Projected environmental and public health benefits of extended-interval dosing: an analysis of pembrolizumab use in a US national health system.

BACKGROUND: Health care is a major source of greenhouse gas emissions, leading to climate change and public health harms. Changes are needed to improve the environmental sustainability of health-care practices, but such changes should not sacrifice patient outcomes or financial sustainability. Alternative dosing strategies that reduce the frequency with which specialty drugs are administered, without sacrificing patient outcomes, are an attractive possibility for improving environmental sustainability. We sought to inform environmentally sustainable cancer care by estimating and comparing the environmental and financial effects of alternative, clinically equivalent strategies for pembrolizumab administration. METHODS: We conducted a retrospective analysis using a cohort of patients from the Veterans Health Administration (VHA) in the USA who received one or more pembrolizumab doses between May 1, 2020, and Sept 30, 2022. Using baseline, real-world administration of pembrolizumab, we generated simulated pembrolizumab use data under three near-equivalent counterfactual pembrolizumab administration strategies defined by combinations of weight-based dosing, pharmacy-level vial sharing and dose rounding, and extended-interval dosing (ie, every 6 weeks). For each counterfactual dosing strategy, we estimated greenhouse gas emissions related to pembrolizumab use across the VHA cohort using a deterministic environmental impact model that estimated greenhouse gas emissions due to patient travel, drug manufacture, and medical waste as the primary outcome measure. FINDINGS: We identified 7813 veterans who received at least one dose of pembrolizumab-containing therapy in the VHA during the study period. 59 140 pembrolizumab administrations occurred in the study period, of which 46 255 (78·2%) were dosed at 200 mg every 3 weeks, 12 885 (21·8%) at 400 mg every 6 weeks, and 14 955 (25·3%) were coadministered with infusional chemotherapies. Adoption of weight-based, extended-interval pembrolizumab dosing (4 mg/kg every 6 weeks) and pharmacy-level stewardship strategies (ie, dose rounding and vial sharing) for all pembrolizumab infusions would have resulted in 24·7% fewer administration events than baseline dosing (44 533 events vs 59 140 events) and an estimated 200 metric tons less CO2 emitted per year as a result of pembrolizumab use within the VHA (650 tons vs 850 tons of CO2, a relative reduction of 24%), largely due to reductions in distance travelled by patients to receive treatment. Similar results were observed when weight-based and extended-interval dosing were applied only to pembrolizumab monotherapy and pembrolizumab in combination with oral therapies. INTERPRETATION: Alternative pembrolizumab administration strategies might have environmental advantages over the current dosing and compounding paradigms. Specialty medication dosing can be optimised for health-care spending and environmental sustainability without sacrificing clinical outcomes. FUNDING: None.

The global temperature-related mortality impact of earlier decarbonization for the Australian health sector and economy: A modelling study.

BACKGROUND: Sustained elevated concentration of GHGs is predicted to increase global mortality. With the Australian health sector responsible for 7% of the nation's GHG emissions, the benefits and costs of various decarbonisation trajectories are currently being investigated. To assist with this effort, we model the impact earlier decarbonisation has on temperature-related mortality. DESIGN: We used DICE-EMR, an Integrated Assessment Model with an endogenous mortality response, to simulate Australian GHG trajectories and estimate the temperature-related mortality impact of early decarbonisation. We modelled a linear decline of the Australian health sector's and economy's GHG annual emissions to net-zero targets of 2040 and 2050. MAIN OUTCOME MEASURE: Deaths averted and monetary-equivalent welfare gain. RESULTS: Decarbonisation of the Australian health sector by 2050 and 2040 is projected to avert an estimated 69,000 and 77,000 global temperature-related deaths respectively in a Baseline global emissions scenario. Australian economy decarbonisation by 2050 and 2040 is projected to avert an estimated 988,000 and 1,101,000 global deaths respectively. Assuming a low discount rate and high global emissions trajectory, we estimate a monetary equivalent welfare gain of $151 billion if the Australian health sector decarbonises by 2040, only accounting for the benefits in reducing temperature-related mortality. CONCLUSIONS: Earlier decarbonisation has a significant impact on temperature-related mortality. Many uncertainties exist and health impacts other than temperature-related mortality are not captured by this analysis. Nevertheless, such models can help communicate the health risk of climate change and improve climate policy decision making.

