Gender differences in osteoporotic hip fractures in Sarawak General Hospital.

INTRODUCTION: Osteoporosis and osteoporotic fracture pose a major public health problem in our ageing population, and particularly concerning is the increased morbidity and mortality associated with osteoporotic hip fractures. While overall diagnosis and treatment for osteoporosis have improved, osteoporosis in men remains underdiagnosed and undertreated. We aim to describe the difference in clinical characteristics between elderly men and women with osteoporotic hip fractures in Sarawak General Hospital. MATERIALS AND METHODS: All patients diagnosed with osteoporotic hip fracture admitted to Sarawak General Hospital from June 2019 to March 2021 were recruited, and demographic data and clinical features were obtained. RESULTS: There were 140 patients with osteoporotic hip fracture, and 40 were men (28.6%). The mean age for males was 74.1 ± 9.5 years, while the mean age for females was 77.4 ± 9.1 years (p=0.06). The types of fracture consisted of neck of femur=78, intertrochanteric=61 and subtrochanteric=1. More men were active smokers (15% vs 1%, p<0.001). There were 20 men with secondary osteoporosis (50%), while 13 women (13%) had secondary osteoporosis (p<0.001). The causes of secondary osteoporosis among the men were hypogonadism, COPD, glucocorticoid-induced osteoporosis, renal disease, androgen deprivation therapy, thyroid disorder, prostate cancer and previous gastrectomy. There were two deaths among the men and four deaths among the women during the inpatient and 3 months follow-up period. There was no statistical significance between the mortality rates between male patients (5%) and female patients (4%) (p=0.55). CONCLUSION: There were more females with osteoporotic hip fractures, and there were significantly more males with secondary osteoporotic hip fractures.

18F-NaF PET/CT for the evaluation of temporomandibular joint disorder.

AIM: To investigate the usefulness of a quantitative parameter (maximum standardised uptake value [SUVmax]) of 18F-sodium fluoride (NaF) positron-emission tomography (PET)/computed tomography (CT) for the evaluation of temporomandibular joint (TMJ) disorder (TMD). MATERIALS AND METHODS: Seventy-six TMD patients (male: female=14:62, age=40.3±17.1 years, bilateral: unilateral=40:36) with 152 TMJs were enrolled. The 18F-NaF PET/CT parameter (SUVmax) was compared with the presence of TMJ arthralgia (arthralgic=86, non-arthralgic=66) and clinical subtypes based on the Research Diagnostic Criteria for TMD Axis I (TMD osteoarthritis=49, non-TMD osteoarthritis=67, and asymptomatic TMJ=36). Splint therapy was applied to 48 patients for 6 months without considering 18F-NaF PET/CT findings. Post-splint therapy 18F-NaF PET/CT was performed in 32 patients and clinical responses to the therapy were classified into improvement (n=33), no change (n=10), or aggravation (n=7) for 50 TMJs excluding asymptomatic TMJs (n=14). RESULTS: SUVmax was significantly greater in arthralgic TMJs than in non-arthralgic TMJs (6.62±3.56 versus 4.32±1.53, p<0.0001). SUVmax was also significantly greater in TMD osteoarthritis (6.75±3.85) than in non-TMD osteoarthritis (5.21±2.70) and asymptomatic TMJs (4.86±1.99; p=0.0386). After splint therapy, SUVmax was significantly increased in aggravated TMJs (from 7.80±3.72 to 11.00±5.74, p=0.0156), whereas no significant change in SUVmax was observed in improved (from 6.16±2.68 to 6.09±2.60, p=0.4915) and unchanged (from 6.46±4.19 to 6.77±4.32, p=0.3223) TMJs. CONCLUSIONS: 18F-NaF PET/CT is a useful imaging tool for TMD evaluation because SUVmax showed a fair diagnostic performance for arthralgic TMJ and TMD osteoarthritis, and a correlation with the therapeutic response.

Maximum standardised uptake value of quantitative bone SPECT/CT in patients with medial compartment osteoarthritis of the knee.

