Pharmacological interventions for antipsychotic-related sialorrhea: a systematic review and network meta-analysis of randomized trials.

Antipsychotic-induced sialorrhea carries a significant burden, but evidence-based treatment guidance is incomplete, warranting network meta-analysis (NMA) of pharmacological interventions for antipsychotic-related sialorrhea. PubMed Central/PsycInfo/Cochrane Central database/Clinicaltrials.gov/WHO-ICTRP and the Chinese Electronic Journal Database (Qikan.cqvip.com) were searched for published/unpublished RCTs of antipsychotic-induced sialorrhea (any definition) in adults, up to 06/12/2023. We assessed global/local inconsistencies, publication bias, risk of bias (RoB2), and confidence in the evidence, conducting subgroup/sensitivity analyses. Co-primary efficacy outcomes were changes in saliva production (standardized mean difference/SMD) and study-defined response (risk ratios/RRs). The acceptability outcome was all-cause discontinuation (RR). Primary nodes were molecules; the mechanism of action (MoA) was secondary. Thirty-four RCTs entered a systematic review, 33 NMA (n = 1958). All interventions were for clozapine-induced sialorrhea in subjects with mental disorders. Regarding individual agents and response, metoclopramide (RR = 3.11, 95% C.I. = 1.39-6.98), cyproheptadine, (RR = 2.76, 95% C.I. = 2.00-3.82), sulpiride (RR = 2.49, 95% C.I. = 1.65-3.77), propantheline (RR = 2.39, 95% C.I. = 1.97-2.90), diphenhydramine (RR = 2.32, 95% C.I. = 1.88-2.86), benzhexol (RR = 2.32, 95% C.I. = 1.59-3.38), doxepin (RR = 2.30, 95% C.I. = 1.85-2.88), amisulpride (RR = 2.23, 95% C.I. = 1.30-3.81), chlorpheniramine (RR = 2.20, 95% C.I. = 1.67-2.89), amitriptyline (RR = 2.09, 95% C.I. = 1.34-3.26), atropine, (RR = 2.03, 95% C.I. = 1.22-3.38), and astemizole, (RR = 1.70, 95% C.I. = 1.28-2.26) outperformed placebo, but not glycopyrrolate or ipratropium. Across secondary nodes (k = 28, n = 1821), antimuscarinics (RR = 2.26, 95% C.I. = 1.91-2.68), benzamides (RR = 2.23, 95% C.I. = 1.75-3.10), TCAs (RR = 2.23, 95% C.I. = 1.83-2.72), and antihistamines (RR = 2.18, 95% C.I. = 1.83-2.59) outperformed placebo. In head-to-head comparisons, astemizole and ipratropium were outperformed by several interventions. All secondary nodes, except benzamides, outperformed the placebo on the continuous efficacy outcome. For nocturnal sialorrhea, neither benzamides nor atropine outperformed the placebo. Active interventions did not differ significantly from placebo regarding constipation or sleepiness/drowsiness. Low-confidence findings prompt caution in the interpretation of the results. Considering primary nodes' co-primary efficacy outcomes and head-to-head comparisons, efficacy for sialorrhea is most consistent for the following agents, decreasing from metoclopramide through cyproheptadine, sulpiride, propantheline, diphenhydramine, benzhexol, doxepin, amisulpride, chlorpheniramine, to amitriptyline, and atropine (the latter not for nocturnal sialorrhea). Shared decision-making with the patient should guide treatment decisions regarding clozapine-related sialorrhea.

Self-Emulsifying Drug Delivery System of Celecoxib for Avoiding Delayed Oral Absorption in Rats with Impaired Gastric Motility.

