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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Hydrogen Bonding in Amorphous Indomethacin

Amorphous Indomethacin has enhanced bioavailability over its crystalline forms, yet amorphous forms can still possess a wide variety of structures. Here, Empirical Potential Structure Refinement (EPSR) has been used to provide accurate molecular models on the structure of five different amorphous Indomethacin samples, that are consistent with their high-energy X-ray diffraction patterns. It is found that the majority of molecules in amorphous Indomethacin are non-bonded or bonded to one neighboring molecule via a single hydrogen bond, in contrast to the doubly bonded dimers found in the crystalline state. The EPSR models further indicate a substantial variation in hydrogen bonding between different amorphous forms, leading to a diversity of chain structures not found in any known crystal structures. The majority of hydrogen bonds are associated with the carboxylic acid group, although a significant number of amide hydrogen bonding interactions are also found in the models. Evidence of some dipole–dipole interactions are also observed in the more structurally ordered models. The results are consistent with a distribution of Z-isomer intramolecular type conformations in the more disordered structures, that distort when stronger intermolecular hydrogen bonding occurs. The findings are supported by 1H and 2H NMR studies of the hydrogen bond dynamics in amorphous Indomethacin.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2021

A High Energy X-ray Diffraction Study of Amorphous Indomethacin

Amorphous pharmaceuticals often possess a wide range of molecular conformations and bonding arrangements. The x-ray pair distribution function (PDF) method is a powerful technique for the characterization of variations in both intra-molecular and inter-molecular packing arrangements. Here, the x-ray PDF of amorphous Indomethacin is shown to be particularly sensitive to the preferred orientations of the chlorobenzyl ring found in isomers in the crystalline state. In some cases, the chlorobenzyl ring has no preferred torsional angle in the amorphous form, while in others evidence of distinct isomer orientations are observed. Amorphous samples with no preferred torsion angles of the chlorobenzyl ring are found to favor enhanced inter-molecular hydrogen bonding, and this is reflected in the intensity of the first sharp diffraction peak. These significant variations in structure rule out amorphous Indomethacin as a possible standard for x-ray PDF measurements. At high humidity, time resolved PDF's for >40 h reveal water molecules forming hydrogen bonds with Indomethacin molecules. Finally, a simple linear hydrogen bond model indicates that water molecules in the wet amorphous form have similar hydrogen bond strengths to those found between Indomethacin dimers or chains in the dry amorphous form.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
NASA NTRS1978

Aspirin- and Indomethacin-Induced Ulcers and their Antagonism by Anthihistamines

Gastric ulceration produced by aspirin and indomethacin was compared in acutely stressed and non-stressed rats. We found a synergism between these anti-inflammatory agents and acute stress in the production of gastric ulcers. Even at relatively high doses, neither agent caused appreciable gastric damage in non-stressed rats, whereas moderate doses of both agents produced massive ulceration in stressed rats. The synergism appears unrelated to the effect of these agents on the pituitary-adrenal response. The size and regional distribution of ulcers produced by aspirin and indomethacin in stressed rats were comparable. However, the dose--response curves of the two drugs were markedly dissimilar. Furthermore, the ulceration produced by indomethacin was attenuated by both H(sub 1) and H(sub 2) histamine receptor antagonists, whereas ulceration produced by aspirin was attenuated only by an H(sub 2) antagonist. The results suggest that the ulcerogenic mechanism of indomethacin may differ from that of aspirin and add to the growing evidence on the importance of endogenous histamine in various forms of gastric ulceration.

Brown, Patricia A.↗
NASA NTRS2001

Indomethacin attenuates post-suspension hypotension in Sprague-Dawley rats

Orthostatic hypotension is a serious condition that is sometimes manifested in astronauts during standing postflight. These observations may be related to impairment of autonomic function and/or excessive production of endothelium-dependent relaxing factors. To evaluate the role of the cyclooxygenase inhibitor indomethacin as a countermeasure against the post-suspension reduction in mean arterial pressure (MAP), we examined the cardiovascular responses to 7-day 30 degrees tail-suspension and a subsequent 6-hr post-suspension period in conscious male Sprague-Dawley rats. Indomethacin (2 mg/kg) or saline were administered intravenously prior to release from suspension and at 2 and 4 hrs post-suspension. Direct MAP and heart rate were determined prior to suspension, daily and every 2 hrs post-suspension. During suspension, MAP did not change, in contrast, during post-suspension; it decreased compared to parallel non-suspended, untreated animals. There were no significant changes in heart rate. The reduction in MAP post-suspension was associated with significant increases in plasma prostacyclin. Indomethacin attenuated the observed post-suspension reduction in MAP and reduced plasma prostacyclin levels. Also, the baroreflex sensitivity for heart rate was modified by indomethacin--the MAP threshold for baroreflex activation was raised and the effective MAP range expanded. Thus, the post suspension reduction in mean arterial pressure may be due to overproduction of vasodilatory prostaglandins and/or other endothelium-dependent relaxing factors and alteration in baroreflex activity.