AIM: To evaluate the correlation between the maximum standardised uptake value (SUVmax) from bone single-photon-emission computed tomography/computed tomography (SPECT/CT) and other imaging parameters for medial compartment osteoarthritis (OA) of the knee. MATERIALS AND METHODS: Patients (n=26; male:female=2:24; age, 55.3±5.8 years) underwent quantitative knee SPECT/CT using technetium-99m (Tc-99m) hydroxymethylene diphosphonate (HDP) before surgical operation for medial OA of the knee. SUVmax was calculated using dedicated quantitative software. Visual grades of tracer uptake on bone SPECT/CT and Kellgren-Lawrence (KL) OA scores on plain radiographs were assessed using a five-point scale. Magnetic resonance imaging (MRI) scores (n=22) and patient symptom scores were also assessed. RESULTS: The operated knees (n=34) had a greater SUVmax than the non-operated knees (n=18) in the medial compartment (14.1±6.1 versus 5.3±4.4, p<0.0001). In the medial compartment, the SUVmax was significantly correlated with SPECT/CT visual grades (rho=0.794, p<0.0001), KL scores (rho=0.703, p<0.0001), and MRI scores (rho=0.714-0.808, p≤0.0002); however, SUVmax and other imaging parameters were not correlated with patient symptom scores (p>0.05). CONCLUSIONS: The SUVmax of quantitative bone SPECT/CT was highly correlated with traditional imaging parameters for medial compartment OA severity of the knee. Quantitative bone SPECT/CT is a promising imaging technique for the objective assessment of knee OA.

Does serum uric acid act as a modulator of cerebrospinal fluid Alzheimer's disease biomarker related cognitive decline?

BACKGROUND AND PURPOSE: The association of serum uric acid, cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) and longitudinal cognitive decline was evaluated using the AD Neuroimaging Initiative database. METHODS: In 271 healthy subjects, 596 mild cognitive impairment patients and 197 AD patients, serum uric acid and CSF AD biomarkers were measured at baseline, and Mini-Mental State Examination and AD Assessment Scale - Cognitive Subscale (ADAS-cog) were assessed serially (mean duration, 2.9 years). The effect of uric acid on longitudinal cognitive decline was evaluated using linear mixed effect models for Mini-Mental State Examination and ADAS-cog scores in female and male subjects separately, with possible confounders controlled (model 1). To determine the effects of uric acid independent of CSF biomarker (Aß1-42 or tau) and to test whether the detrimental effects of CSF biomarker differ according to uric acid, CSF biomarker and its interaction with uric acid were further included in model 1 (model 2). RESULTS: Higher levels of uric acid were associated with slower cognitive decline, particularly in the mild cognitive impairment and dementia subgroups, and more prominently in female subjects. Model 2 with CSF Aß1-42 showed that higher levels of uric acid were associated with a slower cognitive decline and alleviated the detrimental effect of Aß1-42 on cognitive decline. Model 2 with CSF tau showed that higher levels of uric acid alleviated the detrimental effect of tau on cognitive decline in female subjects but not in male subjects. CONCLUSION: Higher levels of uric acid had protective effects on longitudinal cognitive decline independent of and interactively with CSF AD biomarkers.

Long-term control of diabetes in immunosuppressed nonhuman primates (NHP) by the transplantation of adult porcine islets.

