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CO2 reactivity was tested in patients with transcranial Doppler sonography (TCD) and endtidal CO2 measurements after an average time interval of ten months after subarachnoid haemorrhage (SAH). After deliberately changing breathing there was a significant change in endtidal CO2 and in flow velocities in all three examination groups. Comparing 27 patients with SAH and 5 patients treated for incidential aneurysms and 20 patients without cerebrovascular disease there were no significant differences in CO2 reactivity. Furthermore, there were no right to left differences. In 12 patients with vasospasm, two of them treated by percutaneous transluminal angioplasty for delayed ischaemic deficits, CO2 reactivity was normal at the time of investigation. Furthermore, normal CO2 reactivity was found in patients after SAH and surgery for ruptured aneurysms regardless of the severity of the SAH. [ABSTRACT FROM AUTHOR]

Aim: To assess the safety, tolerability and pharmacokinetic (PK) profile of single and multiple doses of CPL207280, a new G-protein-coupled receptor 40 agonist developed to treat type 2 diabetes (T2D)., Methods: The phase 1 study in healthy volunteers (White, age 18-55 years, body mass index 18.5-29.9 kg/m 2 ) was performed after single (24 subjects, 5-480 mg) and multiple (32 subjects, 60-480 mg) once-daily administration of CPL207280.  The effect of food intake and interaction with metformin were evaluated in additional cohort (12 subjects, 120 mg). The primary objective was the safety and tolerability of CPL207280. Secondary objectives included PK and pharmacodynamic (PD) characteristics (glucose, insulin, C-peptide, proinsulin, glucagon levels) observed during the 14-day treatment period., Results: No deaths or serious adverse events (AEs) were reported. All reported AEs were classified as unrelated to the study product. No clinically significant differences in safety parameters were observed between cohorts and no food or metformin effect on safety parameters was identified. The ascending dose of CPL207280 caused an increase in the PK parameters maximum observed plasma concentration (C max ) or area under the plasma concentration-time curve up to 24 h. However, dose-normalized C max decreased with ascending dose. There was no relationship between the CPL207280 dose or prandial state and terminal elimination half-life and terminal elimination rate constant. No clear relationship between CPL207280 dose and PD area under the effect curve values was observed., Conclusions: CPL207280 was found to be safe and well tolerated by healthy volunteers (with a low risk of hepatotoxicity) for up to 14 days of administration. The PK profile of CPL207280 supports single-daily administration and justifies further development of this therapy for patients with T2D., (© 2024 Celon Pharma. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Magnesium ions (Mg 2+ ) increase and prolong opioid analgesia in chronic and acute pain. The nature of this synergistic analgesic interaction has not yet been explained. Our aim was to investigate whether Mg 2+ alter tramadol pharmacokinetics. Our secondary goal was to assess the safety of the combination., Methods: Tramadol was administered to healthy Caucasian subjects with and without Mg 2+ as (1) single 100-mg and (2) multiple 50-mg oral doses. Mg 2+ was administered orally at doses of 150 mg and 75 mg per tramadol dosing in a single- and multiple-dose study, respectively. Both studies were randomized, open label, laboratory-blinded, two-period, two-treatment, crossover trials. The plasma concentrations of tramadol and its active metabolite, O-desmethyltramadol, were measured., Results: A total of 25 and 26 subjects completed the single- and multiple-dose study, respectively. Both primary and secondary pharmacokinetic parameters were similar. The 90% confidence intervals for C max and AUC 0-t geometric mean ratios for tramadol were 91.95-102.40% and 93.22-102.76%. The 90% confidence intervals for C max,ss and AUC 0-τ geometric mean ratios for tramadol were 93.85-103.31% and 99.04-105.27%. The 90% confidence intervals for primary pharmacokinetic parameters were within the acceptance range. ANOVA did not show any statistically significant contribution of the formulation factor (p > 0.05) in either study. Adverse events and clinical safety were similar in the presence and absence of Mg 2+ ., Conclusions: The absence of Mg 2+ interaction with tramadol pharmacokinetics and safety suggests that this combination may be used in the clinical practice for the pharmacotherapy of pain.

