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Sexual Medicine Reviews Apr 2024Although oral phosphodiesterase 5 inhibitors represent a first choice and long-term option for about half of all patients with erectile dysfunction (ED), self-injection...
INTRODUCTION
Although oral phosphodiesterase 5 inhibitors represent a first choice and long-term option for about half of all patients with erectile dysfunction (ED), self-injection therapy with vasoactive drugs remains a viable alternative for all those who are not reacting or cannot tolerate oral drug therapy. This current injection therapy has an interesting history beginning in 1982.
OBJECTIVES
To provide a comprehensive history of self-injection therapy from the very beginnings in 1982 by contemporary witnesses and some members of the International Society for Sexual Medicine's History Committee, a complete history of injection therapy is prepared from eyewitness accounts and review of the published literature on the subject, as well as an update of the current status of self-injection therapy.
METHODS
Published data on injection therapy, as a diagnostic and therapeutic tool for ED, were reviewed thoroughly by PubMed and Medline research from 1982 until June 2023. Early pioneers and witnesses added firsthand details to this historical review. Therapeutic reports of injection therapy were reviewed, and results of side effects and complications were thoroughly reviewed.
RESULTS
The pioneers of the first hours were Ronal Virag (1982) for papaverine, Giles Brindley (1983) for cavernosal alpha-blockade (phentolamine and phenoxybenzamine), Adrian Zorgniotti (1985) for papaverine/phentolamine, and Ganesan Adaikan and N. Ishii (1986) for prostaglandin E1. Moxisylyte (thymoxamine) was originally marketed but later withdrawn. The most common side effect is priapism, with the greatest risk of this from papaverine, which has modified its use for therapy. Currently, prostaglandin E1 and trimixes continue to be the agents of choice for diagnostic and therapeutic use in ED. A recent agent is a mixture of a vasoactive intestinal polypeptide (aviptadil) and phentolamine.
CONCLUSIONS
After 40 years, self-injection therapy represents the medication with the highest efficacy and reliability rates and remains a viable option for many couples with ED. The history of this therapy is rich.
PubMed: 38644056
DOI: 10.1093/sxmrev/qeae020 -
Ulusal Travma Ve Acil Cerrahi Dergisi =... Sep 2023Our target was to show the role of high mobility group box-1/receptor for (HMGB1/RAGE) interaction in feces intraperitoneal injection procedure (FIP)-induced acute lung...
BACKGROUND
Our target was to show the role of high mobility group box-1/receptor for (HMGB1/RAGE) interaction in feces intraperitoneal injection procedure (FIP)-induced acute lung injury (ALI) pathophysiology, to investigate the effect of papaverine on RAGE associated NF-κB pathway by determining the level of soluble RAGE (sRAGE) and HMGB1, and to support this hypothesis by evaluating inflammatory biochemical, oxidative stress markers, Hounsfield unit (HU) value in computed tomography (CT), and histo-pathological results.
METHODS
FIP was performed on 37 Wistar rats for creating a sepsis-induced ALI model. The animals were assigned into four groups as follows: Normal control (no treatment), placebo (FIP and saline), and receiving 20 mg/kg and 40 mg/kg per day papaverine. Twenty h after FIP, CT examination was performed for all animals, and HU value of the lung parenchyma was measured. The plasma levels of tumor necrosis factor (TNF)-α, HMGB1, sRAGE, C-reactive protein (CRP) and malondialdehyde (MDA), and lactic acid (LA) were determined and PaO2 and PaCO2 were measured from arterial blood sample. Lung damage was assessed by histopathological.
RESULTS
TNF-, IL-6, CRP, HMGB1, MDA, LA levels, histopathologic scores, and HU values of CT were significantly increased and sRAGE levels were decreased in the saline-treated group against normal group (all P<0.05). Papaverine significantly reversed all results regardless of the dose (all P<0.05) and demonstrated inhibition of HMGB1/RAGE interaction through increasing sRAGE levels and suppresses the pro-inflammatory cytokines.
CONCLUSION
We concluded that papaverine has ameliorating effects in rat model of ALI.