The mortality cost of carbon.

Many studies project that climate change can cause a significant number of excess deaths. Yet, in integrated assessment models (IAMs) that determine the social cost of carbon (SCC) and prescribe optimal climate policy, human mortality impacts are limited and not updated to the latest scientific understanding. This study extends the DICE-2016 IAM to explicitly include temperature-related mortality impacts by estimating a climate-mortality damage function. We introduce a metric, the mortality cost of carbon (MCC), that estimates the number of deaths caused by the emissions of one additional metric ton of CO2. In the baseline emissions scenario, the 2020 MCC is 2.26 × 10‒4 [low to high estimate -1.71× 10‒4 to 6.78 × 10‒4] excess deaths per metric ton of 2020 emissions. This implies that adding 4,434 metric tons of carbon dioxide in 2020-equivalent to the lifetime emissions of 3.5 average Americans-causes one excess death globally in expectation between 2020-2100. Incorporating mortality costs increases the 2020 SCC from $37 to $258 [-$69 to $545] per metric ton in the baseline emissions scenario. Optimal climate policy changes from gradual emissions reductions starting in 2050 to full decarbonization by 2050 when mortality is considered.

Estimates of country level temperature-related mortality damage functions.

Many studies project that climate change is expected to cause a significant number of excess deaths. Yet, in integrated assessment models that determine the social cost of carbon (SCC), human mortality impacts do not reflect the latest scientific understanding. We address this issue by estimating country-level mortality damage functions for temperature-related mortality with global spatial coverage. We rely on projections from the most comprehensive published study in the epidemiology literature of future temperature impacts on mortality (Gasparrini et al. in Lancet Planet Health 1:e360-e367, 2017), which estimated changes in heat- and cold-related mortality for 23 countries over the twenty-first century. We model variation in these mortality projections as a function of baseline climate, future temperature change, and income variables and then project future changes in mortality for every country. We find significant spatial heterogeneity in projected mortality impacts, with hotter and poorer places more adversely affected than colder and richer places. In the absence of income-based adaptation, the global mortality rate in 2080-2099 is expected to increase by 1.8% [95% CI 0.8-2.8%] under a lower-emissions RCP 4.5 scenario and by 6.2% [95% CI 2.5-10.0%] in the very high-emissions RCP 8.5 scenario relative to 2001-2020. When the reduced sensitivity to heat associated with rising incomes, such as greater ability to invest in air conditioning, is accounted for, the expected end-of-century increase in the global mortality rate is 1.1% [95% CI 0.4-1.9%] in RCP 4.5 and 4.2% [95% CI 1.8-6.7%] in RCP 8.5. In addition, we compare recent estimates of climate-change induced excess mortality from diarrheal disease, malaria and dengue fever in 2030 and 2050 with current estimates used in SCC calculations and show these are likely underestimated in current SCC estimates, but are also small compared to more direct temperature effects.

Taurine concentrations in congestive heart failure.

The concentration of taurine in the left ventricular muscle of hearts of patients who died of chronic congestive heart failure was twice that of patients who died of other causes and had no cardiac pathology. There was no corresponding difference in taurine concentrations in aortic tissue between the two groups. Stress-induced hypertension in rats also led to an increase in taurine concentration in the heart, whereas that in skeletal muscle and brain showed no significant alteration when compared to unstressed animals. Spontaneously hypertensive rats, of the Wistar-derived Okamato strain, showed a similar elevation in cardiac taurine compared to age-matched control Wistar rats.