This randomized, open-label, ambulatory, controlled clinical study investigated biomarkers associated with cardiovascular risk and biomarkers of exposure to 10 selected harmful and potentially harmful constituents (HPHC) in cigarette smoke in 316 male and female Polish smokers. Subjects were randomized to continue smoking conventional cigarettes (CC; N=79) or switch to smoking the Electrically Heated Cigarette Smoking System series-K cigarette (EHCSS-K6; N=237). Biomarker assessments were performed at several time points during the study at baseline and during the 1-month investigational period. The primary biomarkers were high-sensitivity C-reactive protein and white blood cell counts. No statistically significant differences in the two primary biomarkers were found between the study groups at the end of the study. End-of-study comparisons of secondary biomarkers between study groups indicated an increase in high-density lipoprotein cholesterol, and reductions in red blood cell count, hemoglobin, and hematocrit levels in the EHCSS-K6 group. All biomarkers of exposure to cigarette smoke HPHC were decreased in the EHCSS-K6 group, despite an increase in cigarette consumption, compared to the CC group. There were no apparent differences in any of the safety assessment parameters between the groups, and the overall incidence of study-related adverse events was low., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To examine cerebrovascular reactivity in patients after subarachnoid haemorrhage (SAH) during long-term follow-up, using Acetazolamide test and transcranial Doppler (TCD) monitoring of blood flow velocities (BFVs), to compare of CO(2) reactivity between patients after SAH treated with three different methods: surgical (clipping), endovasculary (coiling) and conservative., Methods: The study was performed in a group of 24 patients treated for SAH. Cerebrovascular reactivity (CVR) has been evaluated after intravenous administration of 1000 mg of Acetazolamide. Studied patients were divided into three groups: group I (n = 10) treated with clipping, group II (n = 8) treated with coiling and group III (n = 6)--patients with negative angiography treated conservatively., Results: Results of this study have shown that: (1) BFVs were normal in cerebral arteries and did not differ between right and left head sides, (2) CVR was normal in all studied patients, (3) method of aneurysm treatment as well as its localization had no influence on BFV and CVR, and (4) occurrence of vasospasm in early days after SAH did not result in permanent disturbances of CO(2) arterial reactivity., Conclusion: BFV values in cerebral arteries were in normal range and did not differ on the left and right head sides. CVR was normal in all examinated patients. A method of the ruptured aneurysm treatment and its localization had no influence on CBFV and CRV. Vasospasm in early period after SAH did not provoke a persistent impairment of CO(2) reactivity.

Surgery timing after aneurysmal subarachnoid hemorrhage (SAH) may influence the risk of vasospasm after early surgical procedure and is correlated with SAH extensiveness. A group consisting of 127 patients with aneurysmal SAH was studied. The changes of mean flow velocity (MFV) were measured in middle cerebral artery (MCA) and in anterior cerebral artery (ACA) by transcranial Doppler sonography (TCD) in three groups of patients divided according to the surgery timing (on the first, second and third day after SAH). Changes of MFV values in MCA and in ACA were similar in all groups. MFV values in the group of patients operated on the third day were the lowest and the pathologic values lasted for the shortest time. In patients with massive SAH (Fisher IV group) and mild SAH (Fisher II group), the lowest MFV values were observed, if patients were operated within 24 hours after SAH. In patients without SAH (Fisher I group), the MFV values were the lowest, if they were operated on the third day after SAH. In patients with severe SAH (Fisher III group), the lowest risk of vasospasm was observed, if they were operated on the second day after SAH; however, the highest risk was found in patients operated on the first day after SAH. Our study suggests: (1) in patients with severe SAH operated on the second day, the lowest risk of vasospasm was observed, and the highest risk of vasospasm was observed if those were operated on the first day; (2) the highest risk of vasospasm was observed in patients operated within 24 hours with mild and massive SAH and in patients without SAH operated on the third day after SAH.