Topics: Rats; Animals; HMGB1 Protein; Papaverine; Rats, Wistar; Radiology; Acute Lung Injury; Sepsis; C-Reactive Protein; Lactic Acid
PubMed: 37681716
DOI: 10.14744/tjtes.2023.73580 -
Molecular Pharmaceutics Oct 2023Aggregation in aqueous solution can have important implications on both the exposure of a drug and its pharmaceutical manufacturability. However, the drug aggregates...
Aggregation in aqueous solution can have important implications on both the exposure of a drug and its pharmaceutical manufacturability. However, the drug aggregates formed can be very small and, thus, difficult to interrogate experimentally. On the other hand, at higher supersaturations where larger aggregates are supported, the chemical system is inherently metastable and therefore likewise challenging to study from an experimental standpoint. Understanding aggregation behavior is further complicated in the case of ionizable drugs where, unlike neutral compounds, there can be uncertainty in the kinds of drug molecules (i.e., charged, neutral, or both) that become incorporated into various clusters, particularly at pH values near the p. In this paper, we apply physics-based all-atom molecular dynamics (MD) simulations to study aggregation in the weakly basic drug papaverine and in the weakly acidic drug prostaglandin F2α. We employ tools to construct simulation workflows and comprehensive cluster analysis protocols to elucidate the size distributions and dynamics of the drug aggregates formed at both an experimentally relevant concentration and at high supersaturation. We build on a previously published treatment [Solubility of sparingly soluble ionizable drugs. 2007, 59, 568-590, DOI: 10.1016/j.addr.2007.05.008] to translate the predicted aggregate distributions of each ionized drug into corresponding pH-solubility curves that can be compared directly to experiment. Our findings show that the assumption of a single predominant (charged) aggregate can be misleading in interpreting experimental pH-solubility curves, as it does not adequately reflect the rich diversity revealed in our simulations. Beyond not accounting for the distribution of ionized drug-containing clusters actually observed in solution, for both drugs we find evidence that neutral drug molecules can also participate in the aggregation phenomena. Notably, we observe that many drug molecules remain as free monomers in solution even under simulated conditions designed to mimic those where there is significant deviation of the experimental pH-solubility curve from the Henderson-Hasselbalch (H-H) equation, often taken to be a clear signpost of drug aggregation.
PubMed: 37671526
DOI: 10.1021/acs.molpharmaceut.3c00429 -
Clinical Toxicology (Philadelphia, Pa.) Sep 2023Poppy seed tea is used for its opioid effects and contains multiple opium alkaloids, including morphine, codeine, papaverine, and thebaine. Animal studies indicate... (Observational Study)
Observational Study
INTRODUCTION
Poppy seed tea is used for its opioid effects and contains multiple opium alkaloids, including morphine, codeine, papaverine, and thebaine. Animal studies indicate thebaine has strychnine-like properties, but there is limited literature describing human thebaine poisoning. We describe a cluster of acute thebaine poisoning in people ingesting tea made using poppy seeds with high thebaine content that entered the Australian food supply chain.
METHODS
This is an observational study of patients poisoned after drinking poppy seed tea. Cases were identified by three prospective toxicovigilance systems: the Emerging Drug Network of Australia collaboration, the New South Wales Prescription, Recreational and Illicit Substance Evaluation program, and the Emerging Drugs Network of Australia Victoria study. We report characteristics of clinical toxicity in cases with reported ingestion of poppy seed tea and analytical confirmation of thebaine exposure.
RESULTS
Forty cases presenting with multi-system toxicity following poppy seed tea ingestion were identified across seven Australian states/territories from November 2022 to January 2023. Blood testing in 23 cases confirmed high thebaine concentrations. All 23 were male (median age 35, range 16-71 years). All patients experienced muscle spasms. Rigidity was described in nine, convulsions in six, while rhabdomyolysis, acute kidney injury, and metabolic acidosis occurred in five patients. There were two cardiac arrests. The thebaine median admission blood concentration was 1.6 mg/L, with a range of 0.1-5.6 mg/L, and was the dominant opium alkaloid in all samples. Convulsions, acute kidney injury, metabolic acidosis, and cardiac arrest were associated with increasing median thebaine concentrations. Four patients were managed in the Intensive Care Unit, with two receiving continuous kidney replacement therapy (one also received intermittent haemodialysis) for kidney injury. There was one death.