Radioreceptor assay for 1 alpha,25-dihydroxyvitamin D3.

A competitive protein binding assay with a sensitivity of 80 picograms has been developed for 1alpha,25-dihydroxyvitamin D(3), the hormonal form of vitamin D(3). lalpha,25-Dihydroxyvitamin D(3) displaced tritiated hormone from a cytosol-chromatin receptor preparation isolated from chick small intestine, providing a simple assay for the hormone. The concentration of lalpha, 25-dihydroxyvitamin D(3) in human plasma, as determined by this assay, is approximately 6 nanograms per 100 milliliters; in patients with renal disease the concentration of this kidney-produced hormone is significantly lower.

Characterization of a carrier-mediated transport system for taurine in the fetal mouse heart in vitro.

Cardiac taurine levels are elevated in hypertension and congestive heart failure. A possible mechanism for this increase in taurine is an alteration of its uptake. We sought to identify and characterize a carrier-mediated transport system for taurine in the mammalian myocardium utilizing the fetal mouse heart in organ culture. Hearts from fetuses of 16-19 days gestational age used in these studies had an endogenous taurine content of 14.1+/-0.5 nmol/mg tissue. The uptake of [(3)H]taurine was linear for up to 8 h. Taurine was accumulated against a concentration gradient as demonstrated by a net increase in taurine concentration when hearts were incubated in 0.5 mM taurine. [(3)H]Taurine uptake was saturable, K(m) = 0.44 mM, temperature dependent, and required sodium. The close structural analogues, hypotaurine and beta-alanine, reduced [(3)H]taurine uptake by 87% when present in 100-fold excess. The alpha-amino acids alanine, alpha-aminoisobutyric acid, glycine, leucine, and threonine did not inhibit uptake. Other taurine analogues tested were guanidinotaurine, guanidinopropionic acid, gamma-aminobutyric acid, 2-aminoethane phosphonic acid, aminomethane sulfonic acid, 3-aminopropane sulfonic acid, N-acetyltaurine, and isethionic acid. We conclude that a carrier-mediated transport system for taurine exists in the fetal mouse heart based on the demonstration of (a) temperature dependence, (b) saturability, and (c) structural selectivity of the uptake process. Transport was demonstrated to be mediated by a beta-amino acid uptake system. In addition, taurine uptake was observed to be sodium dependent, energy dependent, and capable of accumulating taurine against a concentration gradient.

The influence of ouabain and alpha angelica lactone on calcium metabolism of dog cardiac microsomes.

The influence of ouabain and alpha angelica lactone on (45)calcium accumulation in cardiac microsomes was studied. Calcium binding (accumulation in the absence of excess oxalate or phosphate) was augmented by both ouabain and alpha angelica lactone in the presence of adenosine triphosphate (ATP) but unaffected in its absence. Calcium turnover (defined as the change in (45)Ca(++) bound to the microsomes after the specific activity is changed) was studied to determine if the augmented bound pool was freely exchangeable at equilibrium. Ouabain and alpha angelica lactone augmented calcium turnover in both the presence and absence of ATP. Calcium-stimulated ATPase was increased by both agents.It is proposed that these two unsaturated lactones, with known cardiotonic activity, may exert their effects by providing an increased contraction-dependent calcium pool to be released upon systolic depolarization.

The in vitro inhibition of insulin secretion by diphenylhydantoin.