NASA Discipline Cardiopulmonary↗
NASA NTRS1981

Indomethacin-antihistamine combination for gastric ulceration control

An anti-inflammatory and analgesic composition containing indomethacin and an H sub 1 or an H sub 2 histamine receptor antagonist in an amount sufficient to reduce gastric distress caused by the indomethacin is described. Usable antagonists include pyrilamine, promethazine, metiamide and cimetidine.

Brown, P. A.↗
NASA NTRS1975

Prostaglandin control of renal circulation in the unanesthetized dog and baboon

Effects of indomethacin and meclofenamate, inhibitors of prostaglandin synthesis, were evaluated in the regulation of renal blood flow in conscious and anesthetized dogs and in tranquilized baboons, instrumented with arterial pressure catheters and renal blood flow probes. Indomethacin, 10 mg/kg, did not alter renal blood flow or resistance significantly in the conscious dog. In the anesthetized dog, however, indomethacin caused a reduction in renal blood flow and an elevation of renal vascular resistance. Meclofenamate, 4 mg/kg, reduced renal flow and increased renal vascular resistance in conscious dogs. In conscious dogs and tranquilized primates, indomethacin and meclofenamate reduced the reactive hyperemia in the renal bed. Methoxamine and angiotensin II infused in graded doses induced significantly greater renal vasoconstriction in conscious dogs in the presence of indomethacin. Thus, in the conscious animal, prostaglandins appear to play only a minor part in the control of renal circulation at rest, but they are of greater importance in mediating the renal responses to reactive hyperemia and to vasoconstriction.

Swain, J. A.↗
NASA NTRS1998

Contrasting actions of pressor agents in severe autonomic failure

BACKGROUND: Orthostatic hypotension is the most disabling symptom of autonomic failure. The choice of a pressor agent is largely empiric, and it would be of great value to define predictors of a response. PATIENTS AND METHODS: In 35 patients with severe orthostatic hypotension due to multiple system atrophy or pure autonomic failure, we determined the effect on seated systolic blood pressure (SBP) of placebo, phenylpropanolamine (12.5 mg and 25 mg), yohimbine (5.4 mg), indomethacin (50 mg), ibuprofen (600 mg), caffeine (250 mg), and methylphenidate (5 mg). In a subgroup of patients, we compared the pressor effect of midodrine (5 mg) with the effect of phenylpropanolamine (12.5 mg). RESULTS: There were no significant differences in the pressor responses between patients with multiple system atrophy or pure autonomic failure. When compared with placebo, the pressor response was significant for phenylpropanolamine, yohimbine, and indomethacin. In a subgroup of patients, we confirmed that this pressor effect of phenylpropanolamine, yohimbine, and indomethacin corresponded to a significant increase in standing SBP. The pressor responses to ibuprofen, caffeine, and methylphenidate were not significantly different from placebo. Phenylpropanolamine and midodrine elicited similar pressor responses. There were no significant associations between drug response and autonomic function testing, postprandial hypotension, or plasma catecholamine levels. CONCLUSIONS: We conclude that significant increases in systolic blood pressure can be obtained in patients with orthostatic hypotension due to primary autonomic failure with phenylpropanolamine in low doses or yohimbine or indomethacin in moderate doses. The response to a pressor agent cannot be predicted by autonomic function testing or plasma catecholamines. Therefore, empiric testing with a sequence of medications, based on the risk of side effects in the individual patient and the probability of a response, is a useful approach.