Among the patients (6854 patients 1990-1999) who underwent computer-assisted stereotactic biopsy most were referred with the presumptive diagnosis of a brain mass lesion. Forty-three cases (0.63%) were found in which the final histopathological diagnosis excluded a neoplastic, infectious or inflammatory lesion but disclosed a cerebral insult. Histologically these could be subdivided into ischemic insults in 38 cases (88%) and hemorrhagic insults in five cases (12%). On the basis of clinical and radiological findings in this group, 35 patients (81%) were sent to our department because of suspected neoplasmatic lesions, two patients (5%) because of multiple sclerosis, two patients (5%) because of inflammatory disease and one patient (2%) because of a suspected infectious parasitic disease. All patients underwent initial CT examinations which showed hypodense lesions of the brain in 38 patients (88%) and hyperdense lesions in five cases (12%). Constant enhancement on CT scans of the mass lesion was found in 12 patients (28%) only. Fourteen lesions (33%) were located in the right hemisphere, five lesions (12%) in the left hemisphere, nine lesions (21%) in the basal ganglia, four lesions (9%) in the midbrain, two lesions (4.5%) in the corpus callosum and one lesion (2%) in a thalamus. Multiple lesions were present in eight cases (19%). The most common initial neurological symptoms upon clinical presentation were hemiparesis (18 patients, 42%), epilepsy (eight patients, 18%), a change in mental status (six patients, 14%). There was no mortality and no operative morbidity associated with the stereotactic biopsy in this group of patients. The most common neurological disorder, cerebrovascular insult, rarely poses diagnostic problems. If there are doubts a serial stereotactic biopsy can safely clarify the situation.

Patients (n = 127) with aneurysmal subarachnoid hemorrhage (SAH) were examined by transcranial Doppler ultrasonography (TCD) in a prospective study to follow the time course of the posthemorrhagic blood flow velocity in both the middle cerebral artery (MCA) and in the anterior cerebral artery (ACA). Results were analysed to reveal their relationship and predictive use with respect to the occurrence of delayed ischemic deficits. Mean flow velocities (MFV) higher than 120 cm sec(-1) in MCA and 90 cm sec(-1) in ACA were interpreted as indicative for significant vasospasm. In 20 of our 127 patients (16%) a delayed ischemic deficit (DID) was subsequently diagnosed clinically (DID+ group). Patients in the DID+ group can be characterized as those individuals who presented early during the observation period post-SAH with highest values of MFV, a faster increase and longer persistence of pathologically elevated MFV-values (exceeding 120 cm sec(-1) in MCA and 90 cm sec(-1) in ACA). They also show a greater difference in MFV-values if one compares the operated to the nonoperated side. Differences in MFV-values obtained in MCA or ACA were statistically significant (p < 0.05) for DID+ and DID- patients. The daily maximal increase of MFV was found between days 9 and 11 after SAH. In the DID+ group, the maximal MFV was 181 +/- 26 cm sec(-1) in MCA and 119 +/- 14 cm sec(-1) in ACA. In contrast to this, patients in the DID- group were found to present with MFV of 138 +/- 11 cm sec(-1) in MCA and 100 +/- 7 cm sec(-1) in ACA respectively. Delayed ischemic deficits appeared three times more often in DID+ patients than in patients with MFV < 120 cm sec(-1), if they showed a MFV > 120 cm sec(-1) in MCA. If pathological values were obtained in ACA, this ratio increases to about four times, if DID + patients presented with MFV > 90 cm sec(-1) versus patients with MFV < 90 cm sec(-1). Daily monitoring of vasospasm using TCD examination is thus helpful to identify patients at high risk for delayed ischemic deficits. This should allow us to implement further preventive treatment regimens.

The relationship between changes of blood flow velocities in cerebral arteries measured by transcranial Doppler ultrasonography and aneurysm localization was investigated in a group of 165 patients after aneurysmal subarachnoid hemorrhage (SAH). Mean blood flow velocities (MFV) in the middle cerebral artery (MCA) and anterior cerebral artery (ACA) were registered. In patients with aneurysm of internal carotid artery and MCA (group A) statistically significant higher values of MFV from the 1st to the 5th day and on the 12th, 13th, 14th, 15th, and 19th day after SAH were found compared to patients with aneurysm of the anterior communicating artery, ACA, and pericallosal artery (group B). Pathological values of MFV exceeding 120 cm sec-1 in MCA were registered during 14 days in group A and during eight days in group B. Blood flow velocities in ACA were statistically significantly higher in group B on the 2nd, 7th, 9th and 11th day compared to group A. Pathological values of MFV exceeding 90 cm sec-1 in ACA were registered during nine days in both groups. MFV differences between group A and group B in 38 patients subjected to delayed surgery were not observed. The influence of aneurysm localization was observed between the 7th and 14th day after SAH. Critical MFV values for vasospasm in the MCA should be 120 cm sec-1 and in the ACA 90 cm sec-1.