This study aimed to develop a self-emulsifying drug delivery system (SEDDS) of celecoxib (CEL) for suppressed delay in oral absorption under impaired gastric motility. A pseudo-ternary phase diagram was constructed for the determination of the optimal component ratio in SEDDS of CEL (SEDDS/CEL), and the SEDDS/CEL was physicochemically characterized. A pharmacokinetic study on orally dosed CEL samples (5-mg CEL/kg) was carried out in normal and propantheline (PPT)-treated rats to mimic impaired gastric motility. SEDDS/CEL rapidly formed a fine emulsion with a mean size of 147 nm in distilled water and significantly improved the dissolution behavior of CEL under pH 1.2 condition with a 20-fold higher dissolved amount than crystalline CEL. In normal rats, orally dosed SEDDS/CEL provided a 4.6-fold higher systemic exposure than that of crystalline CEL, due to the improved dissolution properties of CEL. Crystalline CEL showed delayed and decreased oral absorption of CEL in PPT-treated rats as evidenced by a 6.9-h-delayed mean absorption time and only 12% of the systemic exposure of CEL compared with those in normal rats. In contrast, SEDDS/CEL enhanced the oral absorption of CEL with a 14.6-fold higher systemic exposure with significant suppression of delay in absorption than crystalline CEL even in PPT-treated rats. SEDDS/CEL could be an efficacious option for suppressing delay in CEL absorption even under impairment of gastric motility, possibly leading to rapid and reproducible management of severe acute pain.

Amorphous Solid Dispersion of Meloxicam Enhanced Oral Absorption in Rats With Impaired Gastric Motility.

Meloxicam (MEL) shows a slow onset of action in severe pain patients on account of delayed gastric motility. This study aimed to develop an amorphous solid dispersion (ASD) of MEL to achieve rapid oral absorption in severe pain patients. ASD formulations of MEL with hydroxypropylmethylcellulose (ASD-MEL/HPMC) and polyacrylates and polymethacrylates (ASD-MEL/EUD) were prepared and physicochemically characterized. Oral absorption behavior of MEL samples was also clarified in both normal and propantheline (PPT)-pretreated rats with impaired gastric motility. MEL in the formulations was amorphous, and ASD formulations of MEL exhibited high dissolution behavior in acidic solution. After oral administration of crystalline MEL (1 mg-MEL/kg), a 69% reduction in AUC0-4 was observed between normal and PPT-pretreated rats. For orally dosed ASD-MEL/HPMC (1 mg-MEL/kg), there were approximately 9- and 12-fold increases of AUC0-4 in normal and PPT-pretreated rats, respectively, in comparison with crystalline MEL (1 mg-MEL/kg). However, the oral absorption behavior of ASD-MEL/EUD (1 mg-MEL/kg) was low and similar to that of crystalline MEL. The infrared spectroscopic study revealed potent interactions between MEL and EUD, possibly leading to marked attenuation of MEL absorption. This ASD approach might provide rapid oral absorption of MEL in severe pain patients, possibly leading to better clinical outcomes.

[Propantheline bromide is effective against dog drooling]. / Propanthelinbromid er effektivt mod savlen hos hunde

Hyperhidrosis is a common condition characterized by extensive sweat secretion. Systemic treatment with anticholinergics might prove effective, but patients often suffer from side effects, e.g. dryness of the mouth. We present a clinical case of severe polydipsia in a six-month-old puppy who had accidentally consumed 50 tablets of propantheline bromide 15 mg. Afterwards the puppy suffered from severe polydipsia, which cleared without treatment after three days.

Novel strategy for online monitoring of the degradation kinetics of propantheline bromide via a calixarene-based ion-selective electrode.

Propantheline bromide (PB) is a hydrolysable anti-cholinergic drug. A novel strategy for the online monitoring of PB degradation kinetics catalysed by hydroxyl ions is presented. This is achieved by the incorporation of an on-site PB-selective electrode constructed using as an ionophore. This sensor was used to track the hydrolysis of PB by continuous measurement of the decrease in the produced emf over time. The use of this new technique provides real-time observation and yields a continuous profile of the hydrolysis behaviour of PB under various pH conditions as well as the temperature dependency of each reaction. Moreover, a great advantage of this proposed on-line system is its higher accuracy for rate constant estimation relative to other off-line methods. This kinetic data analysis permitted the determination of the hydrolysis activation energy and prediction of the drug shelf life. The estimated activation energy from Arrhenius plot was 20.77 kcal mol(-1).

Pharmacokinetic assessment of absorptive interaction of oral etoposide and morphine in rats.