Clinical Trial↗
NASA NTRS2001

Simulated microgravity upregulates an endothelial vasoconstrictor prostaglandin

Endothelial nitric oxide contributes to the vascular hyporesponsiveness to norepinephrine (NE) observed in carotid arteries from rats exposed to simulated microgravity. The goal of the present study was to determine whether a cyclooxygenase product of arachidonic acid also influences vascular responsiveness in this setting. Microgravity was simulated in rats by hindlimb unweighting (HU). After 20 days of HU, carotid arteries were isolated from control and HU-treated rats, and vascular rings were mounted in tissue baths for the measurement of isometric contraction. Two cyclooxygenase inhibitors, indomethacin and ibuprofen, and the selective thromboxane A(2) prostanoid-receptor antagonist, SQ-29548, had no effect on the contraction to NE in control vessels but markedly reduced contraction to NE in HU vessels. When the endothelium was removed, indomethacin no longer had any effect on the NE-induced contraction in HU vessels. In endothelium-intact vessels in the presence of indomethacin, the addition of the nitric oxide synthase inhibitor, N(G)-L-nitro-arginine methyl ester, to the medium bathing HU vessels increased the contraction to NE to the level of that of the control vessels. These results indicate that HU treatment induced two endothelial changes in carotid artery that opposed each other. Nitric oxide activity was increased and was responsible for the vascular hyporesponsiveness to NE. The activity of a vasoconstrictor prostaglandin was also increased, and attenuated the vasodilating effect of nitric oxide.

Non-NASA Center↗
DOE OSTI2021

Chloropyridinyl Esters of Nonsteroidal Anti-Inflammatory Agents and Related Derivatives as Potent SARS-CoV-2 3CL Protease Inhibitors

We report the design and synthesis of a series of new 5-chloropyridinyl esters of salicylic acid, ibuprofen, indomethacin, and related aromatic carboxylic acids for evaluation against SARS-CoV-2 3CL protease enzyme. These ester derivatives were synthesized using EDC in the presence of DMAP to provide various esters in good to excellent yields. Compounds are stable and purified by silica gel chromatography and characterized using 1 H-NMR, 13 C-NMR, and mass spectral analysis. These synthetic derivatives were evaluated in our in vitro SARS-CoV-2 3CLpro inhibition assay using authentic SARS-CoV-2 3CLpro enzyme. Compounds were also evaluated in our in vitro antiviral assay using quantitative VeroE 6 cell-based assay with RNAqPCR. A number of compounds exhibited potent SARS-CoV-2 3CLpro inhibitory activity and antiviral activity. Compound 9a was the most potent inhibitor, with an enzyme IC 50 value of 160 nM. Compound 13b exhibited an enzyme IC 50 value of 4.9 µM. However, it exhibited a potent antiviral EC 50 value of 24 µM in VeroE6 cells. Remdesivir, an RdRp inhibitor, exhibited an antiviral EC 50 value of 2.4 µM in the same assay. We assessed the mode of inhibition using mass spectral analysis which suggested the formation of a covalent bond with the enzyme. To obtain molecular insight, we have created a model of compound 9a bound to SARS-CoV-2 3CLpro in the active site.

3CLpro inhibitors↗
DOE OSTI2021

Non-Contact Mass Density and Thermal Conductivity Measurements of Organic Thin Films Using Frequency–Domain Thermoreflectance

Thin-film organic materials are broadly used to study amorphous stabilization of active pharmaceuticals, control explosive detonation phenomena, and introduce insulation in novel thermal barriers. Their synthesis, however, introduces defects and thickness variations that warrant careful characterization of local thermophysical properties such as thermal conductivity and mass density. In this study, wide bandwidth (200 Hz to 20 MHz) frequency–domain thermoreflectance (FDTR) is demonstrated to simultaneously extract the thermal conductivity and mass density of 1 μm physical vapor-deposited indomethacin films on Si and SiO 2 substrates, as well as 10 and 100 μm films on Si. By assuming a bulk specific heat capacity, mass densities are determined with FDTR measurements of volumetric heat capacity and are in good agreement with the literature, as well as models based upon a dependence on porosity and the kinetic theory for phonons. Lastly, it is found that for broad-band FDTR measurements, insulating substrates provide improved fidelity for the extraction of thermal conductivity and volumetric heat capacity in organic thin films. Overall, this work demonstrates the potential for FDTR as a non-contact method to determine microscale mass density variations across the surface and thickness of organic thin films.

36 MATERIALS SCIENCE↗
NASA NTRS1982

Prostacyclin-induced hyperthermia - Implication of a protein mediator

The mechanism of the prostacyclin-linked hyperthermia is studied in rabbits. Results show that intracerebroventricular administration of prostacyclin (PGI2) induces dose-related hyperthermia at room temperature (21 C), as well as at low (4 C) and high (30 C) ambient temperatures. It is found that this PGI2-induced hyperthermia is not mediated by its stable metabolite 6-keto prostaglandin F-1(alpha). Only one of the three anion transport systems, the liver transport system, appears to be important to the central inactivation of pyrogen, prostaglandin E2, and PGI2. Phenoxybenzamine and pimozide have no thermolytic effect on PGI2-induced hyperthermia, while PGI2 still induces hyperthermia after norepinephrine (NE) and dopamine levels are depleted by 6-hydroxydopamine. Indomethacin and SC-19220 (a PG antagonist) do not antagonize PGI2 induced hyperthermia, while theophylline does not accentuate the PGI2-induced hyperthermia. However, the hyperthermic response to PGI2 is attenuated by central administration of the protein synthesis inhibitor, anisomycin. It is concluded that PGI2-induced hyperthermia is not induced by NE, dopamine, or cyclic AMP, but rather that a protein mediator is implicated in the induction of fever by PG12.