Pig islets are an alternative source for islet transplantation to treat type 1 diabetes (T1D), but reproducible curative potential in the pig-to-nonhuman primate (NHP) model has not been demonstrated. Here, we report that pig islet grafts survived and maintained normoglycemia for >6 months in four of five consecutive immunosuppressed NHPs. Pig islets were isolated from designated pathogen-free (DPF) miniature pigs and infused intraportally into streptozotocin-induced diabetic rhesus monkeys under pretreatment with cobra venom factor (CVF), anti-thymocyte globulin (ATG) induction and maintenance with anti-CD154 monoclonal antibody and low-dose sirolimus. Ex vivo expanded autologous regulatory T cells were adoptively transferred in three recipients. Blood glucose levels were promptly normalized in all five monkeys and normoglycemia (90-110 mg/dL) was maintained for >6 months in four cases, the longest currently up to 603 days. Intravenous glucose tolerance tests during the follow-up period showed excellent glucose disposal capacity and porcine C-peptide responses. Adoptive transfer of autologous regulatory T cells was likely to be associated with more stable and durable normoglycemia. Importantly, the recipients showed no serious adverse effects. Taken together, our results confirm the clinical feasibility of pig islet transplantation to treat T1D patients without the need for excessive immunosuppressive therapy.

Experimental demonstration of energy-chirp control in relativistic electron bunches using a corrugated pipe.

The first experimental study is presented of a corrugated wall device that uses wakefields to remove a linear energy correlation in a relativistic electron beam (a "dechirper"). Time-resolved measurements of both longitudinal and transverse wakefields of the device are presented and compared with simulations. This study demonstrates the feasibility to employ a dechirper for precise control of the beam phase space in the next generation of free-electron-lasers.

Determining the Degree of Dopaminergic Denervation Based on the Loss of Nigral Hyperintensity on SMWI in Parkinsonism.

BACKGROUND AND PURPOSE: Nigrostriatal dopaminergic function in patients with Parkinson disease can be assessed using 123I-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)-nortropan dopamine transporter (123I-FP-CIT) SPECT, and a good correlation has been demonstrated between nigral status on SWI and dopaminergic denervation on 123I-FP-CIT SPECT. Here, we aim to correlate quantified dopamine transporter attenuation on 123I-FP-CIT SPECT with nigrosome-1 status using susceptibility map-weighted imaging (SMWI). MATERIALS AND METHODS: Between May 2017 and January 2018, consecutive patients with idiopathic Parkinson disease (n = 109) and control participants (n = 29) who underwent 123I-FP-CIT SPECT with concurrent 3T SWI were included. SMWI was generated from SWI. Two neuroradiologists evaluated nigral hyperintensity from nigrosome-1 on each side of the substantia nigra. Using consensus reading, we compared the 123I-FP-CIT-specific binding ratio according to nigral hyperintensity status and the 123I-FP-CIT specific binding ratio threshold to confirm the loss of nigral hyperintensity was determined using receiver operating characteristic curve analysis. RESULTS: The concordance rate between SMWI and 123I-FP-CIT SPECT was 65.9%. The 123I-FP-CIT-specific binding ratios in the striatum, caudate nucleus, and putamen were significantly lower when nigral hyperintensity in the ipsilateral substantia nigra was absent than when present (all, P < .001). The 123I-FP-CIT-specific binding ratio threshold values for the determination of nigral hyperintensity loss were 2.56 in the striatum (area under the curve, 0.890), 3.07 in the caudate nucleus (0.830), and 2.36 in the putamen (0.887). CONCLUSIONS: Nigral hyperintensity on SMWI showed high positive predictive value and low negative predictive value with dopaminergic degeneration on 123I-FP-CIT SPECT. In patients with Parkinson disease, the loss of nigral hyperintensity is prominent in patients with lower striatal specific binding ratios.

Differences in the prevalence of colorectal polyps in patients undergoing endoscopic removal of gastric adenoma or early gastric cancer and in healthy individuals.