Etoposide and morphine are well known P-glycoprotein (P-gp) substrates. The pharmacokinetic effect of morphine on plasma etoposide concentration after the oral concomitant use of etoposide and morphine in rats was assessed using a population analysis approach. A P-gp substrate quinidine and the anticholinergic drug propantheline were also administered with etoposide to compare with the effects of morphine. Plasma etoposide concentration after oral administration was well described using a linear 2-compartment open model with first-order kinetic absorption from the intestine, although a flip-flop phenomenon was shown. After administration of etoposide with morphine, an increased concentration and extended time at maximum concentration were observed compared with the administration of etoposide alone. However, coadministered quinidine significantly increased the maximum concentration without changing the time of the peak concentration of etoposide. Coadministered propantheline significantly extended the time at maximum concentration, although no changes in the peak concentration of etoposide were observed. These coadministered drugs resulted in different pharmacokinetic parameters of etoposide and acted as a significant covariate. That is, morphine and quinidine significantly increased the bioavailability of etoposide believed to be due to competitive P-gp inhibition in the intestine. In contrast, morphine and propantheline decreased the absorption rate constant and were associated with the suppression of enterokinesis. These results indicate that it is necessary to understand the effects on P-gp as well as have information on other effects on the gastrointestinal tract, such as enterokinesis suppression, and to appropriately assess the pharmacokinetic interactions of the combined oral use of P-gp substrate drugs.

Pharmacological comparison of peristaltic effects in rats and mice.

INTRODUCTION: Conscious rodent models are commonly used to assess the effects of new chemical entities on propulsion (transit) time in the gastrointestinal system. This study was designed to compare three compounds clinically known to cause constipative (morphine sulfate and propantheline bromide) and laxative (metoclopramide hydrochloride) effects on transit time in rats and mice and to note if there are differences between the species. METHODS: Compounds were dosed in conscious rats and mice. At 0.5-2.0h post dosing (estimated time to maximal plasma concentration of each compound) animals were gavaged with an appropriate volume (based on weight) of 10% activated powdered carbon suspended in 5% gum arabic. Forty-five minutes following dosing the animals were sacrificed by CO2 asphyxiation and the small intestine was removed. The position of the leading edge of the charcoal was measured relative to the total length of the intestinal segment. RESULTS: The compounds tested produced variable statistical differences in transit time between species. Morphine and propantheline produced dose-dependent increases in transit time, and metoclopramide decreased transit time, statistically significant in both rodent models. DISCUSSION: The present data demonstrate that at similar doses rats and mice can be used interchangeably for transit studies. Mice were more sensitive to transit changes at higher doses of the compounds tested.

Influencia del tiempo de tránsito orocecal en la percepción de los síntomas de intolerancia a la lactosa / Impact of orocecal transit time on patient’s perception of lactose intolerance

Antecedentes: los síntomas atribuidos a la intolerancia a la lactosa son un importante problema de salud pública. El tiempo de tránsito es un factor implicado en la severidad de los síntomas asociados al consumo de lactosa. Objetivos: elucidar la relación entre el tiempo de tránsito orocecal (TTOC) y los síntomas de intolerancia a la lactosa. Métodos: estudio observacional en pacientes con un test del aliento de hidrógeno con lactosa patológico (excreción de hidrógeno superior a 25 ppm). El TTOC se midió mediante el test del aliento y los síntomas mediante una escala previamente validada. Los síntomas se determinaron dos veces: antes de recibir la lactosa, preguntando acerca de los síntomas en casa cuando se consumen lácteos (“síntomas en casa”), y de nuevo después de completar el test del aliento con lactosa (“síntomas test”). Resultados: se han incluido 161 pacientes. No se observa correlación entre el TTOC y los síntomas en casa (r = -0,1). Cuando el TTOC fue más rápido de 60 minutos, la intensidad de los “síntomas test” fue parecida a la de los “síntomas en casa”. Sin embargo, en los pacientes con TTOC normal o lento, los “síntomas en casa” fueron más intensos que los “síntomas test” (p < 0,05). En casa los síntomas fueron independientes del TTOC mientras que después de la sobrecarga de lactosa los síntomas fueron más intensos cuanto más rápido el TTOC. Conclusiones: los síntomas que refieren las personas con malabsorción de lactosa son más pronunciados en casa que tras una sobrecarga de lactosa. Los síntomas de intolerancia que los pacientes atribuyen al consumo de lactosa en casa no son debidos a un TTOC rápido(AU)