Kandasamy, S. B.↗
NASA NTRS1993

Mechanical stimulation of skeletal muscle mitigates glucocorticoid induced decreases in prostaglandin synthesis

The glucocorticoid dexamethasone (Dex) induces a decline in protein synthesis and protein content of tissue cultured, avian skeletal muscle cells, and this atrophy is attenuated by repetitive mechanical stretch. Since the prostaglandin synthesis inhibitor indomethacin mitigated this stretch attenuation of muscle atrophy, the role of prostaglandins as growth modulators in these processes was examined. Dex at 10(exp -8) M reduced PGF(sub 2(alpha)) production 55 percent - 65 percent and PGE(sub 2) production 84 - 90 percent after 24 - 72 h of incubation in static cultures. Repetitive 10 percent stretch-relaxations of the non-Dex treated cultures increased PGF(sub 2(alpha)) efflux 41 percent at 24 h and 276 percent at 72 h and increased PGE(sub 2) production 51 percent at 24 h and 236 percent at 72 h. Mechanical stimulation of Dex treated cultures increased PGF(sub 2(alpha)) production 162 percent after 24 h, thus returning PGF(sub 2(alpha)) efflux to the level of non-Dex treated cultures. At 72 h, stretch increased PGF(sub 2(alpha)) efflux 65 percent in Dex treated cultures, but PGF(sub 2(alpha)) production was 45-84 percent less than non-Dex treated cultures. Mechanical stimulation of Dex treated cultures increased PGE(sub 2) production at 24 h, but not at 72 h. Dex reduced prostaglandin H synthase (PGHS) activity in the muscle cultures by 70 percent after 8 - 24 h of incubation, and mechanical stimulation increased PGHS activity of the Dex treated cultures by 98 percent. It is concluded that repetitive mechanical stimulation attenuates the catabolic effects of Dex on cultured skeletal muscle cells in part by reversing the Dex-induced declines in PGHS activity and prostaglandin production.

Chromiak, Joseph A.↗
NASA NTRS2002

Estrogen has opposing effects on vascular reactivity in obese, insulin-resistant male Zucker rats

We hypothesized that estradiol treatment would improve vascular dysfunction commonly associated with obesity, hyperlipidemia, and insulin resistance. A sham operation or 17beta-estradiol pellet implantation was performed in male lean and obese Zucker rats. Maximal vasoconstriction (VC) to phenylephrine (PE) and potassium chloride was exaggerated in control obese rats compared with lean rats, but estradiol significantly attenuated VC in the obese rats. Estradiol reduced the PE EC50 in all groups. This effect was cyclooxygenase independent, because preincubation with indomethacin reduced VC response to PE similarly in a subset of control and estrogen-treated lean rats. Endothelium-independent vasodilation (VD) to sodium nitroprusside was similar among groups, but endothelium-dependent VD to ACh was significantly impaired in obese compared with lean rats. Estradiol improved VD in lean and obese rats by decreasing EC50 but impaired function by decreasing maximal VD. The shift in EC50 corresponded to an upregulation in nitric oxide synthase III protein expression in the aorta of the estrogen-treated obese rats. In summary, estrogen treatment improves vascular function in male insulin-resistant, obese rats, partially via an upregulation of nitric oxide synthase III protein expression. These effects are counteracted by adverse factors, such as hyperlipidemia and, potentially, a release of an endothelium-derived contractile agent.

Non-NASA Center↗
NASA NTRS2002

Mechanisms of flow and ACh-induced dilation in rat soleus arterioles are altered by hindlimb unweighting