BACKGROUND AND AIMS: We compared the prevalence of adenomatous and cancerous colon polyps in patients who underwent endoscopic removal of gastric neoplasms and in healthy controls. MATERIALS AND METHODS: This retrospective study reviewed the medical records of 186 patients with gastric neoplasms and 186 healthy subjects from January 2002 to October 2008. The gastric neoplasm group was comprised of patients undergoing endoscopic removal of gastric adenomas or early gastric cancers and serial fiberoptic colonoscopy (FCS) for checkups. The control group was comprised of subjects undergoing fiberoptic esophagogastroduodenoscopy (FEGD) and FCS for general checkup and was matched for age and sex with the gastric neoplasm group. Advanced colonic neoplasm was defined by any of the following: (1) the presence of three or more polyps; (2) polyp size at least 1.0 cm; (3) high-grade dysplasia or adenocarcinoma confirmed by histopathologic examination. RESULTS: Of the 372 persons, colorectal polyps were detected in 124 (33.3 %), advanced colonic neoplasms in 44 (11.8 %), and adenocarcinomas in 10 (2.7 %). The overall prevalence of adenomatous or cancerous polyps ("all polyps") and the prevalence of advanced colonic neoplasms were significantly higher in the gastric neoplasm group than in the control group (all polyps: 40.9 % in the gastric neoplasm group vs. 25.8 % in the control group, P = 0.002; advanced colonic neoplasms: 15.6 % vs. 8.1 %, P = 0.025). The risk factors for all polyps were age, male sex, diabetes mellitus, and being assigned to the gastric neoplasm group, and those for advanced colonic neoplasms were age and being assigned to the gastric neoplasm group. Confining the analysis to the gastric neoplasm group, the risk factors for all polyps were identical with those for the total group; however, those for advanced colonic neoplasm were different (age vs. diabetes and hypertriglyceridemia). CONCLUSION: Endoscopists should consider performing routine FCS in patients undergoing endoscopic removal of gastric neoplasms.

Validation of the Vectra H1 portable three-dimensional photogrammetry system for facial imaging.

Three-dimensional (3D) surface imaging using stereophotogrammetry has become increasingly popular in clinical settings, offering advantages for surgical planning and outcome evaluation. The handheld Vectra H1 is a low-cost, highly portable system that offers several advantages over larger stationary cameras, but independent technical validation is currently lacking. In this study, 3D facial images of 26 adult participants were captured with the Vectra H1 system and the previously validated 3dMDface system. Using error magnitude statistics, 136 linear distances were compared between cameras. In addition, 3D facial surfaces from each system were registered, heat maps generated, and global root mean square (RMS) error calculated. The 136 distances were highly comparable across the two cameras, with an average technical error of measurement (TEM) value of 0.84mm (range 0.19-1.54mm). The average RMS value of the 26 surface-to-surface comparisons was 0.43mm (range 0.33-0.59mm). In each case, the vast majority of the facial surface differences were within a ±1mm threshold. Areas exceeding ±1mm were generally limited to facial regions containing hair or subject to facial microexpressions. These results indicate that 3D facial surface images acquired with the Vectra H1 system are sufficiently accurate for most clinical applications.

FDG uptake and glucose transporter type 1 expression in lymph nodes of non-small cell lung cancer.

AIMS: FDG uptake in NSCLC is related to glucose transporter type 1 (Glut-1) expression. Here, we investigated the direct causal relationship between FDG uptake and Glut-1 expression to determine the role of Glut-1 in FDG uptake by malignant and benign lymph nodes (LNs). METHODS: Fifty-five curative lung resections in 53 NSCLC patients (male:female=36:17, age=62.0+/-11.8 years) were included. Maximum standardized uptake values (maxSUVs) of LNs in preoperative whole body FDG-PET and Glut-1 immunostaining results were compared. RESULTS: Of 316 pathologically confirmed LNs, 12.3% (39/316) were malignant, and in malignant LNs, FDG positive LNs were no different from FDG negative LNs in terms of size (15.0+/-6.7 mm vs 10.0+/-6.1mm, p>0.05), or in terms of the proportion of LNs occupied by tumor (60.0+/-28.8% vs 39.2+/-38.4%, p>0.05), but had greater percentages of Glut-1 positive cells in tumors (74.1+/-31.8% vs 22.7+/-18.7%, p<0.01), and Glut-1 staining intensities (3.4+/-0.9 vs 1.8+/-1.3, p<0.01). FDG negative malignant LNs featured cytoplasmic Glut-1 expression and adenocarcinoma. Glut-1 staining intensities were found to be significantly correlated with the maxSUVs of malignant LNs (rho=0.516, p<0.05), but the percentages of Glut-1 positive cells in tumors were not (r=0.2072, p>0.05). Analysis of FDG positive benign LNs showed that maxSUV was not correlated with degree of follicular hyperplasia, or Glut-1 expression (p>0.05). CONCLUSIONS: Intense Glut-1 immunoreactivity was found to be proportionally related to the degree of FDG uptake by malignant LNs in NSCLC. However, the finding that Glut-1 expression in lymphoid hyperplasia showed no correlation with FDG uptake in benign LNs requires further investigation.