Background: symptoms attributed to the lactose intolerance are an important public health issue because of their prevalence and social relevance. Also because they may cause undue rejection of dairy products consume with potential health consequences. Transit time is a putative factor implied in the severity of symptoms associated with lactose. Objectives: to elucidate the relation between orocecal transit time (OCTT) and lactose intolerance symptoms. Methods: observational study in patients referred to a lactose hydrogen breath test who showed an increase in breath H2 excretion higher than 25 ppm. OCTT was measured with the breath test and symptoms of lactose tolerance with a validated scale. Symptoms were measured twice: before receiving the lactose, inquiring about self perceived symptoms when patients consumed dairy products at home (“home symptoms”), and again after completing the lactose breath test (“test symptoms”). Results: 161 patients were included. There was no correlation between OCTT and home symptoms (r = -0.1). When OCTT was faster than 60 minutes, intensity of “test symptoms” was similar to “home symptoms”. However, in patients with normal or slow OCTT, the “home symptoms” were more intense than the “test symptoms” (p < 0.05). At home, symptoms were independent of OCTT but with the lactose test load the symptoms were proportionately more intense with faster OCTT. Conclusions: in lactose maldigesters, selfreported symptoms of lactose intolerance are more pronounced at home than after a high lactose challenge. Intolerance symptoms that patients attributed to lactose consume at home are due to factors other than fast OCTT(AU)

Development of meloxicam salts with improved dissolution and pharmacokinetic behaviors in rats with impaired gastric motility.

PURPOSE: Because of its poor solubility in acidic solution, oral absorption and efficacy of meloxicam (MEL) may be reduced in severe pain patients with impaired gastric motility. The present study aimed to develop salt forms to overcome these drawbacks. METHOD: Upon MEL salt screening with eight counterions, five MEL salts were obtained. The physicochemical properties of these MEL salts were characterized with a focus on morphology, crystallinity, thermal behavior, dissolution, and chemical/photo-stability. Pharmacokinetic profiling of an orally administered MEL salt was also carried out in both normal rats and rats treated with propantheline for the suppression of gastric motility. RESULTS: Dissolution behaviors for all obtained MEL salts were markedly better than that of crystalline MEL; in particular, the initial dissolution rate of arginine MEL dihydrate (MEL/Arg) was ca. 14-fold higher than that of crystalline MEL. MEL/Arg was found to be chemically and physically stable. There was ca. 18-fold reduction of AUC(0-4) for orally dosed crystalline MEL (1.0 mg-MEL/kg) in propantheline-treated rats compared with that in normal rats. In contrast, there was only a ca. 3-fold difference in AUC(0-4) between normal and propantheline-treated rats after oral administration of MEL/Arg (1.0 mg-MEL/kg). CONCLUSION: From these findings, MEL/Arg may provide improved oral absorption in severe pain patients.

IR, Raman and SERS spectra of propantheline bromide.

The two known propantheline bromide polymorphs (form I and form II) were studied and characterized by a multianalytical approach. In the present work, the identification of propantheline bromide polymorphic forms through vibrational IR spectroscopies are presented and for the first time Raman microscopy and hot stage Raman microscopy (HSRM) studies are reported. Finally, quantum mechanical calculations were performed. For assisting the assignment of the experimental picks, the two IR spectra of the most and least stable representatives of a set of 56 conformers are calculated and studied. DSC thermograms data, are also reported. The surface enhanced Raman scattering (SERS) spectrum was also recorded in a silver colloid; it could be inferred that propantheline bromide is adsorbed on silver colloid through the oxygen atom with the molecular plane perpendicular to the metal surface.

The influence of spasmolytic agents on heart rate variability and gastrointestinal motility in normal horses.