CONCLUSIONS
Thebaine toxicity, like strychnine poisoning, resulted in neuromuscular excitation characterized by muscle spasm, rigidity, and convulsions. Severe toxicity, including acute kidney injury, metabolic acidosis, and cardiac arrest, appears dose-dependent.
Topics: Animals; Humans; Male; Adolescent; Young Adult; Adult; Middle Aged; Aged; Female; Thebaine; Papaver; Opium; Prospective Studies; Strychnine; Morphine; Codeine; Seeds; Seizures; Tea; Acute Kidney Injury; Acidosis; Heart Arrest; Victoria
PubMed: 37855308
DOI: 10.1080/15563650.2023.2265053 -
Molecular Imaging and Biology Jun 2024Tumor hypoxia contributes to aggressive phenotypes and diminished therapeutic responses to radiation therapy (RT) with hypoxic tissue being 3-fold less radiosensitive...
PURPOSE
Tumor hypoxia contributes to aggressive phenotypes and diminished therapeutic responses to radiation therapy (RT) with hypoxic tissue being 3-fold less radiosensitive than normoxic tissue. A major challenge in implementing hypoxic radiosensitizers is the lack of a high-resolution imaging modality that directly quantifies tissue-oxygen. The electron paramagnetic resonance oxygen-imager (EPROI) was used to quantify tumor oxygenation in two murine tumor models: E0771 syngeneic transplant breast cancers and primary p53/MCA soft tissue sarcomas, with the latter autochthonous model better recapitulating the tumor microenvironment in human malignancies. We hypothesized that tumor hypoxia differs between these models. We also aimed to quantify the absolute change in tumor hypoxia induced by the mitochondrial inhibitor papaverine (PPV) and its effect on RT response.
PROCEDURES
Tumor oxygenation was characterized in E0771 and primary p53/MCA sarcomas via EPROI, with the former model also being quantified indirectly via diffuse reflectance spectroscopy (DRS). After confirming PPV's effect on hypoxic fraction (via EPROI), we compared the effect of 0 versus 2 mg/kg PPV prior to 20 Gy on tumor growth delay and survival.
RESULTS
Hypoxic sarcomas were more radioresistant than normoxic sarcomas (p=0.0057, 2-way ANOVA), and high baseline hypoxic fraction was a significant (p=0.0063, Cox Regression Model) hazard in survivability regardless of treatment. Pre-treatment with PPV before RT did not radiosensitize tumors in the sarcoma or E0771 model. In the sarcoma model, EPROI successfully identified baseline hypoxic tumors. DRS quantification of total hemoglobin, saturated hemoglobin, changes in mitochondrial potential and glucose uptake showed no significant difference in E0771 tumors pre- and post-PPV.
CONCLUSION
EPROI provides 3D high-resolution pO quantification; EPR is better suited than DRS to characterize tumor hypoxia. PPV did not radiosensitize E0771 tumors nor p53/MCA sarcomas, which may be related to the complex pattern of vasculature in each tumor. Additionally, understanding model-dependent tumor hypoxia will provide a much-needed foundation for future therapeutic studies with hypoxic radiosensitizers.
Topics: Animals; Tumor Hypoxia; Electron Spin Resonance Spectroscopy; Oxygen; Cell Line, Tumor; Female; Mice; Radiation-Sensitizing Agents; Sarcoma; Radiation Tolerance; Mice, Inbred C57BL
PubMed: 37721686
DOI: 10.1007/s11307-023-01855-0 -
International Journal of Impotence... May 2024Peyronie's disease (PD) is a debilitating pathology which is associated with penile curvature and erectile dysfunction due to the formation of fibrotic plaques in the...
