 24 h. At 24 h, after multiple dosing, the fall in resting and standing systolic BP was significantly greater with LA propranolol than with conventional propranolol 80 mg twice daily or conventional propranolol 160 mg once daily (P at least less than 0.05). 3 The plasma propranolol concentration time curve after LA propranolol showed slowed absorption, and the area under the curve was significantly lower than after conventional propranolol (acute dosing; LA propranolol 160 mg 560 mg ml-1 h, conventional propranolol 80 mg twice daily 1135 mg ml-1 h, conventional propranolol 160 mg daily 1414 mg ml-1 h).