Surface-enhanced Raman spectroscopy of novel psychoactive substances using polymer-stabilized Ag nanoparticle aggregates.

A set of seized "legal high" samples and pure novel psychoactive substances have been examined by surface-enhanced Raman spectroscopy using polymer-stabilized Ag nanoparticle (Poly-SERS) films. The films both quenched fluorescence in bulk samples and allowed identification of µg quantities of drugs collected with wet swabs from contaminated surfaces.

Olfactory dysfunction in patients with head trauma.

BACKGROUND: The ability to smell is commonly altered by head trauma (HT). However, the nature, prevalence, prognosis, and etiology of such alterations are poorly understood. OBJECTIVES: To quantitatively determine the degree of olfactory function in patients with HT-related chemosensory complaints and to examine the influences of age, sex, HT severity, time since HT, and other variables on such function. Also, to use quantitative magnetic resonance imaging (MRI) to establish whether and to what degree damage to the olfactory bulbs and tracts, frontal lobes, and temporal lobes occurs. PATIENTS AND METHODS: Two hundred sixty-eight patients with HT from the University of Pennsylvania Smell and Taste Center, Philadelphia, were administered a quantitative odor identification test, a depression inventory, and a medical history questionnaire; 66 were retested after individual test-retest periods ranging from 1 month to 13 years. The volume of olfactory-related brain structures was determined in 15 patients and 15 controls using MRI. RESULTS: One hundred seventy-nine patients (66.8%) had anosmia, 55 (20.5%) had microsmia, and 34 (12.7%) had normosmia. Frontal impacts produced less dysfunction than back or side impacts. Of the 66 retested patients, 24 (36%) improved slightly, 30 (45%) had no change, and 12 (18%) worsened; only 3 patients, none of whom initially had anosmia, regained normal olfactory function. Trauma severity was related to olfactory test scores in patients with microsmia. Parosmia prevalence decreased from 41.1% to 15.4% over an 8-year posttrauma period. Olfactory bulb and tract volumes of male, but not female, patients with HT were greatly reduced relative to volumes of controls. CONCLUSIONS: Patients complaining of HT-related olfactory dysfunction typically have anosmia and rarely regain normal olfactory ability, parosmia prevalence decreases over time in such patients, and damage to olfaction-related brain structures can be observed in most such patients using an appropriate MRI protocol.

Preferential tumor radiosensitization by analogs of nicotinamide and benzamide.

The effects of a range of different analogs of nicotinamide and benzamide on the X ray response of the EMT-6 tumor in vivo was investigated. Using an in vivo/in vitro survival assay, sensitization was seen at a dose of 2 mmole/kg for all but one of the analogs tested. The enhancement ratios (ER's) ranged from 1.0 to 1.5. Of particular interest were nicotinamide and SR-4350 which gave large ER's (1.5 and 1.4 respectively) at doses which were only about 12% of the LD50 values. In one normal tissue studied (skin reaction) a large single dose of nicotinamide (8 mmole/kg) only gave an ER of 1.1. These results will be discussed with reference to the mechanisms involved and the clinical implications.

Misonidazole neurotoxicity in mice decreased by administration with pyridoxine.