Peyronie's disease (PD) is a debilitating pathology which is associated with penile curvature and erectile dysfunction due to the formation of fibrotic plaques in the penile tunica albuginea. In the present study, we developed a novel rabbit model of PD via subtunical injection of recombinant transforming growth factor (TGF)-β1 protein and characterized erectile function and histopathological endpoints following plaque formation. Ten adult male, New Zealand white rabbits were randomized into 3 experimental groups including nonsurgical controls (NSC, N = 3) and those receiving subtunical injections of vehicle (N = 3) or TGF-β1 protein (0.5 µg/50 µl; N = 4). Following 1 month post-op, focal fibrous plaques composed of disorganized collagen type I and III bundles as well as fragmented elastin fibers at TGF-β1 injection sites were observed in contrast to control groups. Cavernosometric and cavernosographic evaluations revealed no significant differences in maximum intracorporal pressures or substantial curvature during papaverine-induced erection in either the vehicle or TGF-β1 cohorts. Immunohistochemical and histomorphometric analyses demonstrated significant increases in elastase 2B expression in TGF-β1-induced plaques as well as significant declines in matrix metalloproteinase (MMP)-2 and -9 expression relative to control levels. Our results demonstrate that PD-like fibrotic plaques can be created in the rabbit penile tunica albuginea following TGF-β1 injection.
PubMed: 36782023
DOI: 10.1038/s41443-023-00671-y -
Talanta Dec 2023Opioids have become a serious public health concern over the last decade. These compounds are commonly found mixed, or cut, with safer compounds to make the opioids...
Opioids have become a serious public health concern over the last decade. These compounds are commonly found mixed, or cut, with safer compounds to make the opioids appear unadulterated while also enhancing the psychoactive effect on the user. Commercial benchtop and handheld IMS devices are capable of detection but published reduced ion mobility (K) values, used to identify the target analytes with IMS instrumentation, have shown variability. This lack of agreement, even for compounds used for calibration, is often due to the effects of drift tube temperature, drift gas water vapor levels and the use in-house built instrumentation rather than commercial equipment. Multiple reports exist on assessment of IMS reference standards but a single, consensus universal standard does not exist. Assessment of opioid cutting agents as internal standards is a worthwhile pursuit if precise and accurate K values are obtained. The effects of drift gas water vapor content and drift tube temperature were used to evaluate the cutting agents. The K values of papaverine, a representative opioid with a similar K value to heroin and fentanyl, were calculated with respect to quinine and were in agreement with literature data. The use of quinine as an internal standard also improved precision relative to the instrument standard and shows promise in the application presented here.
PubMed: 37364383
DOI: 10.1016/j.talanta.2023.124822 -
Journal of Neurosurgery Feb 2024Direct cerebral revascularization is considered as one of the most technically challenging operations in neurosurgery. Technical errors are often not identified during...
OBJECTIVE
Direct cerebral revascularization is considered as one of the most technically challenging operations in neurosurgery. Technical errors are often not identified during the case, but only after the recirculation stage, making management crucial at that time of the procedure. In this study, the authors sought to describe troubleshooting of the technical errors encountered in initially failed bypass cases.
METHODS
A retrospective analysis describing a single-surgeon, single-institution experience between 2014 and 2021 was performed, based on operative reports and videos, including a 30-day follow-up period. Initially failed bypass was defined if the bypass was not patent or had a significant leak after recirculation, irrespective of the final result.
RESULTS
One hundred thirty-eight bypass cases were reviewed for complex aneurysms (n = 49), moyamoya disease (n = 59), and atherosclerosis (n = 30). Fifty-one initially failed anastomoses were identified; 43 of these were the result of a technical error. Etiologies of these failed anastomoses included a clot (n = 14), vessel kinking (n = 4), spasm (n = 5), suture-related cause (n = 5), inappropriate donor or recipient (n = 3), or lack of demand (n = 8). A major leak was attributed to an uncoagulated side branch (n = 4), vessel injury due to suture/clip placement (n = 1), or inadequate suture line coverage (n = 7). Thirty-seven (86%) of 43 cases were troubleshot successfully, as salvage maneuvers included papaverine vessel massage, donor repositioning, re-anastomosis for occlusion in select cases, local hemostatic agents, and suturing or coagulating side branches in a leak. Thirty-day follow-up revealed similar rates of patency between successfully troubleshot patients (35/37) and the rest of the cases (80/87, p = 0.6).
CONCLUSIONS
Three major patterns of a noncompatible bypass were found: a major leak, an acute occlusion, or a delayed occlusion. Based on the authors' experience, salvage strategies proved successful, showing an eventual high patency rate. The authors suggest a gradual, structured algorithm to address this stage in surgery that may contribute specifically to cerebrovascular neurosurgeons at the beginning of their careers.