The purpose of this study was to test the hypothesis that endothelium-dependent dilation (flow-induced dilation and ACh-induced dilation) in rat soleus muscle arterioles is impaired by hindlimb unweighting (HLU). Male Sprague-Dawley rats (approximately 300 g) were exposed to HLU or weight-bearing control (Con) conditions for 14 days. Soleus first-order (1A) and second-order (2A) arterioles were isolated, cannulated, and exposed to step increases in luminal flow at constant pressure. Flow-induced dilation was not impaired by HLU in 1A or 2A arterioles. The cyclooxygenase inhibitor indomethacin (Indo; 50 microM) did not alter flow-induced dilation in 1As or 2As. Inhibition of nitric oxide synthase (NOS) with N(omega)-nitro-L-arginine (L-NNA; 300 microM) reduced flow-induced dilation by 65-70% in Con and HLU 1As. In contrast, L-NNA abolished flow-induced dilation in 2As from Con rats but had no effect in HLU 2As. Combined treatment with L-NNA + Indo reduced tone in 1As and 2As from Con rats, but flow-induced dilation in the presence of L-NNA + Indo was not different from responses without inhibitors in either Con or HLU 1As or 2As. HLU also did not impair ACh-induced dilation (10(-9)-10(-4) M) in soleus 2As. L-NNA reduced ACh-induced dilation by approximately 40% in Con 2As but abolished dilation in HLU 2As. Indo did not alter ACh-induced dilation in Con or HLU 2As, whereas combined treatment with L-NNA + Indo abolished ACh-induced dilation in 2As from both groups. We conclude that flow-induced dilation (1As and 2As) was preserved after 2 wk HLU, but HLU decreased the contribution of NOS in mediating flow-induced dilation and increased the contribution of a NOS- and cyclooxygenase-independent mechanism (possibly endothelium-derived hyperpolarizing factor). In soleus 2As, ACh-induced dilation was preserved after 2-wk HLU but the contribution of NOS in mediating ACh-induced dilation was increased.

Non-NASA Center↗
NASA NTRS1999

Mechanically induced c-fos expression is mediated by cAMP in MC3T3-E1 osteoblasts

In serum-deprived MC3T3-E1 osteoblasts, mechanical stimulation caused by mild (287 x g) centrifugation induced a 10-fold increase in mRNA levels of the proto-oncogene, c-fos. Induction of c-fos was abolished by the cAMP-dependent protein kinase inhibitor H-89, suggesting that the transient c-fos mRNA increase is mediated by cAMP. Down-regulation of protein kinase C (PKC) activity by chronic TPA treatment failed to significantly reduce c-fos induction, suggesting that TPA-sensitive isoforms of PKC are not responsible for c-fos up-regulation. In addition, 287 x g centrifugation increased intracellular prostaglandin E2 (PGE2) levels 2.8-fold (P<0. 005). Since we have previously shown that prostaglandin E2 (PGE2) can induce c-fos expression via a cAMP-mediated mechanism, we asked whether the increase in c-fos mRNA was due to centrifugation-induced PGE2 release. Pretreatment with the cyclooxygenase inhibitors indomethacin and flurbiprofen did not hinder the early induction of c-fos by mechanical stimulation. We conclude that c-fos expression induced by mild mechanical loading is dependent primarily on cAMP, not PKC, and initial induction of c-fos is not necessarily dependent on the action of newly synthesized PGE2.

Non-NASA Center↗
NASA NTRS1994

Orthostatic hypotension in patients, bed rest subjects, and astronauts

Orthostatic hypotension after even short space flights has affected a significant number of astronauts. Given the need for astronauts to function at a high level of efficiency during and after their return from space, the application of pharmacologic and other treatments is strongly indicated. This report addresses the clinical problem of orthostatic hypotension and its treatments to ascertain whether pharmacologic or physiologic treatment may be useful in the prevention of orthostatic hypotension associated with space flight. Treatment of orthostatic hypotension in patients now includes increasing intravascular volume with high sodium intake and mineralocorticoids, or increasing vascular resistance through the use of drugs to stimulate alpha or block beta vascular receptors. Earlier treatment used oral sympathomimetic ephedrine hydrochloride alone or with "head-up" bed rest. Then long-acting adrenocortical steroid desoxycorticosterone preparations with high-salt diets were used to expand volume. Fludrocortisone was shown to prevent the orthostatic drop in blood pressure. The combination of the sympathomimetic amine hydroxyamphetamine and a monoamine oxidase inhibitor tranylcypromine has been used, as has indomethacin alone. Davies et al. used mineralocorticoids at low doses concomitantly with alpha-agonists to increase vasoconstrictor action. Schirger et al used tranylcypromine and methylphenidate with or without a Jobst elastic leotard garment or the alpha-adrenergic agonist midodrine (which stimulates both arterial and venous systems without direct central nervous system or cardiac effects). Vernikos et al established that the combination of fludrocortisone, dextroamphetamine, and atropine exhibited a beneficial effect on orthostatic hypotension induced by 7-day 6 degrees head-down bed rest (a model used to simulate the weightlessness of space flight). Thus, there are numerous drugs that, in combination with mechanical techniques, including lower body negative pressure to elevate transmural pressure, could be studied to treat orthostatic hypotension after space flight.

Review↗