Glucose intolerance has been observed following diphenylhydantoin (DPH) intoxication. Because of this association between DPH and hyperglycemia, the effect of DPH on insulin release in vitro using preparations of isolated islets of Langerhans and pancreatic pieces was examined. In concentrations identical with those considered necessary for adequate anticonvulsant therapy in man, DPH markedly decreases the insulin secretory response of pancreatic pieces to methacholine, 1 mug/ml, tolbutamide, 250 mug/ml, and glucose, 200 mg/100 ml, without any demonstrable alteration in the oxidative conversion of glucose-1-(14)C or glucose-6-(14)C to (14)CO(2) by isolated islets. This DPH-induced inhibition of insulin secretion is not reversed by higher concentrations of glucose (600 mg/100 ml) or by increasing concentrations of extracellular calcium ion (4-6 mmoles/liter). 0.1 mM potassium and 10(-4) M ouabain, however, effectively restore the DPH-induced block of insulin secretion in pancreatic pieces. 60 mM potassium ion, on the other hand, not only restores the insulin secretory response to glucose (200 mg/100 ml) but results in an added stimulation of insulin secretion in the presence of DPH. In the presence of DPH, (22)Na accumulation by isolated islets is decreased by 26-40% as compared with controls. Such evidence is considered to indirectly support the postulate that the electrophysiological properties of DPH on the pancreas are due to a stimulation of the membrane sodium-potassium-magnesium ATPase.

Stereochemistry of the hydrogen transfer to NAD catalyzed by D-galactose dehydrogenase from Pseudomonas fluorescens.

The stereochemistry of the hydrogen transfer to NAD catalyzed by D-galactose dehydrogenase (E.C. 1.1.1.48) from P. fluorescens was investigated. The label at C-1 of D-[1--3H] galactose was enzymatically transferred to NAD and the resulting [4--3H]NADH was isolated and its stereochemistry at C-4 investigated. It was found that the label was exclusively located at the 4(S) position in NADH which calls for classification as a B-enzyme. This result was confirmed by an alternate approach in which [4--3H]NAD was reduced by D-galactose as catalyzed by D-galactose dehydrogenase. The sterochemistry at C-4 of the nicotinamide ring would then have to opposite to that in the first experiment. As expected, the label was now exclusively located in the 4(R) position, again confirming the B-calssification of the enzyme.

Stereochemistry of the hydrogen transfer to NAD catalyzed by (S)alanine dehydrogenase from Bacillus subtilis.

The stereochemistry of the hydrogen transfer to NAD catalyzed by (S)alanine dehydrogenase [ (S)alanine: NAD oxidoreductase (EC 1.4.1.1) ] from B. subtilis was investigated. The label at C-2 of (S) [2,3--3H] alanine was enzymatically transferred to NAD, and the [4--3H]NADH produced isolated and the stereochemistry at C-4 investigated. It was found that the label was exclusively located at the (R) position which indicates that (S)alanine dehydrogenase is an A-type enzyme. This result was confirmed in an alternate way by reducing enzymatically [4--3H]NAD with non labeled (S)alanine and (S)alanine dehydrogenase and investigating the stereochemistry of the ]4--3H]NADH produced. As expected, the label was now exclusively located at the (S) position. This proves that (S)alanine dehydrogenase isolated from B. subtilis should be classified as an A-enzyme with regard to the stereochemistry of the hydrogen transfer to NAD.

Prevention of diabetic nephropathy by diet control in the db/db mouse.

Diabetes in the C57BL/KsJ(db/db) mouse is initially expressed as hyperinsulinemia, followed by hyperphagia, progressive obesity, and widespread pathologic abnormalities. This study was designed to evaluate the effects of metabolic control on the natural history of the diabetic nephropathy. Beginning at 1 mo of age and continuing for 12 wk, diabetic mice were subjected to controlled dietary restriction, such that their weight was maintained similar to that of age-matched, nondiabetic heterozygotes. Diet-restricted diabetics were compared with diabetics fed ad libitum and heterozygote nondiabetics. Significant lowering of fasting blood glucose, water intake, and plasma insulin was achieved by diet restriction. The diet-restricted diabetes demonstrated enhanced metabolic efficiency, consuming approximately half as much food as the nondiabetics, while maintaining a similar weight. Diabetics fed ad libitum evidenced well-defined renal lesions that included 3 + to 4 + immunoglobulin deposition in the glomerular mesangium, and generalized mesangial matrix expansion. These lesions were completely prevented in diet-restricted diabetes whose glomeruli were normal light microscopy, and demonstrated trace to 1 + mesangial immunoglobulin deposition, features identical in all respects to the nondiabetics. These results indicate that diabetic control achieved by preventing of obesity in the db/db mouse prevents the development of diabetic nephropathy.