A series of toxicological and pharmacological experiments was performed to test the hypothesis that alterations of pyridoxine (Vitamin B6) metabolism may play an important role in the development of misonidazole (MISO) neurotoxicity. The formation of a Schiff's base between the final reduction product of MISO, 2-amino MISO (NH2-MISO), and pyridoxal-HCl in ethanol was demonstrated. Mice receiving daily intraperitoneal injections of MISO suffered significantly less toxicity (as determined by survival, weight gain and neurological tests) when large doses of pyridoxine-HCl (PYR) were delivered concomitantly, and consequently were able to tolerate administration of more than twice as many MISO injections. PYR did not alter the pharmacokinetics of MISO, either when given simultaneously or when given by multiple repeated daily injections prior to MISO. The administration of PYR also did not alter the radiosensitization by MISO in an in vivo-in vitro cloning assay with the EMT6 tumor in BALB/c mice. If depletion or altered metabolism of pyridoxine by reduced metabolites is also responsible for the neurotoxic effects of nitroimidazoles in humans, then concomitant administration of pyridoxine (in doses greater than the molar quantity of NH2-MISO formed) should inhibit the development of such symptoms and allow administration of larger doses of MISO than are currently clinically employable.

SR-4233: a new bioreductive agent with high selective toxicity for hypoxic mammalian cells.

We have examined the effects of the benzotriazine di-N-oxide SR-4233 (3-amino-1,2,4-benzotriazine-1,4 dioxide) on a variety of aerobic and hypoxic cells in culture, and on tumors in mice. The cell lines used were Chinese hamster ovary (HA-1), mouse 10T1/2, RIF-1, and SCC VII cells, and the human cell lines HCT-8, AG1522, and A549. The effect of SR 4233 in combination with irradiation was also examined in the SCC VII tumor growing in the flank of C3H mice using clonogenic assay (tumors excised 24 hr after irradiation). We found SR-4233 to be a potent and selective killer of hypoxic cells. Cell killing as a function of time for the various cell lines was exponential, with no shoulder. Drug concentrations producing equivalent levels of cell killing were 75-200 fold lower in hypoxic than in aerobic cells for the mouse and hamster lines, and 15-50 fold lower for the human cells. In vivo experiments showed that the non-toxic dose of 0.3 mmole/kg of SR-4233 enhanced radiation-induced tumor cell kill when the drug was given between 1 hr before and 2 hr after the radiation dose. We have also shown that the drug metabolizes more rapidly under hypoxic than aerobic conditions, both in vitro and in vivo. The toxic product(s) is unknown, but could be the 1-electron reduction product, the radical anion, because the mono N-oxide (the 2-electron reduction product) did not display cytotoxicity or selective killing under hypoxic conditions. This compound could therefore be a useful tool in tumor biology, as well as being a new lead in the development of bioreductive cytotoxic agents for cancer therapy.

Radiosensitization by diamide analogs and arsenicals.

Several analogs of the glutathione (GSH) oxidizing reagent diamide [diazenedicarboxylic acid bis(N,N'-diethylamide)] were tested as radiosensitizers of aerobic cells. In general, radiosensitization correlates with the rate of reaction with cellular reducing agents and occurs only when the reductive capacity of the cell is exceeded. SR-4077, [diazenedicarboxylic acid bis(N,N-piperidide)], is particularly suitable for mechanistic studies, because it is less cytotoxic than diamide, but is equally reactive toward cellular GSH. SR-4077 sensitizes CHO cells to X rays under aerobic conditions, even when the drug is added after irradiation. Radiosensitization is expressed both as a change in the exponential slope of the radiation cell survival curve and as a decrease in the shoulder of the survival curve. Phenylarsine oxide, a dithiol-binding reagent, sensitizes aerobic CHO cells to X rays by modification of the shoulder of the survival curve. The results are consistent with the hypothesis that the shoulder-modifying effect of GSH oxidants is caused by the loss of protein thiols, which might be involved in the repair of X ray-induced DNA damage.

In vitro and in vivo radiosensitization by 2-nitroimidazoles more electron-affinic than misonidazole.