Neuroepithelial dysembryoplastic tumour was first described by Daumas-Duport in 1988 and in WHO classification was included into the group of neuronal and mixed neuroglial tumours. This is a benign and very rare tumor with a good prognosis occurring in children and young adults. The tumour caused characteristic clinical symptoms: epileptic fits, supratentorial, intracortical localisation, most often in temporal lobe and specific nodular architecture with heterogenic cell composition. Oligodendrocyte-like cells, glial and neuronal elements are usually found. The authors present a case of a 24-years old female with partial epileptic sensorial symptomatology. CT examination revealed a tumour in the left parietal lobe. Histological findings showed a typical texture of DNT. The tumour has no tendency for recurrence even in case of incomplete removal and does not require chemotherapy nor radiotherapy which is significantly important for accurate diagnosis, in order to avoid an aggressive therapy in young patients.

Basal cell carcinoma presents a relatively low potential and local malignancy and very slow growth giving only occasionally metastatic spreading. The frequency of occurrence of metastatic dissemination is estimated in the literature depending on examined population from 0.028% to 0.55%. Metastases are most often found in lymph nodes, lungs bones and internal organs: liver, spleen, kidneys, adrenal glands, pleura and the peritoneum. Authors present a case of a 69-years old female with an extensive basal cell carcinoma of the head convexity, infiltrating the subcutaneous tissue, periostium, bone and dura mater, giving distant metastases to other bone and soft tissue structures of a thoracic spine, which was confirmed by biopsy and histopathological findings of neoplasm tissue in spine. The primary lesion was successfully treated surgically. Despite administered radiotherapy of metastases in spine, progress of the disease during 1-year period was observed. The patient was alive with metastatic tumours present at last follow-up. Basing on the review of the literature and our case report we can distinguish following factors which may increase the risk of occurrence of basal cell carcinoma metastases: the great extent of the primary lesion, deep penetration to stromal tissue, blood and lymph vessel invasion, long history of tumour occurrence and the presence of metatypia in histopathological findings. The above-mentioned case fulfils the criteria of carcinoma basocellulare metastases proposed by Latters and Kessel and may be included to the general registration list of this cancer in the world.

Disturbances of the cerebrovascular reactivity in cases of migraine with aura are well-known. It has been suggested that the vasostabilizing effects of novel prophylactic pharmaceuticals are determined by their antiserotoninergic and/or nitric oxide releasing properties. Dotarizine, a representative of Ca2+ channel blockers from diphenilbutilpiperazines group also reveals antiserotoninergic 5-HT2A and 5-HT2C receptor-specific properties. The vasodilatatory and antivasoconstrictive properties of this compound were reported previously. In this study the efficacy of Dotarizine chronic oral administration on cerebrovascular reactivity during hyperventilation was examined with respect to its duration of action. Experiments were carried out on 13 rabbits. There was an interval of two days between a five days compound administration and performed hyperventilation. Blood flow velocities (BFV) in the middle cerebral artery (MCA) and basilar artery (BA) were measured in control conditions, after 10 min hyperventilation and in the tenth minute of recovery of normoventilation. Our data reveal a decrease of antivasoconstrictive properties of Dotarizine between its administration and vasoconstrictive test. Subsequent normoventilation showed a distinct vasostabilising effect of this compound with evident regional differences in its influence on cerebral vessels. Thus Dotarizine might be useful as prophylactic medication in migraine therapy, due to its Ca2+ channel blocking and antiserotoninergic properties, but the time-frame of its efficacy has to be defined.

Several types of cerebral blood flow disturbances, resulting from head trauma are discussed. Application of Transcranial Doppler Sonography in diagnosing of posttraumatic cerebral vasospasm and cerebral hyperaemia, increased intracranial pressure, autoregulation disturbances, and brain death is described. Clinical examples of isolated cerebral blood flow disturbances, and several types of their co-existence are given. Special attention was paid to the noninvasiveness, repetitiveness, and relative ease of use of the technique. Transcranial Doppler examination can be especially useful in diagnosis and monitoring of different cerebral blood flow disturbances, which is especially important in therapy of brain trauma patients.