The effects of hyoscine-N-butylbromide (hyoscine) and propantheline-bromide (propantheline) on heart rate (HR), HR variability (HRV) and gastrointestinal tract (GIT) contractions in the normal horse were determined. Five adult horses had ECG recordings for 180 min after treatment with propantheline (100mg), hyoscine (120 mg) or saline. Both propantheline and hyoscine reduced GIT sounds, with propantheline having a longer duration of effect (≥120 min). Both drugs elevated HR relative to the control baseline period (P<0.05), with the effects of propantheline again being of longer duration. HRV analysis indicated that propantheline suppressed Total Power (P<0.05), and both the high frequency (HF) and low frequency (LF) components of the power spectral analysis for up to 60-90 min post treatment. Hyoscine had no effect on HRV Total Power but reduced the HF component for 30 min after drug injection. Time domain variables correlated with Total Power and HF data (P<0.01). The marked effect of these compounds on parasympathetic control of cardiac and GIT function in normal horses should be taken into consideration when evaluating a clinical response to these agents.

Pharmacokinetics of meloxicam administered as regular and fast dissolving formulations to the rat: influence of gastrointestinal dysfunction on the relative bioavailability of two formulations.

It is believed that acute pain suppresses nervus vagus, thereby, influencing gastrointestinal secretion and motility, which are the two factors that are necessary for disintegration and dissolution of solid dosage forms. We studied the pharmacokinetics of meloxicam and the effect of vagal suppression on the oral bioavailability and bioequivalence using a marketed (Brand) and a fast dissolving (FD) formulation. In simulated gastric juice, FD was disintegrated in 30s and released 30% of its meloxicam in 15 min and 60% in 2h. Brand was disintegrated in 4.5 min with a dissolution rate of 5.6% in 30 min that stayed plateau for the 2h experiment time. To suppress the vagus nerve, intraperitoneal injection of 20mg/kg propantheline 1 and 2h before meloxicam administration was used. Meloxicam (0.9 mg/kg) was administered to both control and vagally suppressed rats i.v. (n=4-6/group) as well as orally in a paired random fashion as broken pieces of Brand or FD tablets (n=7/ group). Serial (0-48h) blood samples were collected for pharmacokinetic and bioavailability studies. Relative bioavailability was measured according to a method in use for bioequivalence assessments. Systemic pharmacokinetics of meloxicam was not affected by vagal suppression. Absolute bioavailability of meloxicam, based on 0-48h measurement, was >0.68 regardless of the type of formulation and treatment. Vagal suppression, however, significantly reduced AUC(0-24) (microg h mL(-1)) for Brand (control, 58.8+/-22.0 vs treated, 22.1+/-9.7) but not for FD (control, 63.5+/-17.9 vs treated, 64.6+/-8.9) indicating a reduced absorption rate for the former. The peak time for Brand was also significantly delayed by over 20h for Brand and not for FD. Relative bioavailability was confirmed between FD and Brand that were in control but not in the vagally suppressed rats, indicating a disease-dependent bioequivalence. The effect of vagal suppression on the drug absorption rate can be obviated if the disintegration and dissolution become independent of gastrointestinal motility and secretion.

Using the zebrafish lateral line to screen for ototoxicity.

The zebrafish is a valuable model for studying hair cell development, structure, genetics, and behavior. Zebrafish and other aquatic vertebrates have hair cells on their body surface organized into a sensory system called the lateral line. These hair cells are highly accessible and easily visualized using fluorescent dyes. Morphological and functional similarities to mammalian hair cells of the inner ear make the zebrafish a powerful preparation for studying hair cell toxicity. The ototoxic potential of drugs has historically been uncovered by anecdotal reports that have led to more formal investigation. Currently, no standard screen for ototoxicity exists in drug development. Thus, for the vast majority of Food and Drug Association (FDA)-approved drugs, the ototoxic potential remains unknown. In this study, we used 5-day-old zebrafish larvae to screen a library of 1,040 FDA-approved drugs and bioactives (NINDS Custom Collection II) for ototoxic effects in hair cells of the lateral line. Hair cell nuclei were selectively labeled using a fluorescent vital dye. For the initial screen, fish were exposed to drugs from the library at a 100-muM concentration for 1 h in 96-well tissue culture plates. Hair cell viability was assessed in vivo using fluorescence microscopy. One thousand forty drugs were rapidly screened for ototoxic effects. Seven known ototoxic drugs included in the library, including neomycin and cisplatin, were positively identified using these methods, as proof of concept. Fourteen compounds without previously known ototoxicity were discovered to be selectively toxic to hair cells. Dose-response curves for all 21 ototoxic compounds were determined by quantifying hair cell survival as a function of drug concentration. Dose-response relationships in the mammalian inner ear for two of the compounds without known ototoxicity, pentamidine isethionate and propantheline bromide, were then examined using in vitro preparations of the adult mouse utricle. Significant dose-dependent hair cell loss in the mouse utricle was demonstrated for both compounds. This study represents an important step in validating the use of the zebrafish lateral line as a screening tool for the identification of potentially ototoxic drugs.