A series of 5-substituted-methyl-2-nitroimidazoles, more electron-affinic than misonidazole (MISO), has been studied as potential hypoxic cell radiosensitizers. In vitro radiosensitization studies of these compounds showed equivalent or greater radiosensitization than MISO, while LD50 studies of the compounds found them to be, in general, more toxic to Balb/c mice than MISO. Radiosensitization experiments in vivo with compounds SR-2537, SR-2515 and SR-2553 of acceptable toxicity were not able to sensitize the EMT6 tumor to x-irradiation after a single intraperitoneal injection. However, moderate sensitization was achieved when SR-2537 was administered i.v. Rapid metabolism of these more electron-affinic compounds was suggested as a possible cause of the poor sensitization. However, when multiple i.v. injections of SR-2537 were given to maintain a constant drug level in the tumor, radiosensitization by this compound did not improve, suggesting that intact drug was either not reaching or was not penetrating the hypoxic cells.

The development of an oral prodrug, SR-2545, of the 2-nitroimidazole radiosensitizer SR-2508.

SR-2508, a 2-nitroimidazole radiosensitizer, is expected to be clinically superior to desmethylmisonidazole or misonidazole because of its lower lipophilicity with subsequent lower drug levels in neural tissue and more rapid plasma elimination. The intravenous route of administration will be optimal but oral drugs may be necessary. Since decreased lipophilicity will decrease oral absorption we have synthesized, and tested in mice, SR-2545, an acetate ester prodrug of SR-2508. In the liver there is complete first pass metabolism to parent drug with no prodrug detectable in the blood. Compared to an equal dose of oral SR-2508, the prodrug yields a more rapid, reproducible, plasma peak with twice the bioavailability, peak plasma concentration and radiosensitization. If oral preparations of SR-2508 are to be used in the clinic the prodrug, SR-2545, is likely to be superior to oral SR-2508.

Structure-activity relationships for benzotriazine di-N-oxides.

SR 4233 (3-amino-1,2,4-benzotriazine 1,4-dioxide) is a bioreductive agent that selectively kills and radiosensitizes hypoxic mammalian cells in vitro and murine tumors in vivo. In an attempt to better understand the mechanism of action of the drug, and to determine whether a superior analog may exist, 15 benzotriazine-di-N-oxide analogs of SR 4233 have been evaluated to date for the following properties: hypoxic and aerobic toxicity toward CHO cells in vitro, drug-induced stimulation of oxygen consumption by incubation with respiration-inhibited cells, and acute LD50 evaluated in BALB/c mice. We noted several correlations between these biological properties of the drugs and some of their physicochemical characteristics. Both the hypoxic cytotoxicity and stimulation of oxygen consumption by respiration-inhibited cells were positively correlated with E1/2, the polarographic half-wave reduction potential, and a measure of electron affinity. The air-to-nitrogen differential cytotoxicity reached a maximum (corresponding to SR 4233) and then declined with increasing E1/2. The acute LD50 of each analog in mice decreased with increasing E1/2. One new compound, SR 4482, was found to be more toxic to hypoxic cells in vitro, but less toxic to mice, than SR 4233. It is similar in structure to SR 4233, but lacks any substituent in the 3-position of the triazine ring. This promising drug may represent a member of a new subseries of 1,2,4-benzotriazines with different structure-activity relationships.

Adriamycin analogs. Periodate oxidation of adriamycin.

Adriamycin is selectively cleaved in high yield at the C13-C14 bond by 1 equiv of sodium metaperiodate to yield carboxylic acid 3. The corresponding methyl ester 4 is obtained by Fischer esterification. Spectral studies indicate that 3 and 4 bind to calf thymus DNA in a manner similar to adriamycin and daunomycin but Tm measurements suggest that less stable complexes are formed. Ester 4 inhibits DNA and RNA synthesis in cultured L1210 cells at levels comparable to adriamycin but acid 3 is much less effective. Both new compounds are moderately effective as antitumor agents against P388 lymphocytic leukemia in the mouse.