Metabolic control of prevention of nephropathy by 2-tetradecylglycidate in the diabetic mouse (db/db).

The genetically diabetic mouse (db/db) exhibits hyperphagia, progressive weight gain, hyperglycemia, and hyperinsulinemia during the first few months of life during which time characteristic pathologic changes occur in several organ systems including the kidney. The extent to which long chain fatty acid oxidation (LCFAO) contributes to excessive gluconeogenesis and hyperglycemia in these animals in unknown. Therefore, the synthetic fatty acid analogue 2-tetradeclyglycidate (TDHA), a potent inhibitor of LCFAO, was given orally to db/db mice to evaluate its capacity to control the blood glucose and prevent their diabetic nephropathy. Five groups of diabetic mice (N = 6) were assigned to receive TDGA in a dose of 5, 10, and 25 mg/kg/day, vehicle (tragacanth), or nothing (control). TDGA had no observable effects on food intake or growth patterns. Drug-treated animals had significant lowering of fasting glucose at 0 and 4 h after dosing during the midportion of the study (2-6 wk). In the latter part of the study (wk 8-11), blood glucose 4 h after dosing was lowered in mice given 10 and 25 free fatty acids. Animals receiving TDGA 25 mg/kg/day exhibited significant inhibition of immunopathologic changes in the kidney. Heart weight was significantly increased in mice receiving TDGA 25 mg/kg/day, and the total amount of myocardial carnitine content was increased in all three drug-treated groups. Increased tissue deposition of lipid was not apparent on histologic examination of liver in drug-treated animals. Inhibition of long chain fat oxidation in the db/db mouse results in significant lowering of blood glucose, and decreased the renal immunopathologic features of diabetic nephropathy in this animal model.

Water intoxication following moderate-dose intravenous cyclophosphamide.

Moderate-dose (15 to 20 mg/kg) bolus intravenous (IV) cyclophosphamide is increasingly being employed for the treatment of autoimmune diseases. High-dose (30 to 50 mg/kg) IV cyclophosphamide, which is used in transplantation and oncology, may cause water intolerance and water intoxication. Described herein is the first patient, to our knowledge, to develop water intoxication following administration of moderate-dose IV cyclophosphamide. A water challenge test demonstrated the absence of an underlying syndrome of inappropriate antidiuretic hormone secretion. Water intolerance was demonstrated in five additional patients receiving moderate-dose IV cyclophosphamide and hydration with hypotonic fluids. Thus, contrary to previous reports, water intoxication can occur following administration of moderate-dose IV cyclophosphamide. Patients with renal insufficiency who are receiving hypotonic fluids following moderate-dose IV cyclophosphamide administration may be at greatest risk for development of symptomatic water intoxication.

Pharmacological regulation of blood glucose levels in non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus is a metabolic disease that is common and is characterized by insulin insufficiency and resistance. Measures such as body weight reduction and exercise improve the metabolic defects, but pharmacological therapy is the most frequently used and successful therapy. The sulphonylureas stimulate insulin secretion. Metformin and troglitazone increase disposal and decrease hepatic glucose output without causing hypoglycemia. Acarbose is a dietary aid that spreads the dietary carbohydrate challenge to endogenous insulin over time. These pharmacological agents, either alone or in combination, can improve blood glucose regulation in patients with non-insulin-dependent diabetes mellitus.

New pharmacological approaches to therapy of NIDDM.