Cycloheximide and disulfoton are positive in the photoclastogencity assay but do not absorb UV irradiation: another example of pseudophotoclastogenicity?

There is considerable concern regarding the biological plausibility of the response of certain chemicals in the in vitro photoclastogenicity assay, suggesting that this assay is oversensitive and lacks specificity. To explore this further, four coded compounds (aminotriazole, propantheline bromide, cycloheximide and disulfoton) were evaluated for their potential response in a photoclastogenicity assay in cultured Chinese hamster ovary (CHO) cells. None of the four compounds were shown to absorb ultraviolet radiation (UVR) or visible light in the 290- to 700-nm region of the electromagnetic spectrum. A fifth coded compound, tetracycline, which absorbs UVR, was also tested as this has previously been shown to be phototoxic in vitro (3T3-NRU assay) and is cytotoxic, but not genotoxic, at high concentrations in standard 'dark' genotoxicity assays in mammalian cells. The results showed that cycloheximide, disulfoton and tetracycline were clastogenic in CHO cells following UVR exposure (solar-simulated light at 700 mJ/cm(2)) but not in the absence of UVR. Aminotriazole and propantheline were negative in the presence and absence of UVR exposure. Follow-up testing showed that neither cycloheximide nor disulfoton was positive in the 3T3-NRU assay, the standard in vitro regulatory test for phototoxicity, a result consistent with their inability to absorb UVR. These data suggest that both cycloheximide and disulfoton are pseudophotoclastogens, like zinc oxide. Together, these data question the specificity of the in vitro photoclastogencity assay in CHO cells and raises further concern regarding its use for the assessment of chemical photosafety for regulatory purposes. At the very least, a review of the current guidance documents for the photosafety evaluation of pharmaceuticals and cosmetics should be undertaken urgently.

The effectiveness of intravesical oxybutynin, propantheline, and capsaicin in the management of neuropathic bladder following spinal cord injury.

The objective of this study was to compare the therapeutic response of intravesical oxybutynin, propantheline, and capsaicin in the treatment of neurogenic detrusor overactivity. Carried out in the Department of Physical Medicine and Rehabilitation at a university teaching hospital in India, patients acted as their own controls. Oxybutynin 5 mg in solution or propantheline 15 mg in solution and capsaicin were instilled intravesically in each patient. Urodynamic studies were done before and after the intravesical instillation of each drug. The nonparametric tests were used for statistical analysis. The efficacy of intravesical capsaicin in the treatment of neurogenic detrusor overactivity was statistically significant for reflex volume (RV) (p = 0.018), cystometric capacity (CC) (p = 0.0440), leak volume (LV) (p = 0.000), and leak frequency (LF) (p = 0.009). The Kruskal-Wallis test for paired sample comparing pre- and post-LV and LF for intravesical capsaicin was significant at 2nd week (p = 0.002 and 0.054, respectively). There was a significant difference in therapeutic response between intravesical oxybutynin, propantheline, and capsaicin in the treatment of detrusor overactivity for LV and LF at 2nd week (p = 0.017 and 0.003, respectively). When comparing responses of oxybutynin and propantheline, more subjects demonstrated improvement with intravesical propantheline than oxybutynin for RV, detrusor leak point pressure (LPP), clean intermittent catheterization volume (CICV), and LV. This study suggests that intravesical agents may be used as effective adjuvants in the management of incontinence due to neurogenic detrusor overactivity following spinal cord injury.