Topics: Humans; Cerebral Revascularization; Retrospective Studies; Moyamoya Disease; Intracranial Aneurysm; Anastomosis, Surgical
PubMed: 37877963
DOI: 10.3171/2023.6.JNS2356 -
Catheterization and Cardiovascular... Mar 2024Nicorandil is widely used as a vasodilator for the physiological assessment of coronary arteries because of its usefulness and safety; however, there are no data on its...
BACKGROUND
Nicorandil is widely used as a vasodilator for the physiological assessment of coronary arteries because of its usefulness and safety; however, there are no data on its use in peripheral arteries.
AIMS
To identify the utility of nicorandil and its appropriate dose for the physiological assessment on the femoropopliteal artery.
METHODS
We retrospectively enrolled patients from three institutes in which physiological assessment was carried out with various doses of nicorandil before treatment. Twenty-four femoropopliteal artery stenotic lesions from 22 patients were included. The nicorandil doses used were 2, 4, and 6 mg. Twenty-two lesions were also assessed using 30 mg of papaverine. The pressure gradient (PG) and peripheral fractional flow reserve (pFFR) were calculated based on the mean and systolic pressure levels. We examined the correlation of each parameter with the peak systolic velocity ratio (PSVR) based on the duplex ultrasound images using Spearman's rank correlation coefficient. Systemic blood pressure was assessed for safety.
RESULTS
The correlations were higher for mean pressure-based parameters than for systolic pressure-based parameters. As the nicorandil dose increased, the correlations among PG, pFFR, and PSVR also increased (mean pressure-based PG: 2 mg, r = 0.360; 4 mg, r = 0.498; 6 mg, r = 0.694, mean pressure-based pFFR: 2 mg, r = -0.479; 4 mg, r = -0.469; 6 mg, r = -0.641). The blood pressure after the administration of 6 mg of nicorandil was low, and the median systemic mean pressure was 65 mmHg.
CONCLUSION
A 4 mg dose of nicorandil is effective and safe for the mean pressure-based physiological assessment of lesions in the femoropopliteal artery.
Topics: Humans; Nicorandil; Fractional Flow Reserve, Myocardial; Retrospective Studies; Treatment Outcome; Vasodilator Agents; Coronary Vessels
PubMed: 38363043
DOI: 10.1002/ccd.30976 -
Heliyon Oct 2023Radial artery (RA) is a popular coronary artery bypass grafting (CABG) conduit. The challenging issue is vasospasm. A few studies are available on histopathological...
BACKGROUND AND AIMS
Radial artery (RA) is a popular coronary artery bypass grafting (CABG) conduit. The challenging issue is vasospasm. A few studies are available on histopathological differences between RA's proximal and distal ends. This study aims to compare histopathological features of the proximal and distal end of RA to find the best technique for anastomosis.
METHODS
In this matched case-control study, 80 patients were included who underwent CABG and used RA as a graft. Ten subjects were excluded. RA was harvested by open technique, and a cocktail of Papaverine, Verapamil, and Nitroglycerine was frequently applied topically. One centimeter of proximal and distal ends of the RA was evaluated considering its Histopathology. Clinical signs of RA graft vasospasm were monitored from harvesting until the post-operative period. Intima, media, and intima-media thickness (IMT) index were compared between the two cohorts.
RESULTS
Vasospasm occurred in 1.41% of patients. The mean intimal thickness in the proximal and distal ends were, respectively, 0.20 (standard deviation [SD] 0.17 mm) vs. 0.31 (SD 0.18 mm) (p < 0.001). The mean media thickness in the distal end was higher than the proximal end (0.98 [SD 0.36] vs. 1.09 [SD 0.37], p = 0.004). IMT index of the proximal and distal ends showed a statistically significant difference (0.22 [SD 0.17] vs. 0.31 [SD 0.19]) (p < 0.001).
CONCLUSION
The overall incidence rate of vasospasm in our study is comparable with other studies using the same cocktail. Proximal RA has a relatively lower medial thickness compared to the distal part, which may induce less vasospasm in CABG patients.
PubMed: 37867848
DOI: 10.1016/j.heliyon.2023.e20873