Currently available pharmacological agents have not been completely successful in restoring euglycemia in the non-insulin-dependent diabetes mellitus (NIDDM) patient. Several new approaches to the therapy of NIDDM have been formulated in recent years and are in various stages of laboratory or pharmaceutical development. Several of these agents are discussed in this article under categories relating to their mechanisms of lowering blood glucose: 1) inhibition of the release or action of counterregulatory hormones; 2) inhibition of postprandial glucose rise; 3) sensitization of tissues to insulin's actions; and 4) inhibition of gluconeogenesis, including inhibition of the long-chain acyl-CoA-carnitine acyltransferase I, the long-chain acylcarnitine translocase, and pyruvate carboxylase.

Isolation and culture of human endometrial glands.

A simple method for isolation of glands from human endometrium has been developed. The procedure involves collagenase digestion of the endometrial tissue and filtration through sieves of various pore sizes. Isolated glands retained on the sieves were washed and collected in culture dishes. Tubular organization of the isolated glands was ascertained by examination of the preparations under inverted microscope and light microscopy of stained sections. The appearance of the glands was found to reflect different functional states of the endometrium and, possibly, to reveal abnormalities. Growth of monolayers of epithelial cells derived from the glands was observed within 24 h of culturing. Electron microscopy of the cells in 7-day monolayer preparations from both proliferative and secretory endometrium revealed the characteristic features of human endometrial epithelial cells, viz. presence of microvilli and desmosome-like junctions. Nuclear bodies were observed in cells derived from both types of endometrium.

Digoxin bioavailability: formulations and rates of infusions.

The bioavailability of digoxin (lanoxin) tablets, oral aqueous solution of digoxin, and capsules containing a solution of digoxin was compared with digoxin given intravenously over 1 and 3 hr. The mean peak serum concentration of digoxin after the 1-hr intravenous infusion was 5 ng/ml, after the 3-hr infusion, 3.5 ng/ml, and after the oral solution, 2.0 ng/ml. There was an equivalent bioavailability of the oral solution and reference tablets of digoxin. The digoxin in capsules tended to be better absorbed than the reference tablets. There was 21% more digoxin excreted over 6 days after the 3 hr iv infusion than after the 1 hr iv infusion. This indicates that the calculated bioavailability of an orally administered dose of digoxin may vary with the rapidity of injection of the intravenous standard. It is estimated that an oral tablet of digoxin of 0.5 mg has about the same bioavailability as 0.35 of digoxin given by slow intravenous infusion (or 0.4 mg if calculated against a rapid intravenous injection).

Suppression of cortisol by a progestational steroid, melengestrol.

Melengestrol, a steroid with progestational activity but with a structure that does not resemble that of cortisol, suppresses plasma cortisol in humans with a potency 1/40th that of dexamethasone. The 6alpha-methyl and 17alpha-acetoxy substituents and the 6,7 double bond of melengestrol acetate are known to slow the metabolism of similar steroids. Insertion of a 6alpha-methyl group markedly increases the glucocorticoid activity of 17alpha-OH-progesterone. The glucocorticoid activity of melengestrol is presumably attributable to the large dose administered in our study, its slow metabolism and limitations of the specificity of glucocorticoid tissue receptors.

Efficacy of estradiol vaginal cream in postmenopausal women.

In a double-blind parallel study daily intravaginal administration of conjugated estrogen cream and estradiol cream for 14 days relieved vasomotor and vaginal postmenopausal symptoms in 29 postmenopausal women. By day 14, therapy with the estradiol vaginal cream resulted in plasma estrone and estradiol levels closer to those in premenopausal women than therapy with the conjugated estrogen cream. The extent of improvement and final estradiol plasma levels in the estradiol vaginal-cream group correlated. There was no correlation with severity of symptoms or estradiol plasma level at baseline. The metabolism of the conjugated estrogen cream might account for absence of correlation between improvement and final estradiol plasma levels in the conjugated vaginal-cream group.